Isoliquiritigenin pretreatment regulates ER stress and attenuates cisplatin-induced nephrotoxicity in male Wistar rats.

Cisplatin (CP) is a chemotherapeutic drug used to treat solid tumors. However, studies have revealed its nephrotoxic effect. Oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction are involved in CP-induced renal damage. Thus, preconditioning (hormetic effect) of ER stress is a strategy to prevent CP-induced renal damage. On the other hand, isoliquiritigenin (IsoLQ) is recognized as a flavonoid with antioxidant properties and an inducer of ER stress. Therefore, we evaluated the ER stress-inducing capacity of IsoLQ and its possible protective effect against CP-induced nephrotoxicity in adult male Wistar rats. The findings reflected that IsoLQ pretreatment might decrease renal damage by reducing plasma creatinine and blood urea nitrogen levels in animals with CP-induced nephrotoxicity. These may be associated with IsoLQ activating ER stress and unfolded protein response (UPR). We found increased messenger RNA levels of the ER stress marker glucose-related protein 78 kDa (GRP78). In addition, we also found that pretreatment with IsoLQ reduced the levels of CCAAT/enhancer-binding protein-homologous protein (CHOP) and X-box-binding protein 1 (XBP1) in the renal cortex, reflecting that IsoLQ can regulate the UPR and activation of the apoptotic pathway. Moreover, this preconditioning with IsoLQ of ER stress had oxidative stress-regulatory effects, as it restored the activity of glutathione peroxidase and glutathione reductase enzymes. Finally, IsoLQ modifies the protein expression of mitofusin 2 (Mfn-2) and voltage-dependent anion channel (VDAC). In conclusion, these data suggest that IsoLQ pretreatment has a nephroprotective effect; it could functionally regulate the ER and mitochondria and reduce CP-induced renal damage by attenuating hormesis-mediated ER stress.

Principal component analysis on LC­MS/MS and 2DE­MALDI­TOF in glioblastoma cell lines reveals that mitochondria act as organelle sensors of the metabolic state in glioblastoma.

Glioblastoma is a difficult disease to diagnose. Proteomic techniques are commonly applied in biomedical research, and can be useful for early detection, making an accurate diagnosis and reducing mortality. The relevance of mitochondria in brain development and function is well known; therefore, mitochondria may influence the development of glioblastoma. The T98G (with oxidative metabolism) and U87MG (with glycolytic metabolism) cell lines are considered to be useful glioblastoma models for studying these tumors and the role of mitochondria in key aspects of this disease, such as prognosis, metastasis and apoptosis. In the present study, principal component analysis of protein abundance data identified by liquid chromatography coupled to tandem mass spectrometry (LC­MS/MS) and matrix­assisted laser desorption/ionization­time of flight mass spectrometry (MALDI­TOF) from 2D gels indicated that representative mitochondrial proteins were associated with glioblastoma. The selected proteins were organized into T98G­ and U87MG­specific protein­protein interaction networks to demonstrate the representativeness of both proteomic techniques. Gene Ontology overrepresentation analysis based on the relevant proteins revealed that mitochondrial processes were associated with metabolic changes, invasion and metastasis in glioblastoma, along with other non­mitochondrial processes, such as DNA translation, chaperone responses and autophagy. Despite the lower resolution of 2D electrophoresis, principal component analysis yielded information of comparable quality to that of LC­MS/MS. The present analysis pipeline described a specific and more complete metabolic status for each cell line, defined a clear mitochondrial performance for distinct glioblastoma tumors, and introduced a useful strategy to understand the heterogeneity of glioblastoma.