Repurposing synthetic and natural derivatives induces apoptosis in an orthotopic glioma-induced xenograft model by modulating WNT/ß-catenin signaling.

BACKGROUND: Glioblastomas arise from multistep tumorigenesis of the glial cells. Despite the current state-of-art treatment, tumor recurrence is inevitable. Among the innovations blooming up against glioblastoma, drug repurposing could provide profound premises for treatment enhancement. While considering this strategy, the efficacy of the repurposed drugs as monotherapies were not up to par; hence, the focus has now shifted to investigate the multidrug combinations. AIM: To investigate the efficacy of a quadruple-combinatorial treatment comprising temozolomide along with chloroquine, naringenin, and phloroglucinol in an orthotopic glioma-induced xenograft model. METHODS: Antiproliferative effect of the drugs was assessed by immunostaining. The expression profiles of WNT/ß-catenin and apoptotic markers were evaluated by qRT-PCR, immunoblotting, and ELISA. Patterns of mitochondrial depolarization was determined by flow cytometry. TUNEL assay was performed to affirm apoptosis induction. In vivo drug detection study was carried out by ESI-Q-TOF MS analysis. RESULTS: The quadruple-drug treatment had significantly hampered glioma proliferation and had induced apoptosis by modulating the WNT/ß-catenin signaling. Interestingly, the induction of apoptosis was associated with mitochondrial depolarization. The quadruple-drug cocktail had breached the blood-brain barrier and was detected in the brain tissue and plasma samples. CONCLUSION: The quadruple-drug combination served as a promising adjuvant therapy to combat glioblastoma lethality in vivo and can be probed for translation from bench to bedside.

Troxerutin reverses fibrotic changes in the myocardium of high-fat high-fructose diet-fed mice.

A previous study from our laboratory showed that troxerutin (TX) provides cardioprotection by mitigating lipid abnormalities in a high-fat high-fructose diet (HFFD)-fed mice model of metabolic syndrome (MS). The present study aims to investigate the reversal effect of TX on the fibrogenic changes in the myocardium of HFFD-fed mice. Adult male Mus musculus mice were grouped into four and fed either control diet or HFFD for 60 days. Each group was divided into two, and the mice were either treated or untreated with TX (150 mg/kg bw, p.o) from the 16th day. HFFD-fed mice showed marked changes in the electrocardiographic data. Increased levels of myocardial superoxide, p22phox subunit of NADPH oxidase, transforming growth factor (TGF), smooth muscle actin (α-SMA), and matrix metalloproteinases (MMPs)-9 and -2, and decreased levels of tissue inhibitors of MMPs-1 and -2 were observed. Furthermore, degradation products of troponin I and myosin light chain-1 were observed in the myocardium by immunoblotting. Rise in collagen was observed by hydroxyproline assay, while fibrotic changes were noticed by histology and Western blotting. Hypertrophy of cardiomyocytes and myocardial calcium accumulation were also observed in HFFD-fed mice. TX treatment exerted cardioprotective and anti-fibrotic effects in HFFD-fed mice by improving cardiac contractile function, reducing superoxide production and by favorably modifying the fibrosis markers. These findings suggest that TX could be cardioprotective through its antioxidant and antifibrogenic actions. This new finding could pave way for translation studies to human MS.