Treatment of chemotherapy-induced cachexia with BST204: a multimodal validation study.

INTRODUCTION: Chemotherapy is a major etiology of cachexia. Ginseng products are known to have various anti-cachectic and health-promoting effects, such as inhibiting inflammation and promoting energy production. In particular, BST204, purified ginseng dry extract, contains multiple ginsenosides that can reduce chemotherapy-related fatigue and toxicity. OBJECTIVES: To investigate the effects of BST204 on the alleviation of chemotherapy-induced cachexia using a multimodal approach. METHODS: In a CT26 mouse syngeneic colon cancer model, cachexia was predominantly induced by chemotherapy with 5-fluorouracil (5-FU) than by tumor growth. BST204 at a dose of 100 or 200 mg/kg was administered to 5-FU-treated mice. RESULTS: BST204 significantly mitigated the decrease in tumor-excluded body weight (change in 5-FU group and BST204 groups: - 13% vs. - 6% on day 7; - 30% vs. - 20% on day 11), muscle volume (- 19% vs. - 11%), and fat volume (- 91% vs. - 56%). The anti-cachectic effect of BST204 was histologically demonstrated by an improved balance between muscle regeneration and degeneration and a decrease in muscle cross-sectional area reduction. CONCLUSION: Chemotherapy-induced cachexia was biochemically and metabolically characterized by activated inflammation, enhanced oxidative stress, increased protein degradation, decreased protein stabilization, reduced glucose-mediated energy production, and deactivated glucose-mediated biosynthesis. These adverse effects were significantly improved by BST204 treatment. Overall, our multimodal study demonstrated that BST204 could effectively alleviate chemotherapy-induced cachexia.

Gadoxetate-enhanced dynamic contrast-enhanced MRI for evaluation of liver function and liver fibrosis in preclinical trials.

BACKGROUND: To facilitate translational drug development for liver fibrosis, preclinical trials need to be run in parallel with clinical research. Liver function estimation by gadoxetate-enhanced dynamic contrast-enhanced MRI (DCE-MRI) is being established in clinical research, but still rarely used in preclinical trials. We aimed to evaluate feasibility of DCE-MRI indices as translatable biomarkers in a liver fibrosis animal model. METHODS: Liver fibrosis was induced in Sprague-Dawley rats by thioacetamide (200 mg, 150 mg, and saline for the high-dose, low-dose, and control groups, respectively). Subsequently, DCE-MRI was performed to measure: relative liver enhancement at 3-min (RLE-3), RLE-15, initial area-under-the-curve until 3-min (iAUC-3), iAUC-15, and maximum-enhancement (Emax). The correlation coefficients between these MRI indices and the histologic collagen area, indocyanine green retention at 15-min (ICG-R15), and shear wave elastography (SWE) were calculated. Diagnostic performance to diagnose liver fibrosis was also evaluated by receiver-operating-characteristic (ROC) analysis. RESULTS: Animal model was successful in that the collagen area of the liver was the largest in the high-dose group, followed by the low-dose group and control group. The correlation between the DCE-MRI indices and collagen area was high for iAUC-15, Emax, iAUC-3, and RLE-3 but moderate for RLE-15 (r, - 0.81, - 0.81, - 0.78, - 0.80, and - 0.51, respectively). The DCE-MRI indices showed moderate correlation with ICG-R15: the highest for iAUC-15, followed by iAUC-3, RLE-3, Emax, and RLE-15 (r, - 0.65, - 0.63, - 0.62, - 0.58, and - 0.56, respectively). The correlation coefficients between DCE-MRI indices and SWE ranged from - 0.59 to - 0.28. The diagnostic accuracy of RLE-3, iAUC-3, iAUC-15, and Emax was 100% (AUROC 1.000), whereas those of RLE-15 and SWE were relatively low (AUROC 0.777, 0.848, respectively). CONCLUSION: Among the gadoxetate-enhanced DCE-MRI indices, iAUC-15 and iAUC-3 might be bidirectional translatable biomarkers between preclinical and clinical research for evaluating histopathologic liver fibrosis and physiologic liver functions in a non-invasive manner.

Changes to gamma-aminobutyric acid levels during short-term epileptiform activity in a kainic acid-induced rat model of status epilepticus: A chemical exchange saturation transfer imaging study.

PURPOSE: To evaluate temporal changes in gamma-aminobutyric acid (GABA) signals in the hippocampus during epileptiform activity induced by kainic acid (KA) in a rat model of status epilepticus using chemical exchange saturation transfer (CEST) imaging technique. METHODS: CEST imaging and 1H magnetic resonance spectroscopy (1H MRS) were applied to a systemic KA-induced rat model to compare GABA signals. All data acquisition and analytical procedures were performed at three different time points (before KA injection, and 1 and 3 h after injection). The CEST signal was analyzed based on regions of interests (ROIs) in the hippocampus, while 1H MRS was analyzed within a 12.0 µL ROI in the left hippocampus. Signal correlations between the two methods were evaluated as a function of time change up to 3 h after KA injection. RESULTS: The measured GABA CEST-weighted signal intensities of the rat epileptic hippocampus before injection showed significant differences from those after (averaged signals from both hippocampi: 4.37% ±â€¯0.87% and 7.305 ±â€¯1.11%; P < 0.05), although the signal had increased slightly at both time points after KA injection, the differences were not significant (P > 0.05). In contrast, the correlation between the CEST imaging values and 1H MRS was significant (r ≥ 0.64; P < 0.05; in all cases). CONCLUSIONS: GABA signal changes during epileptiform activity in the rat hippocampus, as detected using CEST imaging, provided a significant contrast according to changes in metabolic activity. Our technical approach may serve as a potential supplemental option to provide biomarkers for brain disease.