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•HFD consumption alteres the expression of genes involved in lipid metabolism.•PGG reduces HFD-mediated body weight gain and hepatic steatosis.•PGG reverses HDF-induced alterations in ...hepatic lipid metabolic gene expression.•PGG, a well tolerated natural product, holds the potential for NAFLD treatment.
Non-alcoholic fatty liver disease (NAFLD) is currently the most frequently occurring liver disorder in the world. However, a specific drug for the treatment of patients with NAFLD is not available. Therefore, the discovery of novel compounds for the treatment of NAFLD and elucidation of the underlying mechanisms of therapeutic drugs that can be used to treat this disease are urgently needed. 1,2,3,4,6 penta-O-galloyl-β-d-glucose (PGG) is known to exert anti-inflammatory, antidiabetic, and hepatoprotective effects. However, little is known about the therapeutic potential of PGG in NAFLD. In this study, we investigated the effects of PGG on a high-fat diet (HFD)-induced mouse model of NAFLD. PGG was co-administered along with an HFD to C57BL/6 mice. After eight weeks of treatment, serum biochemistry, liver steatosis, and lipid metabolism-related genes were examined. The results showed that PGG treatment significantly reduced HFD-induced gain in body weight, liver steatosis, and leukocyte infiltration in a dose-dependent manner. Furthermore, PGG treatment markedly reduced serum triglyceride and glucose levels in HFD mice. Moreover, alterations in the mRNA expression of genes involved in lipid metabolism, including Hmgcr, Acc1, Abca1, Mttp, and Cd36, observed in the livers of HFD-treated mice were significantly reversed by PGG treatment. PGG significantly reduced HFD-induced protein expression of CD36, which is associated with fatty acid uptake, insulin resistance, hyperinsulinemia, and increased hepatic steatosis, in the liver of HFD mice. These results suggest that PGG inhibits HFD-induced hepatic steatosis and reverses HFD-induced alterations of gene expression in lipid metabolism. PGG has been shown to be well tolerated; therefore, it has potential uses in NAFLD treatment.
Objectives
Early mortality, defined as death within 120 days after initiated antitumor therapy, is an important issue especially for elder patients with B‐cell lymphoma. This study aimed to evaluate ...the clinical value of comprehensive geriatric assessment (CGA) in early mortality prediction in elderly patients with B‐cell lymphoma receiving immunochemotherapy.
Methods
Seventy‐six consecutive patients with newly diagnosed B‐cell lymphoma receiving immunochemotherapy from a medical center in Taiwan were prospectively enrolled. Patients were divided into fit (n = 49) and frail (n = 27) groups per pretreatment CGA for early mortality comparison.
Results
The early mortality rate in our patient cohort was 16% (n = 12): from 6% in patients with no CGA domain impairment to 43% in patients with ≥4 CGA domain impairment. The early mortality rate was 6% and 33% in fit and frail patients (odds ratio, 7.67; 95% CI, 1.86‐31.6; P = .005), respectively. Frailty was the significant predictor for early mortality in univariate and multivariate analysis.
Conclusion
In this study, the number of geriatric domain impairment is positively associated with the early mortality risk in elderly patients with B‐cell lymphoma. Therefore, CGA can help clinicians to identify the risk of early mortality in elderly patients and provide alternative treatment.
Airborne particulate matter (PM) is one of the indicators of air pollution, and it is also the main factor causing oxidative stress in the skin. Oleanolic acid (OA), a natural terpenoid compound, ...effectively inhibited PM-induced skin aging; however, OA has poor water solubility and skin absorption, which limit its application in medicines and cosmetics. The aim of this study was to prepare oleanolic acid nanofibers (OAnf) and evaluate the effects of OA and OAnf in PM-treated keratinocytes. The results showed that OA dissolved in dissolved in dimethyl sulfoxide (DMSO) attenuated PM-induced reactive oxygen species overproduction, stress-activated protein kinase/Jun-amino-terminal kinase (SAPK/JNK) activation, and the expressions of inflammatory and skin-aging-related proteins. In addition, the nanofiber process of OA effectively improved the water solubility of OA more than 99,000-fold through changing its physicochemical properties, including a surface area increase, particle size reduction, amorphous transformation, and hydrogen bonding formation with excipients. The skin penetration ability of OAnf was consistently over 10-fold higher than that of OA. Moreover, when dissolved in PBS, OAnf displayed superior antioxidant, anti-inflammatory, and anti-skin aging activities in PM-treated keratinocytes than OA. In conclusion, our findings suggest that OAnf could be a topical antioxidant formulation to attenuate skin problems caused by PM.
Background
Whether the prevalence of frailty and its clinical significance are relevant to treatment outcomes in younger (aged < 65 years) cancer patients remains uncertain. This study aimed to ...evaluate the impact of frailty on treatment outcomes in younger cancer patients with head and neck and esophageal malignancy.
Material and methods
This multicenter prospective study recruited 502 patients with locally advanced head and neck and esophageal cancer during 2016–2017 in Taiwan, aged 20–64 years who received curative-intent concurrent chemoradiotherapy (CCRT) as first-line antitumor treatment. Baseline frailty assessment using geriatric assessment (GA) was performed for each patient within 7 days before CCRT initiation.
Results
Frailty was observed in 169 (33.7%) of 502 middle-aged patients. Frail patients had significantly higher incidences of chemotherapy incompletion (16.6% versus 3.3%, P < .001) and radiotherapy incompletion (16.6% versus 3.6%, P < .001) than fit patients. During CCRT, frail patients had a significantly higher percentage of hospitalizations (42.0% versus 24.6%, P < .001) and a trend toward a higher percentage of emergency room visits (37.9% versus 30.0%, P = .08) than fit patients. Frail patients more likely had a significantly higher incidence of grade ≥ 3 adverse events than fit patients during CCRT. The 1-year survival rate was 68.7% and 85.2% (hazard ratio 2.56, 95% confidence interval 1.80–3.63, P < .001) for frail and fit patients, respectively.
Conclusions
This study demonstrated the significance of pretreatment frailty on treatment tolerance, treatment-related toxicity, and survival outcome in younger patients with head and neck and esophageal cancer undergoing CCRT. While GA is commonly targeted toward the older population, frailty assessment by GA may also be utilized in younger patients for decision-making guidance and prognosis prediction.
Non-alcoholic fatty liver disease (NAFLD) is a type of steatosis caused by excess lipids accumulating in the liver. The prevalence of NAFLD has increased annually due to modern lifestyles and a lack ...of adequate medical treatment. Thus, we were motivated to investigate the bioactive components of Formosan plants that could attenuate lipid droplet (LD) accumulation. In a series of screenings of 3000 methanolic extracts from the Formosan plant extract bank for anti-LD accumulation activity, the methanolic extract of aerial parts of Elaeagnus glabra Thunb. showed excellent anti-LD accumulation activity. E. glabra is an evergreen shrub on which only a few phytochemical and biological studies have been conducted. Here, one new flavonoid (1), two new triterpenoids (2 and 3), and 35 known compounds (4–38) were isolated from the ethyl acetate layer of aerial parts of E. glabra via a bioassay-guided fractionation process. Their structures were characterized by 1D and 2D NMR, UV, IR, and MS data. Among the isolated compounds, methyl pheophorbide a (37) efficiently reduced the normalized LD content to 0.3% with a concentration of 20 μM in AML12 cell lines without significant cytotoxic effects. 3-O-(E)-Caffeoyloleanolic acid (13) and methyl pheophorbide a (37) showed inhibitory effects on superoxide anion generation or elastase release in fMLP/CB-treated human neutrophils (IC50 < 3.0 μM); they displayed effects similar to those of the positive control, namely, LY294002. These findings indicate that E. glabra can be used for developing a new botanical drug for managing LD accumulation and against inflammation-related diseases.
Frailty is common in older patients with cancer; however, its clinical impact on the survival outcomes has seldom been examined in these patients. This study aimed to investigate the association of ...frailty with the survival outcomes and surgical complications in older patients with cancer after elective abdominal surgery in Taiwan.
We prospectively enrolled 345 consecutive patients aged ≥65 years with newly diagnosed cancer who underwent elective abdominal surgery between 2016 and 2018. They were allocated into the fit, pre-frail, and frail groups according to comprehensive geriatric assessment (CGA) findings.
The fit, pre-frail, and frail groups comprised 62 (18.0%), 181 (52.5%), and 102 (29.5%) patients, respectively. After a median follow-up of 48 (interquartile range, 40–53) months, the mortality rates were 12.9%, 31.5%, and 43.1%, respectively. The adjusted hazard ratio was 1.57 (95% confidence interval CI, 0.73–3.39; p = 0.25) and 2.87 (95% CI, 1.10–5.35; p = 0.028) when the pre-frail and frail groups were compared with the fit group, respectively. The frail group had a significantly increased risk for a prolonged hospital stay (adjusted odds ratio, 2.22; 95% CI, 1.05–4.69; p = 0.022) compared with the fit group.
Pretreatment frailty was significantly associated with worse survival outcomes and more surgical complications, with prolonged hospital stay, in the older patients with cancer after elective abdominal surgery. Preoperative frailty assessment can assist physicians in identifying patients at a high risk for surgical complications and predicting the survival outcomes of older patients with cancer.
Characterized with a high recurrence rate and low detection rate, prevention is the best approach to reduce mortality in hepatocellular carcinoma (HCC). The overexpression of ...Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is observed in various tumors, including HCC; and the frequent PREX2 mutations in melanoma are associated with invasiveness. We sought to identify somatic mutations and the functional changes in mutational signatures of PREX2. Genomic DNA sequencing was performed in 68 HCC samples with three types of hepatitis viral infection status: HBs Ag-positive, anti-HCV Ab-positive, and negative for any hepatitis B or C markers. Stabilities and interactions of proteins as well as cell proliferation and migration were evaluated. Fourteen non-silent point mutations in PREX2 were detected, with 16 of 68 HCC patients harboring at least one non-silent mutation. All mutant forms of PREX2, except for K400f, had an extended half-life compared with wild-type PREX2. Moreover, only the half-life of S1113R was twice that of the wild-type. PREX2 mutant-S1113R also promoted migration and activated the AKT pathway as well as impaired HectH9-mediated ubiquitination. Our study identified a gain-of-function mutation of PREX2 - S1113R in HCC. Such mutation enhanced PREX2 protein stability, promoted cell proliferation, and was associated with aggressiveness of HCC.
: Activation of NRF2, a key transcription factor of cytoprotectant against oxidative stress, and its target genes are associated with aggressive tumor progression, metastasis and poor survival. In ...addition, NRF2 signaling mediates cancer stem cell (CSC)-like properties in hepatocellular carcinoma (HCC) cells. Moreover, CSCs have been associated with HCC onset and unfavorable prognosis. Transcatheter arterial embolization (TAE) and/or transcatheter arterial chemoembolization (TACE), which attempt to restrict blood supply to diminish tumor growth, can create a hypoxic environment. However, its effect on NRF2 signaling and CSC marker CD133 in the context of prognosis of HCCs have not been investigated. Therefore, we studied the possible role of the expressions of NRF2, its target genes and CSC markers CD133 and EpCAM on the survival of HCC patients after TAE/TACE.
: RT-qPCR was performed with 120 tumor (T) and adjacent tumor (N) tissue pairs. Expression of a single marker or combination was assessed for associations with survival of HCC patients after TAE/TACE.
: The result of multivariate Cox regression showed that vascular invasion (HR, 1.821;
= 0.015), metastasis (HR, 2.033;
= 0.049) and CD133 overexpression (HR, 2.013;
= 0.006) were associated with poor survival. In a Kaplan-Meier survival analysis, patients with high expression of CD133 had shorter overall survival (OS) than those with low expression of CD133 in post-TAE/TACE HCC (
< 0.001). In contrast, neither NRF2 nor components of its signaling pathway correlated with survival. Combination marker analysis showed that co-expression of NQO1 and CD133 was associated with poor outcome.
: This study suggests that analyzing the expression status of CD133 alone and co-expression of NQO1 and CD133 may have additional value in predicting the outcome of TAE/TACE-treated HCC patients.
Background: Diffuse large B-cell lymphoma (DLBCL) is a malignant lymphoid tumor disease that is characterized by heterogeneity, but current treatment does not benefit all patients, which highlights ...the need to identify oncogenic genes and appropriate drugs. G9a is a histone methyltransferase that catalyzes histone H3 lysine 9 (H3K9) methylation to regulate gene function and expression in various cancers. Methods: TCGA and GTEx data were analyzed using the GEPIA2 platform. Cell viability under drug treatment was assessed using Alamar Blue reagent; the interaction between G9a and niclosamide was assessed using molecular docking analysis; mRNA and protein expression were quantified in DLBCL cell lines. Finally, G9a expression was quantified in 39 DLBCL patient samples. Results: The TCGA database analysis revealed higher G9a mRNA expression in DLBCL compared to normal tissues. Niclosamide inhibited DLBCL cell line proliferation in a time- and dose-dependent manner, reducing G9a expression and increasing p62, BECN1, and LC3 gene expression by autophagy pathway regulation. There was a correlation between G9a expression in DLBCL samples and clinical data, showing that advanced cancer stages exhibited a higher proportion of G9a-expressing cells. Conclusion: G9a overexpression is associated with tumor progression in DLBCL. Niclosamide effectively inhibits DLBCL growth by reducing G9a expression via the cellular autophagy pathway; therefore, G9a is a potential molecular target for the development of therapeutic strategies for DLBCL.
Glycine N-methyltransferase (GNMT) expression is vastly downregulated in hepatocellular carcinomas (HCC). High rates of GNMT knockout mice developed HCC, while overexpression of GNMT prevented ...aflatoxin-induced carcinogenicity and inhibited liver cancer cell proliferation. Therefore, in this study, we aimed for the identification of a GNMT inducer for HCC therapy. We established a GNMT promoter-driven luciferase reporter assay as a drug screening platform. Screening of 324 pure compounds and 480 crude extracts from Chinese medicinal herbs resulted in the identification of Paeonia lactiflora Pall (PL) extract and the active component 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) as a GNMT inducer. Purified PL extract and PGG induced GNMT mRNA and protein expression in Huh7 human hepatoma cells and in xenograft tumors. PGG and PL extract had potent anti-HCC effects both in vitro and in vivo. Furthermore, PGG treatment induced apoptosis in Huh7 cells. Moreover, PGG treatment sensitized Huh7 cells to sorafenib treatment. Therefore, these results indicated that identifying a GNMT enhancer using the GNMT promoter-based assay might be a useful approach to find drugs for HCC. These data also suggested that PGG has therapeutic potential for the treatment of HCC.
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