Icaritin inhibits the invasion and epithelial-to-mesenchymal transition of glioblastoma cells by targeting EMMPRIN via PTEN/AKt/HIF-1α signalling.

Icaritin, a hydrolytic product of icariin from the Epimedium genus, exerts anti-tumour effects on a variety of tumour cell types, mainly by inhibiting cell proliferation and inducing apoptosis. However, little is known about the role of icaritin in cancer invasion and epithelial-to-mesenchymal transition (EMT). In the present study, the glioblastoma (GBM) cell line U87MG was used as a model to investigate the effects of icaritin on the invasion and EMT of cancer cells. The results showed that icaritin significantly inhibited the invasion and EMT of GBM cells by targeting extracellular matrix metalloproteinase (EMMPRIN). Furthermore, the findings strongly indicate that the modulatory effect of icaritin on EMMPRIN is mediated via the PTEN/Akt/HIF-1α signalling pathway. The data provide the first experimental evidence of the inhibitory effect of icaritin on cancer cell invasion and EMT, thus highlighting the potential of icaritin to be employed as a promising anti-cancer agent in the treatment of GBM.

Resibufogenin suppresses tumor growth and inhibits glycolysis in ovarian cancer by modulating PIM1.

Ovarian cancer is a common human malignancy of the female reproductive system. However, chemotherapy has been proven to have limited effectiveness in a majority of patients. Resibufogenin (RB) is a major active ingredient in cinobufacini, which has been used in the treatment of human malignancies as adjunct agents. This study was designed to examine the anti-cancer effect of RB and the underlying mechanisms in ovarian cancer. Our results showed that RB treatment resulted in cell death, cell cycle arrest, and apoptosis in ovarian cancer cells. The anti-growth and pro-apoptotic effects of RB were also validated in xenograft mice models. Proteomics analysis indicated that RB was able to alter the expressions of several genes, which were involved in the regulation of glycolysis. The suppression effect of RB in the glycolysis pathway of ovarian cancer cells was validated by decreased glucose consumption, lactate production, and extracellular acidification rate (ECAR). We proposed that PIM1 functioned as the key target that mediated the anti-cancer effect of RB against ovarian cancer cells. Our results have revealed that RB downregulated PIM1 in ovarian cancer cells and its downstream genes involved in glycolysis. Moreover, our results indicated that the anti-growth activities and suppressing effect of RB on glycolysis were enhanced significantly by PIM1 knockdown but was attenuated by ectopic PIM1 expression. This provided evidence to support the role of PIM1 in the anti-cancer activities of RB.

Euxanthone Attenuates Aß1-42-Induced Oxidative Stress and Apoptosis by Triggering Autophagy.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and is characterized by the deposition of ß-Amyloid (Aß) plaques which contribute to its pathology. The present study was aimed at exploring the protective effects of euxanthone against Aß-induced neurotoxicity both in vivo and in vitro. We found that euxanthone significantly attenuated Aß1-42-induced memory and spatial learning dysfunction and also significantly reversed Aß1-42-induced neuronal apoptosis and autophagy in the hippocampal region. Euxanthone also protected the neuroblastic PC12 cells against Aß1-42-induced oxidative stress and apoptosis by inducing autophagy. In conclusion, euxanthone exerts its neuroprotective effect against Aß1-42 by inducing autophagy, indicating its potential therapeutic role in AD.

Activation of PPARγ mediates icaritin-induced cell cycle arrest and apoptosis in glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is the most prevalent primary malignancy of the brain. This study was designed to investigate whether icaritin exerts anti-neoplastic activity against GBM in vitro. MATERIALS AND METHODS: Cell Counting Kit-8 (CCK-8) assay was utilized to examine the viability of GBM cells. The apoptotic cell population was measured by flow cytometry analysis. Cell cycle distribution was detected by flow cytometry as well. Western blot analysis was performed to examine the level of biomarker proteins in GBM cells. Levels of PPARγ mRNA and protein were detected by qPCR and western blot analysis, respectively. To examine the role of PPARγ in the anti-neoplastic activity of icaritin, PPARγ antagonist GW9662 or PPARγ siRNA was used. The activity of PPARγ was determined by DNA binding and luciferase assays. RESULTS: Our findings revealed that icaritin markedly suppresses cell growth in a dose-dependent and time-dependent fashion. The cell population at the G0/G1 phase of the cell cycle was significantly increased following icaritin treatment. Meanwhile, icaritin promoted apoptotic cell death in T98G and U87MG cells. Further investigation showed upregulation of PPARγ played a key role in the anti-neoplastic activities of icaritin. Moreover, our result demonstrated activation of AMPK signaling by icaritin mediated the modulatory effect of icaritin on PPARγ. CONCLUSION: Our results suggest the PPARγ may mediate anti-neoplastic activities against GBM.

Icaritin Sensitizes Human Glioblastoma Cells to TRAIL-Induced Apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered to be one of the most promising candidates in research on treatments for cancer, because it induces apoptosis in a wide variety of cancer cells but not in most normal human cell types. However, many cells including glioblastoma (GBM) cells are resistant to TRAIL-induced apoptosis, which limits the potential application of TRAIL in cancer therapy. Icaritin, a hydrolytic product of icariin from Epimedium Genus, has been identified as a potential therapeutic and preventive agent in renal cell carcinoma and breast cancer. In this study, we investigated whether Icaritin treatment could modulate TRAIL-induced apoptosis in GBM. The effect of icaritin on TRAIL sensitivity was assessed in human GBM U87 and U373 cells. The underlying regulatory cascades were approached by biochemical and pharmacological strategies. We found that nontoxic concentration of icaritin alone had no significant effect on the level of apoptosis, but a combination treatment of TRAIL and icaritin caused a significantly more profound apoptosis. The sensitization was accompanied by c-FLIP down-regulation and inhibition of NF-κB activity. Studies have further demonstrated that silencing NF-κB alone was sufficient to down-regulate c-FLIP expression and sensitized both tested cells to TRAIL-induced apoptosis. These data suggest that icaritin sensitizes TRAIL-induced tumor cell apoptosis via suppression of NF-κB-dependent c-FLIP expression, providing in vitro evidence supporting the notion that icaritin is a potential sensitizer of TRAIL in anticancer therapy against human GBM.

The functional TP53 rs1042522 and MDM4 rs4245739 genetic variants contribute to Non-Hodgkin lymphoma risk.

As a heterogeneous kind of malignances, Non-Hodgkin lymphoma (NHL) is the most common hematologic cancer worldwide with the significantly increased morbidity in China. Accumulated evidences demonstrated that oncoprotein MDM4 plays a crucial role in the TP53 tumor suppressor signaling pathway. An rs4245739 A>C polymorphism locating in the MDM4 3'-untranslated region creates a miR-191 target site and results in allele-specific MDM4 expression. In this study, we examined the association between this polymorphism as well as the TP53 Arg72Pro (rs1042522 G>C) genetic variant and Non-Hodgkin Lymphoma (NHL) risk in a Chinese Han population. Genotypes were determined in 200 NHL cases and 400 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. We found significantly increased NHL risk among carriers of the TP53 72Pro allele compared with those with the 72Arg allele (P = 0.002 for the Pro/Pro genotype). We also observed a significantly decreased NHL risks among carriers of the MDM4 rs4245739 C allele compared with those with the A allele in Chinese (P = 0.014 for the AC genotype). Stratified analyses revealed the associations between these SNPs and NHL risk are especially noteworthy in young or male individuals. Additionally, the associations are much pronounced in NHL patients with B-cell lymphomas or grade 3 or 4 disease. Our results indicate that the TP53 Arg72Pro and the MDM4 rs4245739 polymorphisms contribute to NHL susceptibility and support the hypothesis that genetic variants in the TP53 pathway genes can act as important modifiers of NHL risk.

Pseudo-continuous arterial spin labeling quantifies cerebral blood flow in patients with acute ischemic stroke and chronic lacunar stroke.

OBJECTIVE: We employed non-invasive pseudo-continuous arterial spin labeling (pCASL) to quantify cerebral blood flow (CBF) in infarcted and nearby neural regions in patients with acute ischemic stroke (AIS) and chronic lacunar stroke (CLS). The results were compared with CBF in healthy individuals. METHODS: AIS and CLS patients were imaged with ASL, diffusion-weighted imaging (DWI) and conventional MRI. CBF maps were created with 3DASL software. Two expert readers identified AIS and CLS lesions on conventional images, DWI images and CBF maps. A senior radiologist calculated CBF values for lesions and nearby regions. Lesion, nearby regions and normal corresponding region values were analyzed using a two-sample t-test. RESULTS: Fifty-six stroke patients (21 with AIS and 35 with CLS) and 30 healthy subjects participated in this study. In the AIS group, AIS lesions appeared in the cortex/white matter, external/internal capsule (EC/IC), and basal ganglia. AIS lesions had lower CBF values than the normal corresponding regions (p<0.05). The mean CBF values in AIS nearby regions were significantly higher than those in normal corresponding regions (p<0.05). In the CLS group, the CBF values in white matter and EC/IC were lower than the CBF values in normal corresponding regions (p=0.063 and 0.052, respectively). The CBF values in CLS nearby regions and normal corresponding regions were not significantly different (p>0.05). CONCLUSION: In some regions of the brain, CLS lesions, AIS lesions, and their nearby regions have different perfusion statuses. In particular, the AIS nearby regions perfusion in our subjects was significantly higher than that previously reported. pCASL can be a robust imaging technique for diagnosing strokes in clinical practices.

Diagnostic accuracy of fiberoptic ductoscopy plus in vivo iodine staining for intraductal proliferative lesions.

BACKGROUND: Iodine staining during endoscopy has been successfully used to detect early carcinomatous and precancerous lesions in the esophagus, cervix, and oral cavity. The objective of this study was to determine the diagnostic accuracy of fiberoptic ductoscopy (FDS) plus in vivo iodine staining for intraductal proliferative lesions of the breast. METHODS: We performed periodic acid-Schiff (PAS) and in vitro iodine staining on 52 and 64 specimens of benign mammary hyperplasia, respectively, and 57 and 53 specimens of ductal carcinoma in situ (DCIS), respectively. Next, FDS was performed on 177 recurrent nipple discharge patients who were randomly divided into two groups. One group was iodine-staining group in which 92 patients were randomly selected to undergo iodine staining during FDS, and the remaining 85 were assigned to the control group. Biopsy specimens of suspicious lesions were obtained and subjected to histopathological examination. RESULTS: Following PAS staining, benign mammary hyperplasia lesions were positively stained, while negligible PAS positivity was observed in the DCIS lesions (P < 0.05). Following in vitro iodine staining, benign mammary hyperplasia specimens appeared dark brown, whereas DCIS samples appeared significantly lighter or unstained. Compared with the pathological examination results, FDS with iodine staining showed an agreement rate in the diagnosis of ductal intraepithelial neoplasia (DIN), sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and Youden index of 97.82%, 98.83%, 83.33%, 5.93, 0.014, and 0.8216, respectively; the corresponding values for FDS without iodine staining were 88.24%, 89.16%, 50.00%, 1.78, 0.217, and 0.3916, respectively. CONCLUSION: FDS with iodine staining was superior to conventional FDS for the diagnosis of DIN and is valuable for breast cancer prevention.