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In this study, erianin was found to reduce the viability of cancer cells, inhibit their proliferation and migration, induce G2/M phase arrest, enhance cancer cell apoptosis, promote an increase in levels of intracellular reactive oxygen species and a decrease in mitochondrial membrane potential, and regulate the expression levels of anti- and pro-apoptosis-related proteins in HepG2 and SMMC-7721 cells. Erianin inhibited tumor growth in HepG2- and SMMC-7721-xenograft tumor nude mouse models, reduced the expression levels of anti-apoptosis proteins and enhanced the expression levels of pro-apoptosis proteins in tumor tissues. Erianin inhibited tumor growth in immunosuppressed BALB/c mice bearing heterotopic tumors. Among 111 types of cytokines detected in proteome profiling of tumor tissues, erianin substantially influenced levels of 38 types of cytokines in HepG2-xenografted tumors and of 15 types of cytokines in SMMC-7721-xenografted tumors, most of which are related to immune functions. Erianin strongly affected the serum levels of cytokines, and regulated the activation of nuclear factor-kappa B (NF-κB), and the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins in spleen. The anti-liver cancer properties of erianin were found to be related mostly to its modulation of oxidative stress-mediated mitochondrial apoptosis and immune response.

Background Epidemiological studies have found that prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with increased risk for neural tube defects (NTDs). Aberrant DNA methylation, excessive apoptosis, and oxidative stress have been implied as the mechanism underlying the association between PAH exposure and NTDs, respectively. However, the role of DNA methylation aberration of apoptotic initiator CASP8 (caspase-8, apoptosis-related cysteine peptidase) in the formation of NTDs in association with PAH exposure is not known. By combining a case–control study and mouse model, we aimed to explore the full spectrum of the links from PAH exposure, oxidative stress, CASP8 methylation change, caspase-8 activation, apoptosis, to NTD formation. Results Hypomethylation of CASP8 promoter was noticed in the microarray profiled by Infinium HumanMethylation450 BeadChip using neural tissues from 10 terminated NTD fetuses and 8 terminated non-malformed fetuses (14 CpG sites, with β difference ranging between 8.8 and 26.3%), and was validated in a larger case–control sample performed with neural tissues from 80 NTD cases and 32 non-malformed fetuses, using the Sequenom MassARRAY system (7 CpG sites). Hypomethylation of CASP8 was a risk factor for NTDs (aOR = 1.11; 95% CI, 1.05–1.17) based on the logistic regression model. According to Pearson’s correlation, methylation levels of CASP8 were inversely correlated with PAH concentrations in maternal serum and with oxidative stress markers in fetal neural tissues ( p < 0.05). In the animal study, increased NTD rates (13.5% frequency), Casp8 hypomethylation, caspase-8 upregulation, increased caspase-8 cleavage, and excessive apoptosis were found in mouse embryos cultured with benz(a)pyrene (BaP) in vitro. Antioxidant N -acetyl-L-cysteine (NAC) and BaP co-treatment attenuated the changes found in BaP treatment group. Conclusions Hypomethylation of Casp8 promoter is associated with the formation of NTDs, and Casp8 hypomethylation may be induced by oxidative stress that resulted from exposure to PAHs. Electronic supplementary material The online version of this article (10.1186/s13148-019-0673-6) contains supplementary material, which is available to authorized users.

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BACKGROUNDPancreatic mixed serous-neuroendocrine neoplasms (MSNNs) are mixed tumors containing two components with different pathologies, namely, pancreatic serous cystic neoplasm (PSCN) and pancreatic neuroendocrine tumor (PanNET). For MSNNs, diffuse PSCN involving the whole pancreas is extremely rare, with only eight previous case reports.CASE SUMMARYA 45-year-old Chinese woman, with a free previous medical history and no obvious symptoms, was found to have a pancreatic neoplasm and admitted to our hospital for further diagnosis in March 2018. Abdominal palpation revealed a painless, mobile mass in the epigastrium, and no abnormalities were observed in an examination of the nervous system and ocular system. A computed tomography scan showed multiple cystic lesions involving the whole pancreas ranging in diameter from 0.4 to 2 cm and also revealed an enhanced mass, 2.2 cm in diameter, in the head of the pancreas. Moreover, multiple cysts were found in the kidneys bilaterally, and the right lobe of the liver contained a small cyst. A Whipple operation with total pancreatectomy and splenectomy was performed. A diagnosis of pancreatic MSNN was established, consisting of diffuse serous microcystic cystadenoma with a concomitant grade 2 PanNET. Of note, the patient had no personal or family history of Von Hippel-Lindau syndrome or other disease.CONCLUSIONWe report the first case of MSNN with a diffuse PSCN component involving the entire pancreas in a Chinese woman. It is important to be aware of its relationship with VHL syndrome, and close clinical follow-up is recommended.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary cerebral artery disease. The HtrA serine protease 1 (HTRA1) gene has been identified as the causative gene of CARASIL. Here, we report a novel mutation in the HTRA1 gene in a CARASIL pedigree and explore its pathogenesis at the protein level. Subcutaneous tissue biopsy and HTRA1 gene analysis were performed in a CARASIL patient, and HTRA1 and TGF-β1 protein expression in subcutaneous tissue and cultured fibroblasts from the proband were detected by immunohistochemistry and western blotting. A 28-year-old male proband and his brother experienced recurrent stroke, hair loss and low back pain. Abnormalities in the proband were found in the elastic plate of subcutaneous small arteries, and a novel homozygous frameshift mutation (c.161_162insAG), leading to the formation of a stop codon 159 amino acids downstream of the insertion (p.Gly56Alafs*160) was detected. Reduced HTRA1 protein and increased TGF-β1 expression were detected in subcutaneous tissue and in cultured fibroblasts. A frameshift mutation in the HTRA1 gene detected in a CARASIL pedigree resulted in reduced HTRA1 protein and increased TGF-β1 expression, which may cause severe CARASIL and peripheral small arterial disease.

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The aim of the present study was to explore the antitumor effects of sinoporphyrin sodium (DVDMS)-mediated photodynamic therapy (PDT) and sonodynamic therapy (SDT) in glioma, and to reveal the underlying mechanisms. The uptake of DVDMS by U-118 MG cells was detected by flow cytometry (FCM). A 630-nm semiconductor laser and 1-MHz ultrasound were used to perform PDT and SDT, respectively. Cell proliferation and apoptosis were evaluated using the Cell Counting Kit-8 assay, FCM and Hoechst 33258 staining, respectively. Western blot analysis was used to detect protein expression and phosphorylation levels. BALB/c nude mice were used to establish a xenograft model of U-118 MG cells. DVDMS was injected intravenously and PDT and SDT were performed 24 h later. An in vivo imaging system was used to evaluate the fluorescence of DVDMS, to measure tumor sizes, and to evaluate the therapeutic effects. The uptake of DVDMS by U-118 MG cells was optimal after 4 h. PDT and SDT following DVDMS injection significantly inhibited the proliferation and increased apoptosis of glioma cells in vitro (P<0.05, P<0.01) respectively. In vivo, the fluorescence intensity of DVDMS was lower in the PDT and SDT groups compared with the DVDMS group, while tumor cell proliferation and weight were lower in the PDT and SDT groups than in the control group (P<0.05, P<0.01). However, there was no significant difference when laser, ultrasound or DVDMS were applied individually, compared with the control group. Hematoxylin and eosin staining suggested that both PDT and SDT induced significant apoptosis and vascular obstruction in cancer tissues. DVDMS-mediated PDT and SDT inhibited the expression levels of proliferating cell nuclear antigen (PCNA) and Bcl-xL, increased cleaved-caspase 3 levels, and decreased the protein phosphorylation of the PI3K/AKT/mTOR signaling pathway. Changes in the expression of PCNA, and Bcl-xL and in the levels of cleaved-caspase 3 were partly reversed by N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger. Similar results were obtained with FCM. DVDMS-mediated PDT and SDT inhibited glioma cell proliferation and induced cell apoptosis in vitro and in vivo, potentially by increasing the generation of ROS and affecting protein expression and phosphorylation levels.