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Our previous studies found that M10, a myricetin-3-O-β-d-lactose sodium salt, possessed higher effects of ameliorating ulcerative colitis (UC) than Myricetin in mice. Here, we aim to investigate whether the inhibition of UC is the consequence of the effects of M10 that leads to the changed microbiota. Mice model of UC was induced by dextran sulfate sodium (DSS) treatment. M10 and Myricetin were orally administrated for 12 weeks. We performed 16S rDNA sequencing assay to analyze the composition of gut microbiota isolated from ileocecum. Both M10 and Myricetin normalized the composition of Firmicutes and Actinobacteria as healthy mice had. At genus level, the effects of M10 and Myricetin on colitis were associated to the increase of probiotics, such as Akkermansia, and the inhibition of pathogenic microorganisms, such as Ruminococcus and Parabacteroides. M10 had stronger activity than Myricetin in the improvement of biosynthesis and degradation activities, resulting to increasing metabolism of sulfur, pyruvate, steroid biosynthesis and unsaturated fatty acid biosynthesis in gut. Furthermore, M10 normalized the proportion of Firmicutes and Actinobacteria in gut microbiota. It suggests that the improvements in UC are the consequence of the effect of M10 that leads to the changed intestinal microbiota. Conclusion: M10 contributed the pharmacological effects on UC by modification of the intestinal microbiota.

Background and purpose It is well known that microsatellite instability-high (MSI-H) is associated with 5-fluorouracil (5-FU) resistance in colorectal cancer. MSI-H is the phenotype of DNA mismatch repair deficiency (MMR-D), mainly occurring due to hypermethylation of MLH1 promoter CpG island. However, the mechanisms of MMR-D/MSI-H are unclear. We aim to investigate the pathway of MMR-D/MSI-H involved in 5-FU resistance. Experimental approach Human colorectal cancer specimens were diagnosed for MSI-H by immunohistochemistry and western blotting. Proteome microarray interactome assay was performed to screen nuclear proteins interacting with ATG5. Nuclear ATG5 and ATG5-Mis18α overexpression were analysed in ATG5high colorectal cancer bearing mice. The methylation assay determined the hypermethylation of hMLH1 promoter CpG island in freshly isolated human colorectal cancer tissue samples and HT29atg5 and SW480atg5 cancer cells. Key results In ATG5high colorectal cancer patients, 5-FU-based therapy resulted in nuclear translocation of ATG5, leading to MSI-H. Colorectal cancer in Atg5 Tg mice demonstrated 5-FU resistance, compared to Atg5+/- and WT mice. Proteome microarray assay identified Mis18α, a protein localized on the centromere and a source for methylation of the underlying chromatin, which responded to the translocated nuclear ATG5 leading to ATG5-Mis18α conjugate overexpression. This resulted in MLH1 deficiency due to hypermethylation of hMLH1 promoter CpG island, while the deletion of nuclear Mis18α failed to induce ATG5-Mis18α complex and MMR-D/MSI-H. Conclusions and implications Nuclear ATG5 resulted in MMR-D/MSI-H through its interaction with Mis18α in ATG5high colorectal cancer cells. We suggest that ATG5-Mis18α or Mis18α may be a therapeutic target for treating colorectal cancer.

BACKGROUND Computed tomography (CT) has become a routine preoperative examination for tibial plateau fractures (TPFs). Assessing the location of the fragment and intercondylar eminence fracture can provide clinicians with valuable information; however, the evaluation of traumatic meniscal lesion (TML) and arthroscopic management are controversial. AIM To predict TML by three-dimensional skeletal anatomy changes in unilateral TPF and bilateral TPF on preoperative thin layer CT. METHODS Acute fracture of tibial plateau patients undergoing arthroscopic surgery between December 2017 and December 2019 were included in this retrospective study. The type, zone, and location of TMLs were diagnosed based on the operation records and/or arthroscopic videos. Measurement of three-dimensional fracture morphology included the following: Frontal fragment width of plateau, sagittal fragment subsiding distance (FSD), sagittal fracture line distance, sagittal posterior tibial slope, and transversal area ratio of fragment area) on preoperative CT three-dimensional plane. The correlation of TML with skeletal values was calculated according to unicondylar TPFs and bicondylar TPFs. RESULTS A total of 67 patients were enrolled in this study, among which 30 patients had TMLs, lateral/medial (23/7). FSD was a particularly positive factor to predict TML, with odds ratio of 2.31 (1.26-5.63). On sagittal view of CT, FSD degree of 8 mm and posterior tibial slope exceeding 11.74° implied enhanced risk of TML in bicondylar TPFs. On coronal view, once fragment width of plateau surpassed 3 cm, incidence of TML reached 100%. On transverse view, area ratio of fragment as enhanced risk of 5.5% and FSD > 4.3 mm for predicting TML were observed in unicondylar TPFs. CONCLUSION TML can be predicted by different parameters on preoperative CT views according to unicondylar fractures and bicondylar TPFs.

One new phenolic glycoside, methyl 3,4-dihydroxyphenylacetate-4-O-[2-O-β-D-apisoyl-6-O-(2-hydroxybenzoyl)]-β-D-glucopyranoside (1), together with 10 known compounds (2–11), were isolated from the r...

Background: Laryngeal Squamous Cell Carcinoma (LSCC) is a malignant epithelial tumor with poor prognosis and its incidence rate increased recently. rLj-RGD3, a recombinant protein cloned from the buccal gland of Lampetra japonica, contains three RGD motifs that could bind to integrins on the tumor cells. Methods: MTT assay was used to detect the inhibitory rate of viability. Giemsa’s staining assay was used to observe the morphological changes of cells. Hoechst 33258 and TUNEL staining assay, DNA ladder assay were used to examine the apoptotic. Western blot assay was applied to detect the change of the integrin signal pathway. Wound-healing assay, migration, and invasion assay were used to detect the mobility of Hep2 cells. H&E staining assay was used to show the arrangement of the Hep2 cells in the solid tumor tissues. Results: In the present study, rLj-RGD3 was shown to inhibit the viability of LSCC Hep2 cells in vitro by inducing apoptosis with an IC50 of 1.23µM. Western blot showed that the apoptosis of Hep2 cells induced by rLj- RGD3 was dependent on the integrin-FAK-Akt pathway. Wound healing, transwells, and western blot assays in vitro showed that rLj-RGD3 suppressed the migration and invasion of Hep2 cells by integrin-FAKpaxillin/ PLC pathway which could also affect the cytoskeleton arrangement in Hep2 cells. In in vivo studies, rLj-RGD3 inhibited the growth, tumor volume, and weight, as well as disturbed the tissue structure of the solid tumors in xenograft models of BALB/c nude mice without reducing their body weights. Conclusion: hese results suggested that rLj-RGD3 is an effective and safe suppressor on the growth and metastasis of LSCC Hep2 cells from both in vitro and in vivo experiments. rLj-RGD3 might be expected to become a novel anti-tumor drug to treat LSCC patients in the near future.

A sodium N-lauryl amino acids (shortly silk sericin surfactant, SSS) is synthesized with lauryl chloride and sericin amino acids recovered from silk industrial waste. The purpose of this study is to explore whether the sericin surfactant can be used as a potential drug delivery carrier. By controlling the proportion of cationic drugs, cytarabine hydrochloride (CH) and anionic SSS, the aggregation behavior, slow release capability and toxicological effects of catanionic aggregates or vesicles, formed through CH and SSS, have been investigated in detail. Dynamic light scattering (DLS), transmission electron microscopy (TEM), and zeta potential analysis showed that the aggregate solution could form a stable vesicle structure when the mass fraction of CH is less than or equal to 0.3. The drug release results showed that the cumulative release rate of the catanionic aggregation solution with CH mass fraction of 0.2 reached a maximum at 18 h, being approximately 9 times greater than that of pure cytarabine. The CH/SSS aggregates had a significant sustained release effect compared with the control group. At the same time, vesicles formed by SSS and CH have better anti-tumor effects compared with the pure drug group. In summary, sericin surfactant from silk industrial waste has a potential use as a drug delivery carrier.

As the use of zinc oxide nanoparticles (ZnO NPs) in everyday products grows, so does concern about health risks. However, no findings on the gastrointestinal toxicity of ZnO NPs have been published. We investigated the possible malignant transformation of ZnO NPs in the mice’s colonic tissues using the APCmin/+ mouse model with a premalignant lesion in intestinal epithelial cells. Higher doses and long-term oral exposure to ZnO NPs were found to mildly promote colonic inflammation in WT mice, while they moderately or strongly exacerbated the severity of chronic inflammation and tumorigenesis in APCmin/+ mice with intestinal adenomatous polyposis. The ZnO NPs-induced inflammation and tumorigenesis in colonic epithelial cells was linked to the activation of CXCR2/NF-κB/STAT3/ERK and AKT pathways. Analysis of the ZnO NPs-exacerbated intestinal adenomatous polyposis in APCmin/+ mice revealed that ZnO NPs could activate the APC-driven Wnt/β-catenin signaling pathway, exacerbating intestinal tumorigenesis. In fact, ZnO NPs have been shown to increase intestinal inflammation and tumorigenesis in APCmin/+ mice by releasing free Zn2+. In WT mice, a low dose of ZnO NPs (26 mg/kg/day) did not cause intestinal inflammation. In conclusion, higher doses and prolonged exposure to ZnO NPs promote the malignant transformation of precancerous epithelial cells.

Sphingosine-1-phosphate receptor 2 (S1PR2) has been identified as a brand-new GPCR target for designing antagonists to reverse 5-FU resistance. We herein report the structural optimization and structure-activity relationship of JTE-013 derivatives as S1PR2 antagonists. Compound 9d was the most potent S1PR2 antagonist (KD = 34.8 nM) among developed compounds. Here, compound 9d could significantly inhibit the expression of dihydropyrimidine dehydrogenase (DPD) to reverse 5-FU-resistance in HCT116DPD and SW620/5-FU cells. Further mechanism studies demonstrated that compound 9d not only inhibited S1PR2 but also affected the transcription of S1PR2. In addition, compound 9d also showed acceptable selectivity to normal cells (NCM460). Importantly, compound 9d with suitable pharmacokinetic properties could significantly reverse 5-FU-resistance in the HCT116DPD and SW620/5-FU xenograft models without obvious toxicity, in which the inhibition rates of 5-FU were increased from 23.97% to 65.29% and 27.23% to 60.81%, respectively. Further immunohistochemistry and western blotting analysis also demonstrated that compound 9d significantly decreases the expression of DPD in tumor and liver tissues. These results indicated that compound 9d is a promising lead compound to reverse 5-FU-resistance for colorectal cancer therapy.

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes., Genome wide association studies have identified multiple loci associated with risk of developing prostate cancer but the functional significance of many of these are unknown. Here, after generating models to predict methylation, the authors identify CpG methylation sites associated with prostate cancer.

5-Fluorouracil (5-FU) and its prodrugs are the essential clinical drugs for colorectal cancer (CRC) treatment. However, the drug resistance of 5-FU has caused high mortality of CRC patients. Thus, it is urgent to develop reversal agents of 5-FU resistance. Sphingosine-1-phosphate receptor 2 (S1PR2) was proved to be a potential target for reversing 5-FU resistance, but the activity of known S1PR2 antagonists JTE-013 were weak in 5-FU-resistant cell lines. To develop more potent S1PR2 antagonists to treat 5-FU-resistant cancer, a series of JTE-013 derivatives were designed and synthesized. The most promising compound 40 could markedly reverse the resistance in 5-FU-resistant HCT116 cells and 5-FU-resistant SW620 cells via inhibiting the expression of dihydropyrimidine dehydrogenase (DPD). The key was that compound 40 with improved pharmacokinetic properties significantly increased the inhibitory rate of 5-FU in the SW620/5-FU cells xenograft model with no observable toxicity by inhibiting the expression of DPD in tumor and liver tissues. Altogether, these results suggest that compound 40 may be a promising drug candidate to reverse 5-FU resistance in the treatment of CRC.

The important role of insulin-like growth factor-1 receptor (IGF-1R) in tumorigenesis has been well established. The classical model involves IGF-1R binding to IGF-1/2, the following activation of PI3K-Akt-signaling cascades, driving cell proliferation and apoptosis inhibition. Here we report a new signal transduction pathway of IGF-1R in the intestinal epithelium. Using heterozygous knockout mice (Igf1r+/−), we analyzed the expressions of viral RNA sensors MDA5 and RIG-I in the intestinal epithelium. Igf1r+/− mice exhibited higher MDA5 and RIG-I than wild-type (WT) mice, indicating that knockdown of IGF-1R could trigger MDA5 and RIG-I. IGF-1R knockdown-triggered MDA5 and RIG-I were further investigated in human colonic cancer cells. Increased MDA5 and RIG-I were clearly seen in the cytoplasm in cancer cells as well as normal human colonic cells with silenced IGF-1R. Notably, the upregulations of MDA5 and RIG-I was not affected by blockage of the PI3K-Akt pathway with LY294002. These results suggested a new signal transduction pathway of IGF-1R. Importantly, IGF-1R knockdown-triggered MDA5 and RIG-I resulted in colorectal cancer apoptosis through activation of the mitochondrial pathway. These in vitro observations were evidenced in the azoxymethane (AOM)-dextran sulfate sodium (DSS) colorectal cancer model of mice. In conclusion, knockdown of IGF-1R triggers viral RNA sensor MDA5- and RIG-I-mediated mitochondrial apoptosis in cancer cells. Keywords: IGF-1R, viral RNA sensors, MDA5, RIG-I, mitochondrial apoptosis

Although insulin-like growth factor-1 receptor (IGF-1R) has been accepted as a major determinant of cancers, its biological roles and corresponding mechanisms in tumorigenesis have remained elusive. Herein, we demonstrate that IGF-1R plays pivotal roles in the regulation of mitochondrial respiratory chain and functions during colitis and tumorigenesis. Heterozygous knockout IGF-1R attenuated azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis and colitis associated cancer (CAC) in Igf1r+/- mice. Heterozygous knockout IGF-1R confers resistance to oxidative stress-induced damage on colorectal epithelial cells by protecting mitochondrial dynamics and structures. IGF-1R low expression improves the biological function of mitochondrial fusion under oxidative stress. Mechanically, an increase in respiratory coupling index (RCI) and oxidative phosphorylation index (ADP/O) was seen in colorectal epithelial cells of Igf1r+/- mice. Seahorse XFe-24 analyzer analysis of mitochondrial bioenergetics demonstrated an increase in oxygen consumption rate (OCR) and a decrease of extracellular acidification rate (ECAR) in Igf1r+/- cells. Further analysis suggests the protection mechanisms of Igf1r+/- cells from oxidative stress through the activation of the mitochondrial respiratory chain and LKB1/AMPK pathways. These results highlight the biological roles of IGF-1R at the nexus between oxidative damage and mitochondrial function and a connection between colitis and colorectal cancer.

At present, central venous access devices (CVADs) are widely used in clinical practice. The reasons for CVAD obstruction caused by precipitated medication or lipids are increasingly complex. However, there is no clear treatment program for CVAD obstruction caused by precipitated medication or lipids. The target of this study was to analyze data regarding obstruction caused by precipitated medication or lipids in CVADs and to calculate the efficacy of different treatment methods. A systematic review with meta-analysis was conducted in alignment with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The PubMed, Web of Science, EMBASE, Cochrane Library, CINAHL, and China National Knowledge Internet databases were searched for original research published before 2018. There were 1356 publications initially screened, with one additional study identified through snowballing. Seven studies met the inclusion criteria. The reasons for obstruction, except for clot formation, primarily included the following: mechanical complications; lipid deposition; mineral deposition; or drug precipitation. Meta-analysis showed that sodium hydroxide resulted in the highest recanalization rate in lipid deposition, followed by ethanol, and the difference was significant. The efficacy analysis revealed that hydrochloric acid and l-cysteine have similar effects on mineral deposition and drug precipitation. According to this review, the most effective methodology was shown to be the intravenous perfusion of sodium hydroxide in several treatments when the obstruction is caused by lipid deposition. In contrast, mineral deposition and drug deposition are best treated with l-cysteine to recover the patency of central venous access devices.

BackgroundThis study aimed to comprehensively analyze the characteristics, treatment patterns, and survival outcomes of non-small-cell lung cancer (NSCLC) patients initially diagnosed with brain metastases (BMs) in real-world practice.MethodsWe enrolled NSCLC patients initially diagnosed with BMs between Jan 2004 and Jan 2018 in our institution. Patient demographics, treatment modalities, and survival outcomes were then analyzed. Brain localized treatment (BLT) included early brain radiotherapy (EBR), deferred brain radiotherapy (DBR), and surgery.ResultsA total of 954 patients were identified. Concerning initial treatment, 525 patients (55.0%) received systemic medication (SM)+BLT, 400 patients (41.9%) received SM only, and 29 patients received BLT only (3.0%). SM+BLT cohort was associated with longer median overall survival (mOS) than the SM only and the BLT only cohorts both in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-negative/unknown patients (15.3 months, 95% confidence interval [CI], 14.2–16.4; 11.1 months, 9.0–13.2; 7.0 months, 5.4–8.6; p

AIM To evaluate the effect of a ketogenic diet (KD) in women with polycystic ovary syndrome (PCOS) and liver dysfunction who were obese. METHODS Women with PCOS and liver dysfunction who were obese were enrolled in this prospective, open-label, parallel-group, controlled pilot trial, and randomly received KD (KD group) or conventional pharmacological treatment (Essentiale plus Yasmin, control group) in a 1:1 ratio for 12 weeks. The primary endpoint was the liver function markers. Secondary endpoints included the menstrual cycle, anthropometric characteristics, body composition, hormonal levels, and metabolic biomarkers. RESULTS Of the 20 eligible participants enrolled, 18 participants completed the study. The KD group reported a significant reduction in anthropometric characteristics and body composition from baseline to week 12 (all p

Objectives: The purpose of this research is to describe and understand nurses’ knowledge of drug-induced peripherally inserted central catheter obstruction management in developing countries. This research aims to identify the reasons why nurses lack knowledge of the management of drug-induced peripherally inserted central catheter obstruction and do not use the drug-induced peripherally inserted central catheter obstruction management techniques recommended by the Infusion Therapy Standards of Practice. Methods: The descriptive phenomenological method was used to investigate nurses’ knowledge of the management of drug-induced peripherally inserted central catheter obstruction. Semi-structured in-depth interviews with 17 nurses from three hospitals in northeast China were used in this qualitative study. Data collection and analysis were conducted simultaneously during the research. Nvivo software 12.0 was used to organize and code the data, and Colaizzi’s seven phases of data analysis were used to form themes. Findings: The findings showed that there is inconsistency in nurses’ knowledge of drug-induced peripherally inserted central catheter obstruction and its management, and we suggest reasons for this phenomenon. Conclusion: This research has shown that inconsistent practice in the management of drug-induced peripherally inserted central catheter obstruction is a more complex issue than originally thought. These inconsistencies are related to time pressure on nurses, nurses’ knowledge of peripherally inserted central catheter obstruction, and limitations of the clinical work model.

Both chemokine receptors (CXCRs) 7 and 4 can facilitate immune cell migration and mediate a vast array of physiological and pathological events. Herein we report, in both human and animal studies, that these two CXCRs can form heterodimers in vivo and promote colorectal tumorigenesis through histone demethylation. Compared with adjacent non-neoplastic tissue, human colorectal cancer (CRC) tissue showed a significant higher expression of CXCR4 and CXCR7, which was colocalized in the cancer cell epithelium. The CXCR/CXCR4 heterodimerization was associated with increased histone demethylase JMJD2A. Villin-CXCR7-CXCR4 transgenic mice demonstrated a greater degree of exacerbated colitis and tumorigenesis than villin-CXCR7 and villin-CXCR4 mice. The CXCR7/CXCR4 heterodimerization also promoted APC mutation-driven colorectal tumorigenesis in APCMin/+/villin-CXCR7-CXCR4 mice. Further analysis showed that the CXCR7/CXCR4 heterodimer induced nuclear βarr1 recruitment and histone demethylase JMJD2A, leading to histone demethylation and resulting in transcription of inflammatory factors and oncogenes. This study uncovered a novel mechanism of colorectal tumorigenesis through the CXCR7/CXCR4 heterodimer-induced histone demethylation. Inhibition of CXCR7/CXCR4 heterodimer-induced histone demethylation could be an effective strategy for the prevention and treatment of colorectal cancer.

As ZnO nanoparticles have been applied in many fields, their biological risks on human health, of course, are worthy of our attention. Whether ZnO NPs have the risk and how colonic cells respond to the invaded ZnO NPs are still unknown. Herein, we evaluated the biological effects of ZnO NPs on colonic mucosal cells by in vitro and in vivo methods. IMCE cells, with APC mutation but phenotypically normal, demonstrated hyperproliferation through activating the CXCR2/NF-κB/STAT3/ERK and AKT pathways when exposed to ZnO NPs for 24 h. Long-term exposure of ZnO NPs resulted in the malignant transformation of IMCE cells, showing the morphological changes, anchorage-independent cell growth ability. Importantly, IMCE cells exposed to ZnO NPs subcutaneously grew and induced tumorigenesis in nude mice. In conclusion, exposure of ZnO NPs could induce malignant transformation of colonic mucosal cells through the CXCR2/NF-κB/STAT3/ERK and AKT pathways. We suggest that it was necessary to consider using the precautionary principle for gastrointestinal contact nanomaterials.

Background Brain metastasis (BM) is one of the principal causes of mortality for lung cancer patients. While the molecular events that govern BM of lung cancer remain frustrating cloudy. Methods The miRNA expression profiles are checked in the paired human BM and primary lung cancer tissues. The effect of miR-143-3p on BM of lung cancer cells and its related mechanisms are investigated. Results miR-143-3p is upregulated in the paired BM tissues as compared with that in primary cancer tissues. It can increase the invasion capability of in vitro blood brain barrier (BBB) model and angiogenesis of lung cancer by targeting the three binding sites of 3’UTR of vasohibin-1 (VASH1) to inhibit its expression. Mechanistically, VASH1 can increase the ubiquitylation of VEGFA to trigger the proteasome mediated degradation, further, it can endow the tubulin depolymerization through detyrosination to increase the cell motility. m6A methyltransferase Mettl3 can increase the splicing of precursor miR-143-3p to facilitate its biogenesis. Moreover, miR-143-3p/VASH1 axis acts as adverse prognosis factors for in vivo progression and overall survival (OS) rate of lung cancer. Conclusions Our work implicates a causal role of the miR-143-3p/VASH1 axis in BM of lung cancers and suggests their critical roles in lung cancer pathogenesis.

Acute liver failure is a serious clinical problem of which the underlying pathogenesis remains unclear and for which effective therapies are lacking. The Fas receptor/ligand system, which is negatively regulated by AKT, is known to play a prominent role in hepatocytic cell death. We hypothesized that AKT activation may represent a strategy to alleviate Fas-induced fulminant liver failure. We report here that a novel AKT activator, SC79, protects hepatocytes from apoptosis induced by agonistic anti-Fas antibody CH11 (for humans) or Jo2 (for mice) and significantly prolongs the survival of mice given a lethal dose of Jo2. Under Fas-signaling stimulation, SC79 inhibited Fas aggregation, prevented the recruitment of the adaptor molecule Fas-associated death domain (FADD) and procaspase-8 [or FADD-like IL-1β-converting enzyme (FLICE)] into the death-inducing signaling complex (DISC), but SC79 enhanced the recruitment of the long and short isoforms of cellular FLICE-inhibitory protein at the DISC. All of the SC79-induced hepatoprotective and DISC-interruptive effects were confirmed to have been reversed by the Akt inhibitor LY294002. These results strongly indicate that SC79 protects hepatocytes from Fas-induced fatal hepatic apoptosis. The potent alleviation of Fas-mediated hepatotoxicity by the relatively safe drug SC79 highlights the potential of our findings for immediate hepatoprotective translation.

Naringin, a natural occurring flavonoid compound, enriches in citrus fruits. We aimed to evaluate the inhibitory effect of naringin on colitis and chronic inflammation-driven carcinogenesis. Male C57BL/6 mice were exposed to AOM/DSS to induce colorectal inflammation and carcinogenesis. Naringin by oral administration prevented AOM/DSS-induced ulcerative colitis and carcinogenesis without significant side effects. Naringin attenuated the severity of colitis and colorectal adenomas through inhibiting myeloid-derived suppressor cells (MDSCs), pro-inflammatory mediators GM-CSF/M-CSF, IL-6 and TNF-α and the NF-κB/IL-6/STAT3 cascades in colorectal tissues. Naringin-treated mice exhibited normalized structures of colorectal tissues. Electron microscopy analysis showed the suppression of robust endoplasmic reticulum (ER) stress-induced autophagy. Naringin inhibited the secretion of the ER-spanning transmembrane proteins, such as GRP78 ATF6, IRE1α and activated PERK phosphorylated eIF-2α and complex of autophagosomes ATG3, ATG5, ATG7, ATG12, ATG16 and ATG16L1 in the colorectal mucosal cells. Conclusion: Naringin prevented colitis and colorectal carcinogenesis through suppressing robust ER stress-induced autophagy in colorectal mucosal cells. Naringin could develop a promising therapeutic agent for the prevention of ulcerative colitis and colorectal tumor.

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disease caused by a deficiency of the enzyme arylsulfatase A (ARSA), which is encoded by the ARSA gene. Mutations discovered in the ARSA gene continuously improve our knowledge and understanding of this rare disease. We identified a Chinese family with 15 members. Two of them were diagnosed as MLD. We used Sanger sequencing to analyze eight exons of the ARSA gene and measured the ARSA activity in leukocyte or amniotic cells with p-nitrocatechol sulfate as the substrate. The potential pathological functions of these variants were predicted through SIFT, Polyphen2, and Mutation Taster. Two family members with a diagnosis of MLD were a two-year-old boy and a fetus. Both had a complex heterozygous mutation: c.413C > T (p.Pro138Leu) in exon 2 and c.1344dupC (p.G449fs) in exon 8. This complex heterozygous mutation is the first case of concurrent missense and code shift mutations reported in MLD in China. In these two family members, ARSA activity (20 nmol/17 h/mg protein and 9.8 nmol/17 h/mg protein) is only 10% compared to the normal population.

Background: Advanced cancer (AC) patients experience serious physical and psychological problems with the disease progression. When approaching the end of life, these patients have to cope with not only the bodily illness, but also the spiritual crisis. Conventional psychological treatments reduce distress to a certain extent, but for patients with AC, especially when they face progressive illness and are approaching death, their psychological problems are complex, and no simple solutions are in sight. Therefore, we designed this study to evaluate the efficacy of the combined Naikan therapy (NT) and Morita therapy (MT) on psychological distress and posttraumatic growth in patients with AC. Method: One hundred thirty patients newly diagnosed with AC were allocated randomly into treatment (n = 65) and control (n = 65) groups. Patients in the treatment group received combined NT and MT for 7 consecutive weeks, while the control group received normal medical treatments without NT and MT. Patients were assessed before and after the therapies. The primary outcome measures include distress thermometer (DT) and posttraumatic growth, and the secondary outcome measure contains the list of distress problems. Results: At the post-treatment stage, the treatment group displayed a decreased score of psychological distress as compared to that in the control group, which accompanied by a higher post-traumatic growth total score and subscale scores in relationship to others, new possibilities, personal strength, spiritual changes, and appreciation of life. A significant decrease in fear, sleeping difficulty/insomnia, nervousness/anxiety, and loss of appetite was also observed in the treatment group. Conclusion: The results proved that the combined Naikan and Morita therapies decreased the psychological distress and improved the posttraumatic growth of the patients with AC. Trial Registration: ChiCTR1900026691.

Background The current published prognosis models for brain metastases (BMs) from cancer have not addressed the issue of either newly diagnosed non–small-cell lung cancer (NSCLC) with BMs or the lung cancer genotype. We sought to build an adjusted prognosis analysis (APA) model, a new prognosis model specifically for NSCLC patients with BMs at the initial diagnosis using adjusted prognosis analysis (APA). Patients and Methods The model was derived using data from 1158 consecutive patients, with 837 in the derivation cohort and 321 in the validation cohort. The patients had initially received a diagnosis of BMs from NSCLC at Sun Yat-Sen University Cancer Center from 1994 to 2015. The prognostic factors analyzed included patient characteristics, disease characteristics, and treatments. The APA model was built according to the numerical score derived from the hazard ratio of each independent prognostic variable. The predictive accuracy of the APA model was determined using a concordance index and was compared with current prognosis models. The results were validated using bootstrap resampling and a validation cohort. Results We established 2 prognostic models (APA 1 and 2) for the whole group of patients and for those with known epidermal growth factor receptor (EGFR) genotype, respectively. Six factors were independently associated with survival time: Karnofsky performance status, age, smoking history (replaced by EGFR mutation in APA 2), local treatment of intracranial metastases, EGFR-tyrosine kinase inhibitor treatment, and chemotherapy. Patients in the derivation cohort were stratified into low- (score, 0-2), moderate- (score, 3-5), and high-risk (score 6-7) groups according to the median survival time (16.6, 10.3, and 5.2 months, respectively; P Conclusion Compared with recursive partition analysis and graded prognostic assessment, APA seems to be more suitable for initially diagnosed NSCLC with BMs.

// Wen-Na Shi 1 , Shu-Xiang Cui 2 , Zhi-Yu Song 1 , Shu-Qing Wang 1 , Shi-Yue Sun 1 , Xin-Feng Yu 1 , Ye Li 1 , Yu-Hang Zhang 1 , Zu-Hua Gao 3 and Xian-Jun Qu 1 1 Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China 2 Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China 3 Department of Pathology, McGill University, Montreal, Quebec, Canada Correspondence to: Xian-Jun Qu, email: quxj@ccmu.edu.cn Zu-Hua Gao, email: zu-hua.gao@mcgill.ca Keywords: sphingosine kinase 2 (SphK2), retinoid therapy resistance, cytoplasmic RXRα, polyubiquitination Received: December 06, 2016 Accepted: March 26, 2017 Published: April 18, 2017 ABSTRACT The resistance mechanisms that limit the efficacy of retinoid therapy in cancer are poorly understood. Sphingosine kinase 2 (SphK2) is a highly conserved enzyme that is mainly located in the nucleus and endoplasmic reticulum. Unlike well-studied sphingosine kinase 1 (SphK1) located in the cytosol, little has yet understood the functions of SphK2. Here we show that SphK2 overexpression contributes to the resistance of all-trans retinoic acid (ATRA) therapy in colon cancer through rapid degradation of cytoplasmic retinoid X receptor α (RXRα) by lysine 48 (K48)- and lysine 63 (K63)-based polyubiquitination. Human colonic adenocarcinoma HCT-116 cells transfected with SphK2 (HCT-116 Sphk2 cells) demonstrate resistance to ATRA therapy as determined by in vitro and in vivo assays. Sphk2 overexpression increases the ATRA-induced nuclear RXRα export to cytoplasm and then rapidly degrades RXRα through the polyubiquitination pathway. We further show that Sphk2 activates the ubiquitin-proteasome system through the signal mechanisms of (1) K48-linked proteosomal degradation and (2) K63-linked ubiquitin-dependent autophagic degradation. These results provide new insights into the biological functions of Sphk2 and the molecular mechanisms that underlie the Sphk2-mediated resistance to retinoid therapy.

BACKGROUND We investigated the relationship of the polymorphisms of SET and MYND domain-containing protein 3 (SMYD3) with risk and prognosis of ovarian cancer. MATERIAL AND METHODS The polymerase chain reaction (PCR) amplification method was applied to detect the polymorphisms of variable number of tandem repeats (VNTR) in the SMYD3 gene promoter region for 156 patients with ovarian cancer (case group) and 174 healthy people (control group). Quantitative reverse transcription polymerase chain reaction and Western blot were applied to detect SMYD3 mRNA and protein expressions. RESULTS The frequencies of VNTR genotype 3/3 and allele genotype 3 in the case group were significantly higher than those in the control group, while the frequency of genotype 2/2 in the control group was significantly higher than that in case group (all P

Diabetes mellitus, one of the fastest growing epidemics worldwide, has become a serious health problem in modern society. Gynura divaricata (GD), an edible medicinal plant, has been shown to have hypoglycaemic effects. The molecular mechanisms by which GD improves hepatic insulin resistance (IR) in mice with type 2 diabetes (T2D) remain largely unknown. The aerial parts of GD were prepared in a lyophilized powder, which was added into the diet of T2D mice for 4 weeks. GD could result in an obvious decrease in fasting blood glucose and insulin levels in T2D mice. Meanwhile, the underlying mechanisms involved in the insulin-signalling pathway, glucose metabolism, lipid metabolism and inflammatory reaction in the liver tissue were also investigated by western blot, which indicated that GD further ameliorated hepatic IR by activating the PI3K/p-AKT pathway, decreasing the levels of hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and increasing the levels of glucokinase and peroxisome proliferator-activated receptor-γ in the livers of T2D mice. GD has the potential to alleviate both hyperglycaemia and hepatic IR in T2D mice. Therefore, GD might be a promising functional food or medicine for T2D treatment.

Tumor-associated macrophages (TAMs) are important immunocytes associated with cancer metastasis. However, whether TAMs play a dominant role in mediating CXCL12/CXCR4-induced liver metastasis of colorectal cancer (CRC) remains unexplored. Herein, we found that CD206+ TAMs, which infiltrated at the invasive front, were correlated with CXCR4 expression and liver metastasis of CRC in clinical specimens. Several miRNAs (miR-25-3p, miR-130b-3p, miR-425-5p), upregulated in CRC cells by activation of the CXCL12/CXCR4 axis, could be transferred to macrophages via exosomes. These exosomal miRNAs induced M2 polarization of macrophages by regulating PTEN through activation of PI3K/Akt signaling pathway. In turn, M2 polarized macrophages promoted cancer metastasis by enhancing epithelial-mesenchymal transition (EMT) and secreting vascular endothelial growth factor (VEGF). Co-culture of CRC cells with macrophages transfected with these miRNAs or treated with exosomes enhanced their metastatic capacity both in vitro and in vivo. Clinically, the serum levels of exosomal miR-25-3p, miR-130b-3p and miR-425-5p were correlated with progression and metastasis of CRC. In conclusion, these results reveal a crucial role of exosomal miRNAs in mediating the crosstalk between CXCR4 overexpressing cancer cells and TAMs, providing potential therapeutic targets for circumventing liver metastasis of CRC.

The sericin protein from silk-processing waste added to the normal diet at 0.8% (g%) level was administered orally to type 2 diabetic (T2D) mice to investigate its hypoglycaemic effects and mechanism. The oral protein is in the form of silk sericin hydrolysate, obtained from a boiling treatment of 0.025% calcium hydroxide solution. The protein significantly decreased fasting blood glucose, fasting plasma insulin, and glycosylated serum protein levels; improved oral glucose tolerance and insulin tolerance, and enhanced antioxidative activities. The protein could ameliorate the pathological damage in pancreatic β-cells and the liver tissue. It enhanced the expression of key proteins and enzymes, including insulin receptor, insulin receptor substrate, PI3K, phosphorylated-AKT, hepatic kinase, GLUT4, glycogen synthase, GSK3β, GLK, PFK1, PKM2, and AMPKα, which are related to insulin metabolism and glycolysis. The protein also reduced the expression of G6Pase, PCK, and ACC, which are related to gluconeogenesis and lipid metabolism in the liver, and decreased the expression of TNF-α, IL-6, P65, and IKKβ related to inflammation. In general, sericin could maintain normal glucose levels and regulate insulin secretion, insulin and lipid metabolism, and inhibition of inflammation. Therefore, sericin protein could be developed into a novel functional health food with significantly hypoglycaemic effect.

BackgroundPrevious studies have documented that disordered eating is associated with a wide range of impaired physical and mental health conditions among children and adolescents. The relationship between disordered eating and health-related quality of life (HRQOL) has been predominantly examined in children and adolescents who are overweight or obese or suffer from chronic illnesses. In the last decade, several studies have been conducted to investigate the relationship between disordered eating and HRQOL among school and community children and adolescents. No systematic review or meta-analysis has synthesized the findings from these population-based studies. The purpose of this systematic review and meta-analysis was to synthesize the relationship between disordered eating and HRQOL among the general population of children and adolescents.MethodsWe performed a computer search for the English language literature using the databases PUBMED, EMBASE and PSYCINFO to retrieve eligible studies published between 1946 and August 9, 2018. We also searched the relevant articles using PubMed related article search features and manually examined the reference lists of the retrieved full text articles selected from the database search. The association between disordered eating and HRQOL was synthesized using both a qualitative method and a meta-analysis. The review was conducted adhering to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.ResultsWe identified eight studies that met the inclusion criteria and were included in the final synthesis. The studies included six cross-sectional studies and two longitudinal studies. The systematic review found that disordered eating attitudes and behaviors were associated with lower HRQOL among children and adolescents. Children and adolescents with bulimia nervosa (BN), binge eating disorder (BED), purging disorder (PD) and other eating disorder symptoms had poorer HRQOL than their healthy peers without the eating disorder conditions. The meta-analysis using four out of the eight studies showed that disordered eating was significantly associated with poor psychosocial health and lower overall HRQOL among children and adolescents.ConclusionThe present review reveals that disordered eating behaviors and eating disorders are associated with decreased HRQOL in children and adolescents. More prospective studies are needed to ascertain the directions in the relationship between disordered eating and HRQOL among children and adolescents. The findings of this review suggest that health programs for promoting healthy eating and reducing disordered eating behaviors among school children and adolescents may help to enhance the HRQOL and overall health status of these individuals.

Milk lipid secretion is a critical process for the delivery of nutrition and energy from parent to offspring. However, the underlying molecular mechanism is less clear. Here we report that TDP-43, a RNA-binding protein, underwent positive selection in the mammalian lineage. Furthermore, TDP-43 gene (Tardbp) loss induces accumulation of large lipid droplets and severe lipid secretion deficiency in mammary epithelial cells to outside alveolar lumens, eventually resulting in lactation failure and pup starvation within three weeks postpartum. In human milk samples from lactating women, the expression levels of TDP-43 is positively correlated with higher milk output. Mechanistically, TDP-43 exerts post-transcriptional regulation of Btn1a1 and Xdh mRNA stability, which are required for the secretion of lipid droplets from epithelial cells to the lumen. Taken together, our results highlights the critical role of TDP-43 in milk lipid secretion, providing a potential strategy for the screening and intervention of clinical lactation insufficiency., Milk lipid secretion is a critical process for the delivery of nutrition and energy from parent to offspring. Here the authors found that TDP-43, a RNA-binding protein, is required for milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh mRNA stability.

Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-α can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-α-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-α-induced apoptosis and protects mice from d-galactosamine (d-Gal)/lipopolysaccharide (LPS)-induced TNF-α-mediated liver injury and damage. SC79 not only enhances the nuclear factor-κB (NF-κB) prosurvival signaling in response to TNF-α stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-α-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury. NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-α-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-α act through both AKT-mediated activation of NF-κB and upregulation of FLIPL/S.

Des-γ-carboxyprothrombin (DCP), an abnormal prothrombin produced in human hepatocellular carcinoma (HCC), plays crucial roles in the progression of HCC. DCP binding to cellular mesenchymal-epithelial transition factor (c-Met) is an initial event and consequently stimulates HCC through the increase of c-Met-Janus kinase 1- signal transducers and activators of transcription pathways. DCP stimulates HCC invasion through activation of matrix metalloproteinase via upregulation of extracellular signal-regulated kinase-mitogen-activated protein kinase (MAPK) pathway. DCP stimulates HCC angiogenesis through activation of the DCP-kinase insert domain receptor-phospholipaseC-γ-MAPK pathway. Identification of these pathways is important for designing the therapeutic strategy for HCC.

Identification of the anaplastic lymphoma kinase (ALK) gene has refined the classification of non‐small cell lung cancer (NSCLC) and promoted research on molecularly targeted drugs such as crizotinib, an ALK inhibitor with good efficacy, in ALK‐rearranged NSCLC. At present, few studies have reported the efficacy of crizotinib in patients with ALK‐rearranged NSCLC with brain metastases. In a patient with NSCLC harboring ALK‐rearrangement who had brain metastases and poor performance status (PS), we obtained a durable response with crizotinib administered following multi‐line chemotherapy regimens.

// Ye Li 1, * , Shu-Xiang Cui 2, * , Shi-Yue Sun 3 , Wen-Na Shi 3 , Zhi-Yu Song 3 , Shu-Qing Wang 3 , Xin-Feng Yu 3 , Zu-Hua Gao 4 , Xian-Jun Qu 3 1 Department of Pharmacology, School of Chemical Biology & Pharmaceutical Sciences, Capital Medical University, Beijing, China 2 Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China 3 Department of Pharmacology, Capital Medical University School of Basic Medical Sciences, Beijing, China 4 Department of Pathology, McGill University, Montreal, Quebec, Canada * These authors have contributed equally to this work Correspondence to: Xian-Jun Qu, email: quxj@ccmu.edu.cn Zu-Hua Gao, email: zu-hua.gao@mcgill.ca Keywords: myricetin, APC Min/+ mouse model, intestinal adenomatous polyps, Wnt/β-catenin pathway, chronic inflammation Received: December 22, 2015 Accepted: July 26, 2016 Published: August 06, 2016 ABSTRACT Myricetin is a natural dietary flavonoid compound. We evaluated the efficacy of myricetin against intestinal tumorigenesis in adenomatous polyposis coli multiple intestinal neoplasia ( APC Min/+ ) mice. Myricetin was given orally once a day for 12 consecutive weeks. APC Min/+ mice fed with myricetin developed fewer and smaller polyps without any adverse effects. Histopathological analysis showed a decreased number of dysplastic cells and degree of dysplasia in each polyp. Immunohistochemical and western blot analysis revealed that myricetin selectively inhibits cell proliferation and induces apoptosis in adenomatous polyps. The effects of myricetin were associated with a modulation the GSK-3β and Wnt/β-catenin pathways. ELISA analysis showed a reduced concentration of pro-inflammatory cytokines IL-6 and PGE2 in blood, which were elevated in APC Min/+ mice. The effect of myricetin treatment was more prominent in the adenomatous polyps originating in the colon. Further studies showed that myricetin downregulates the phosphorylated p38 MAPK/Akt/mTOR signaling pathways, which may be the mechanisms for the inhibition of adenomatous polyps by myricetin. Taken together, our data show that myricetin inhibits intestinal tumorigenesis through a collection of biological activities. Given these results, we suggest that myricetin could be used preventatively to reduce the risk of developing colon cancers.

// Shu-Xiang Cui 1 , Wen-Na Shi 2 , Zhi-Yu Song 2 , Shu-Qing Wang 2 , Xin-Feng Yu 2 , Zu-Hua Gao 3 , Xian-Jun Qu 2 1 Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China 2 Department of Pharmacology, Capital Medical University School of Basic Medical Sciences, Beijing, China 3 Department of Pathology, McGill University, Montreal, Quebec, Canada Correspondence to: Xian-Jun Qu, e-mail: quxj@ccmu.edu.cn Zu-Hua Gao, e-mail: zu-hua.gao@mcgill.ca Keywords: human hepatocellular carcinoma (HCC), Sorafenib, des-gamma-carboxy prothrombin (DCP), Ras/Raf/MEK/ERK cascade, Ras/PI3K/Akt/mTOR cascade Received: November 13, 2015 Accepted: April 23, 2016 Published: May 4, 2016 ABSTRACT Despite significant progress, advanced hepatocellular carcinoma (HCC) remains an incurable disease, and the overall efficacy of targeted therapy by Sorafenib remains moderate. We hypothesized that DCP (des-gamma-carboxy prothrombin), a prothrombin precursor produced in HCC, might be one of the reasons linked to the low efficacy of Sorafenib. We evaluated the efficacy of Sorafenib in HLE and SK-Hep cells, both of which are known DCP-negative HCC cell lines. In the absence of DCP, Sorafenib effectively inhibited the growth of HCC and induced cancer cell apoptosis. In the presence of DCP, HCC was resistant to Sorafenib-induced inhibition and apoptosis, as determined by in vitro assays and in mice xenografted with HLE cells. Molecular analysis of HLE xenografted-nude mice showed that DCP activates the transduction of the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR cascades. DCP might stimulate the formation of compensatory feedback loops in the intricately connected signaling pathways when kinases are targeted by Sorafenib. Our results indicate that DCP antagonizes the inhibitory effects of Sorafenib on HCC through activation of the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR signaling pathways. Taken together, our findings define a DCP-mediated mechanism of inhibition of Sorafenib in HCC, which is critical for targeting therapy in advanced HCC.

Carbapenem resistance mechanisms were investigated in 32 imipenem-resistant Pseudomonas aeruginosa clinical isolates recovered from hospitalised children. Sequence analysis revealed that 31 of the isolates had an insertion sequence element ISRP10 disrupting the porin gene oprD, demonstrating that ISRP10 inactivation of oprD conferred imipenem resistance in the majority of the isolates. Multilocus sequence typing (MLST) was used to discriminate the isolates. In total, 11 sequence types (STs) were identified including 3 novel STs, and 68.3% (28/41) of the tested strains were characterised as clone ST253. In combination with random amplified polymorphic DNA (RAPD) analysis, the imipenem-resistant isolates displayed a relatively high degree of genetic variability and were unlikely associated with nosocomial infections.

Although a mountain of papers have showed that metformin plays a role in inhibiting cancers, but the mechanism underpinning this has not yet fully elucidated. Herein, we used AOM/DSS model, the clinicopathological features are similar to those found in humans, to investigate the effects of metformin as well as combination with 5-FU in the prevention of colitis and colitis associated cancer (CAC). Oral metformin significantly inhibited DSS-induced ulcerative colitis and AOM/DSS-induced CAC. Metformin also ameliorated 5-FU-induced colorectal gastrointestinal symptoms in mice. Metformin combination with 5-FU strongly inhibited colorectal cancer. Metformin reduced levels of the NFκB signaling components p-IKKα/β, p-NFκB, p-IκBα in colorectal mucosal cells. Transmission electron microscopy analysis suggested that the inhibition of metformin on colitis and CAC might associate with its biological activity of protecting mitochondrial structures of colorectal epithelial cells. Further analysis by Mito Tracker Red staining assay indicated that metformin prevented H(2)O(2)-induced mitochondrial fission correlated with a decrease of mitochondrial perimeter. In addition, metformin increased the level of NDUFA9, a Q-module subunit required for complex I assembly, in colorectal epithelial cells. These observations of metformin in the inhibition of colitis and CAC might associate with its activity of activating the LKB1/AMPK pathway in colorectal epithelial cells. In conclusion, metformin inhibited colitis and CAC through protecting the mitochondrial structures of colorectal epithelial cells.

The present study explored a suitable parthenogenetic activation (PA) procedure for rabbit oocytes and investigated the developmental potential of somatic cell nuclear transfer (SCNT) embryos using rabbit foetal fibroblasts (RFFs). The electrical activation had the optimal rate of blastocyst (14.06%) when oocytes were activated by three direct current (DC) pulses (40 V/mm, 20 μs each) followed by 6-dimethylaminopurine (6-DMAP) and cycloheximide (CHX) treatment; the blastocyst rate of ionomycin (ION) + 6-DMAP + CHX (12.07%) activation was higher than that of ION + 6-DMAP (8.6%) activation or ION + CHX (1.24%) activation; there was no significant difference in blastocyst rate between ION + 6-DMAP + CHX and DC + 6-DMAP + CHX groups. The blastocyst rate of ION + 6-DMAP + CHX-activated oocytes in the basic rabbit culture medium (M-199) + 10% foetal bovine serum (FBS; 14.28%) was higher than that in buffalo conditioned medium (5.75%) or G1/G2 medium (0), and the blastocyst rate was increased when M-199 + 10% FBS was supplemented with amino acids. Refreshing culture medium every day or every other day significantly increased the blastocyst rate. Treatment of donor cells with 0.5% FBS for 3-5 days increased blastocyst rate of SCNT embryos (33.33%) than no serum starvation (22.47%) or 0.5% FBS treatment for 6-9 days (23.61%); the blastocyst rate of SCNT embryos derived from nontransgenic RFFs was higher than that derived from transgenic RFFs by electroporation. The blastocyst development ability of SCNT embryos derived from RFFs by electroporation (32.22%) was higher than that of liposome (19.11%) or calcium phosphate (20.00%) transfection, and only the embryos from electroporation group have the EGFP expression (24.44%). In conclusion, this study for the first time systematically optimized the conditions for yield of rabbit embryo by SCNT.

The Fas receptor/ligand system plays a prominent role in hepatic apoptosis and hepatocyte death. Although hepatitis B virus (HBV) surface Ag (HBsAg) is the most abundant HBV protein in the liver and peripheral blood of patients with chronic HBV infection, its role in Fas-mediated hepatocyte apoptosis has not been disclosed. In this study, we report that HBsAg sensitizes HepG2 cells to agonistic anti-Fas Ab CH11-induced apoptosis through increasing the formation of SDS-stable Fas aggregation and procaspase-8 cleavage but decreasing both the expression of cellular FLIPL/S and the recruitment of FLIPL/S at the death-inducing signaling complex (DISC). Notably, HBsAg increased endoplasmic reticulum stress and consequently reduced AKT phosphorylation by deactivation of phosphoinositide-dependent kinase-1 (PDPK1) and mechanistic target of rapamycin complex 2 (mTORC2), leading to enhancement of Fas-mediated apoptosis. In a mouse model, expression of HBsAg in mice injected with recombinant adenovirus-associated virus 8 aggravated Jo2-induced acute liver failure, which could be effectively attenuated by the AKT activator SC79. Based on these results, it is concluded that HBsAg predisposes hepatocytes to Fas-mediated apoptosis and mice to acute liver failure via suppression of AKT prosurviving activity, suggesting that interventions directed at enhancing the activation or functional activity of AKT may be of therapeutic value in Fas-mediated progressive liver cell injury and liver diseases.

Chronic gut inflammation disposes to an increased risk of colitis-associated cancer. Chemoprevention is an attractive complementary strategy. We aimed to evaluate the chemopreventive effects of M10, a novel derivative of Myricetin, in the murine azoxymethane/dextran sodium sulfate model. Oral administration of M10 at 50-100 mg/kg once a day for consecutive 12 weeks significantly prevented ulcerative colitis (UC) and colorectal tumor. Pathological analysis of intestines showed that M10 reduced the degree of chronic inflammation and prevented the progression of colorectal tumorigenesis. Flow cytometry analysis of the immunocytes isolated from intraepithelial and lamina propria showed that M10 prevented the infiltration of myeloid-derived suppressor cells and increased CD8+T and CD4+T cells in colorectal tissues. Enzyme-linked immunosorbent analysis revealed the reduction of pro-inflammatory mediators granulocyte-macrophage colony-stimulating factor/macrophage colony-stimulating factor, IL-6 and TNF-α in colonic mucosa. Western blot assay also showed M10 prevention of the NF-κB/IL-6/STAT3 pathways and the biomarkers of inflammation and colorectal tumorigenesis. Electron microscopy analysis revealed that M10 prevent robust endoplasmic reticulum (ER) stress-induced autophagy in inflamed colonic mucosal cells. In conclusion, oral administration of Myricetin derivative M10 exerts chemoprevention of UC and colorectal tumor in mice. The mechanism of chemoprevention is associated with the reduction of biomarkers of chronic inflammation and proliferation through attenuating robust ER stress in inflamed colonic mucosal cells. M10 exerts chemoprevention activity without evidence of toxicity in mice. These results justify further evaluation of M10 in clinical trials. M10 could develop a promising regimen in the chemoprevention of colitis and colorectal cancer.