Sorafenib Resistance Contributed by IL7 and MAL2 in Hepatocellular Carcinoma Can Be Overcome by Autophagy-Inducing Stapled Peptides.

Drug resistance poses a great challenge in systemic therapy for hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms associated with resistance to anti-cancer drugs, such as Sorafenib, remain unclear. In this study, we use transposon insertional mutagenesis to generate Sorafenib-resistant HCC cell lines in order to identify potential drug resistant causative genes. Interleukin 7 (IL7) and mal, T cell differentiation protein 2 (MAL2) were identified as candidate genes that promote survival by activating JAK/STAT and PI3K/AKT signaling pathways. Sorafenib-resistant cells exhibited higher clonogenic survival and lower drug sensitivity due to IL7 and MAL2 upregulation. Higher anti-apoptotic effect, clonogenic survival and increased PI3K/AKT/STAT3 activities were observed in IL7 and MAL2 co-overexpressing cells compared with controls or cells overexpressing IL7 or MAL2 individually. Given the critical role of MAL2 in endocytosis, we propose that MAL2 might facilitate the endocytic trafficking of IL7 and its cognate receptors to the plasma membrane, which leads to upregulated JAK/STAT and PI3K/AKT signaling pathways and Sorafenib resistance. Additionally, our previous studies showed that an autophagy-inducing stapled peptide promoted the endolysosomal degradation of c-MET oncogene and overcame adaptive Sorafenib resistance in c-MET+ HCC cells. In this study, we demonstrate that these stapled peptides readily induced autophagy and inhibited the proliferation of both wild-type and Sorafenib-resistant HCC cells co-overexpressing both IL7 and MAL2. Furthermore, these peptides showed synergistic cytotoxicity with Sorafenib in drug-resistant HCC cells co-overexpressing both IL7 and MAL2. Our studies suggest that targeting autophagy may be a novel strategy to overcome IL7/MAL2-mediated Sorafenib resistance in HCC.

Transposon delivery for CRISPR-based loss-of-function screen in mice identifies NF2 as a cooperating gene involved with the canonical WNT signaling molecular class of hepatocellular carcinoma.

Various molecular subclasses of hepatocellular carcinoma (HCC) exists, with many novel cooperating oncogenes and tumor suppressor genes involved in its tumorigenesis. The emerging importance of WNT signaling in HCC has been established. However, the intricate genetic mechanisms involved in this complex signaling pathway remains to be elucidated. Importantly, while some cooperating genes have been identified, there are still many unknown genes associated with catenin beta 1 (CTNNB1)-induced HCC. Mutations in both oncogenes and tumor suppressor genes are required for HCC tumorigenesis. The emergence of the CRISPR/Cas9 system has allowed researchers now to target both alleles efficiently. In this novel study, the Sleeping Beauty transposon system was used as a gene delivery system in vivo to stably integrate an expression cassette that carry pools of gRNAs and overexpress a mutant version of CTNNB1 into the hepatocyte genome. We identified 206 candidate genes that drive HCC tumorigenesis in the context of WNT signaling activation and, neurofibromin 2 (NF2) gene, a known tumor suppressor gene with clinical relevance was validated in this proof-of-principle study.

[Effects and mechanism of p53 gene deletion on energy metabolism during the pluripotent transformation of spermatogonial stem cells].

Previous studies have shown that long-term spermatogonial stem cells (SSCs) have the potential to spontaneously transform into pluripotent stem cells, which is speculated to be related to the tumorigenesis of testicular germ cells, especially when p53 is deficient in SSCs which shows a significant increase in the spontaneous transformation efficiency. Energy metabolism has been proved to be strongly associated with the maintenance and acquisition of pluripotency. Recently, we compared the difference in chromatin accessibility and gene expression profiles between wild-type (p53+/+) and p53 deficient (p53-/-) mouse SSCs using the Assay for Targeting Accessible-Chromatin with high-throughput sequencing (ATAC-seq) and transcriptome sequencing (RNA-seq) techniques, and revealed that SMAD3 is a key transcription factor in the transformation of SSCs into pluripotent cells. In addition, we also observed significant changes in the expression levels of many genes related to energy metabolism after p53 deletion. To further reveal the role of p53 in the regulation of pluripotency and energy metabolism, this paper explored the effects and mechanism of p53 deletion on energy metabolism during the pluripotent transformation of SSCs. The results of ATAC-seq and RNA-seq from p53+/+ and p53-/- SSCs revealed that gene chromatin accessibility related to positive regulation of glycolysis and electron transfer and ATP synthesis was increased, and the transcription levels of genes encoding key glycolytic enzymes and regulating electron transport-related enzymes were markedly increased. Furthermore, transcription factors SMAD3 and SMAD4 promoted glycolysis and energy homeostasis by binding to the chromatin of the Prkag2 gene which encodes the AMPK subunit. These results suggest that p53 deficiency activates the key enzyme genes of glycolysis in SSCs and enhances the chromatin accessibility of genes associated with glycolysis activation to improve glycolysis activity and promote transformation to pluripotency. Moreover, SMAD3/SMAD4-mediated transcription of the Prkag2 gene ensures the energy demand of cells in the process of pluripotency transformation and maintains cell energy homeostasis by promoting AMPK activity. These results shed light on the importance of the crosstalk between energy metabolism and stem cell pluripotency transformation, which might be helpful for clinical research of gonadal tumors.

Edible HIPE-Gels and oleogels formed by synergistically combining natural triterpenoid saponin and citrus dietary fiber.

High-internal-phase emulsion gels (HIPE-Gels) and oleogels were successfully fabricated through synergistically combination of natural triterpenoid Quillaja saponin (QS) and citrus dietary fiber (CDF). The amphiphilic QS significantly lowered the oil-water interface tension; whereas CDF could form compact structure at the interface as well as in the bulk under a hydrogen-bonding interaction with saponin. The combination endowed the emulsion gels with enhanced performance, such as decreasing droplet size, strengthening gel network structure and better viscoelastic. At a very low QS of 0.045 %, stable HIPE-Gels can be produced with 0.3 % CDF, which mainly attributing to the highly viscoelastic fiber networks in continuous phase and thus actively trap the QS-coated emulsion droplets. Consequently, the robust HIPE-Gels were applied as soft template to fabricate oleogels with controlled by QS and CDF loading. These findings proved an effective strategy towards structuring edible liquid oil into healthy gels for alternating saturated and trans fats in foods.

Preparation and identification of an antioxidant peptide from wheat embryo albumin and characterization of its Maillard reaction products.

Wheat embryo albumin (WEA) extracted from wheat embryo possesses multiple effects including antioxidant, anti-inflammatory, and immunoregulatory effects. In this study, a single factor experiment was conducted to determine the optimal enzymolysis conditions of WEA. Five components (F1-F5) were obtained via ultrafiltration, among which F3 (molecular weight 3-5 kDa) displayed the best antioxidant activity. WEA and F3 were characterized by transmission electron microscopy, scanning electron microscopy, circular dichroism spectrum analysis, and amino acid composition tests. Results revealed that F3 significantly increased the contents of ß-tablets, aromatic amino acids, and hydrophobic amino acids compared to WEA. LC-MS/MS analysis demonstrated that F3 had more tyrosine and histidine moieties than WEA. Moreover, analysis of the Maillard reaction products (MRPs) showed that F3-MRPs had strong browning strength, ultraviolet absorption, higher number of free amino acids, and umami amino acid ratio compared with WEA. In conclusion, enzymolysis can improve the functional properties of WEA, which broadens the application spectrum of WEA in food and pharmaceutical fields. PRACTICAL APPLICATION: This study provides a new approach for identifying potential antioxidants and developing functional foods from WEA, and broadens the application spectrum of wheat germ resources.

Systematic comparison of structural and lipid oxidation in oil-in-water and water-in-oil biphasic emulgels: effect of emulsion type, oil-phase composition, and oil fraction.

BACKGROUND: Because many common foods are emulsions (mayonnaise, margarine, salad dressing, etc.), a better understanding of lipid oxidation is crucial for the formulation, production, and storage of the relevant consumer products. We prepared oil-in-water (O/W) and water-in-oil (W/O) emulgels, and their architecture was characterized before monitoring lipid oxidation under thermally accelerated conditions to systematically compare the effect of emulsion type, oil composition, and oil fraction on the structure and lipid oxidation in thee biphasic emulgel systems. RESULTS: Higher susceptibility of lipids to oxidation (>2.5 times) was observed in the biphasic O/W and W/O emulgels than in soybean oil owing to an interfacial region. In the heterogeneous emulsion systems, W/O emulgels had oxidation resistance than O/W emulgels did. Compared with the oil-phase composition of high oleic sunflower, soybean, and flaxseed oils, oxidation sensitivity of emulsified lipids was significantly raised as the degree of unsaturation increased from 100.72 to 203.07. Moreover, increasing oil fraction from 75% to 85% led to an obvious increase in total oxidation in O/W emulgels but a decrease in W/O emulgels. In addition to emulsion size and oil unsaturation, viscoelasticity had a remarkable effect on the low-unsaturated oil oxidation (e.g. high oleic sunflower oil). CONCLUSION: Physical and structural phenomena played important roles in lipid oxidation based on a mass transport principle. These findings provide novel information for designing the structures of emulsion gels for controlling lipid oxidation through the cooperation of both formulation and architecture principles. © 2022 Society of Chemical Industry.

Structuring of Edible Liquid Oil into Smart Thermo-Triggered Soft Matters for Controlled Bioactive Delivery.

Growing interest is being dedicated to smart soft matters because of their potential in controlling bioactives upon exposure to an appropriate stimulus. Herein, structuring of edible liquid oil into oleogels and emulgels as smart thermo-triggered soft vehicles for controllable release of diverse nutrients was developed. Edible liquid oil was trapped inside the crystal network structure of phytosterols and monoglycerides resulting in bicomponent solidlike oleogels. Subsequently, both water-in-oleogel (W/O) emulgels and glycerol-in-oleogel (G/O) emulgels were further fabricated by spatial distribution of the stabilizing interfacial crystals around dispersed droplets as well as the network crystals in the continuous phase. Rheological measurements showed that the gel strength of the oleogel-based emulgels depends on the fraction of the aqueous phase and is greater than that of corresponding oleogels due to a filler effect of dispersed aqueous droplets within the crystal network, offering an additional strategy to tune the structure and rheology. Comparatively, introducing glycerol endowed a higher gel strength for the oleogel-based emulgels than water, particularly at increased filler loads. In addition, these soft matters exhibited interesting thermoresponsive nature, which exhibit the flexibility for programmed release of coencapsulated bioactive components upon exposure to an appropriate thermal triggered switchable. The resulted smart thermo-triggered soft matters have emerging opportunities for application in functional active ingredient delivery by on-demand strategies.

Identification of FAM107A as a potential biomarker and therapeutic target for prostate carcinoma.

FAM107A may have a dual role in regulating the biological functions of tumors; however, its role in prostate adenocarcinoma (PRAD) remains unknown. We analyzed FAM107A expression by employing databases to clarify its potential prognostic value for PRAD, as well as its role in the pathogenesis of PRAD. We observed that the FAM107A expression level is decreased in PRAD, and the reduced expression is considerably associated with poor overall survival and progression-free survival (PFS). To explore the mechanism of FAN107A in PRAD, we performed an immune cell infiltration analysis and a gene set enrichment analysis. The results showed that FAM107A expression is positively related to mast cells and natural killer cells. The Wnt signaling pathway, the MAPK signaling pathway, and the immune responses are differentially enriched in the FAM107A high-expression phenotype. The FAM107A low-expression phenotype is linked to apoptosis-induced DNA fragmentation and DNA methylation in PRAD. To assess the relationship between the clinical features and the FAM107A expression, we performed a logistic regression analysis and observed that a decreased FAM107A expression is associated with poor prognostic features, including the T stage, the N stage, the Gleason score, residual tumors, and the TP53 status. Our multivariate Cox regression results showed that the Gleason score, the primary therapy outcome, and the FAM107A expression are independent prognostic factors in PFS. In summary, we consider FAM107A an independent risk factor for PFS in PRAD. Moreover, several pathways may reveal the role of FAM107A in triggering carcinogenesis. These discoveries provide novel perspectives for future research to elucidate the pathogenic mechanism underlying PRAD.

Wheat embryo globulin nutrients ameliorate d-galactose and aluminum chloride-induced cognitive impairment in rats.

Wheat embryo globulin nutrient (WEGN), with wheat embryo globulin (WEG) as the main functional component, is a nutritional combination that specifically targets memory impairment. In this study, we explored the protective role of WEGN on Alzheimer's disease (AD)-triggered cognitive impairment, neuronal injury, oxidative stress, and acetylcholine system disorder. Specifically, we established an AD model via administration of d-galactose (d-gal) and Aluminum chloride (AlCl3) for 70 days, then on the 36th day, administered animals in the donepezil and WEGN (300, 600, and 900 mg/kg) groups with drugs by gavage for 35 days. Learning and memory ability of the treated rats was tested using the Morris water maze (MWM) and novel object recognition (NOR) test, while pathological changes and neuronal death in their hippocampus CA1 were detected via HE staining and Nissl staining. Moreover, we determined antioxidant enzymes by measuring levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in serum, cortex, and hippocampus, whereas changes in the acetylcholine system were determined by evaluating choline acetyltransferase (ChAT), and acetylcholinesterase (AChE) activities, as well as choline acetylcholine (Ach) content. Results revealed that rats in the WEGN group exhibited significantly lower escape latency, as well as a significantly higher number of targeted crossings and longer residence times in the target quadrant, relative to those in the model group. Notably, rats in the WEGN group spent more time exploring new objects and exhibited lower damage to their hippocampus neuron, had improved learning and memory activity, as well as reversed histological alterations, relative to those in the model group. Meanwhile, biochemical examinations revealed that rats in the WEGN group had significantly lower MDA levels and AChE activities, but significantly higher GSH, SOD, and ChAT activities, as well as Ach content, relative to those in the model group. Overall, these findings indicate that WEGN exerts protective effects on cognitive impairment, neuronal damage, oxidative stress, and choline function in AD rats treated by d-gal/AlCl3.

Natural flavone tricin exerted anti-inflammatory activity in macrophage via NF-κB pathway and ameliorated acute colitis in mice.

BACKGROUND: Ulcerative colitis is a subtype of inflammatory bowel disease, characterized by relapsing inflammation in the gastrointestinal tract with limited treatment options. Previous studies suggested that the natural compound tricin, a flavone isolated from rice bran, could suppress chemically-induced colitis in mice, while our recent study also demonstrated the anti-metastatic effect of tricin in colon tumor-bearing mice. HYPOTHESIS/PURPOSE: Here we further investigated the underlying mechanism of the inhibitory effects of tricin on lipopolysaccharides-activated macrophage RAW264.7 cells and explored the efficacy of tricin in acute colitis mouse model induced by 4.5% dextran sulfate sodium (DSS) for 7 days. METHODS: Tricin (75, 100, and 150 mg/kg) or the positive control drug sulfasalazine (200 mg/kg) were orally administered to mice for 7 days. Stool consistency scores, stool blood scores, and body weight were recorded daily. Disease activity index (DAI) was examined on day 7, and colon tissues were collected for biochemical analyses. The fecal microbiome of colitis mice after tricin treatment was characterized for the first time in this study using 16S rDNA amplicon sequencing. RESULTS: Results showed that tricin (50 µM) remarkably reduced nitric oxide production in lipopolysaccharides-activated RAW264.7 cells and the anti-inflammatory activity of tricin was shown to act through the NF-κB pathway. Besides, tricin treatment at 150 mg/kg significantly reversed colon length reduction, reduced myeloperoxidase activities and DAI scores, as well as restored the elevated myeloid-derived suppressive cells population in acute colitis mice. The influence from DSS on gut microbiota, such as the increased population of Proteobacteria phylum and Ruminococcaceae family, was shown to be relieved after tricin treatment. CONCLUSION: Our present study firstly demonstrated that tricin ameliorated acute colitis by improving colonic inflammation and modulating gut microbiota profile, which supports the potential therapeutic use of tricin for colitis treatment.

[Effect of electroacupuncture on neurovascular unit and Wnt/ß-catenin signaling in rats with cerebral ischemia].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Baihui" (GV20), "Shuigou" (GV26), etc. on the expressions of vascular endothelial growth factor (VEGF), collagen fibrillary acidic protein (GFAP), neuronal nucleus antigen(NeuN), ß-catenin and Axin2 protein and mRNA in rats with cerebral ischemia (CI), so as to explore its mechanism underlying improvement of ischemic stroke. METHODS: A total of 108 male SD rats were randomly divided into control, model and EA groups, which were further divided into 7 d, 14 d and 21 d subgroups, with 12 rats in each group. The CI model was established by occlusion of the middle cerebral artery. EA (2 Hz/100 Hz, 2-4 V) was applied to GV20, GV26, bilateral "Sanyinjiao" (SP6) and bilateral "Neiguan" (PC6) for 30 min, once daily (except Sundays) for 21 days at most. The neurological deficit score was evaluated according to Longa's methods. The cerebral infarction state was assessed by using a magnetic resonance T2 imaging system. The expression levels of neurovascular markers as VEGF,GFAP and NeuN, and ß-catenin and Axin2 protein and mRNA in the ischemic brain tissue were detected by using immunohistochemistry and quantitative real-time PCR, respectively. RESULTS: After modeling, the neurological deficit score and cerebral infarction size were significantly increased (P<0.01), and the expression of NeuN and Axin2 proteins and mRNAs were significantly and gradually decreased with time (day 7, 14 and 21) (P<0.01), whereas the expression levels of VEGF, GFAP, ß-catenin proteins and mRNAs were significantly increased on day 7, 14 and 21 in the model group relevant to the control group (P<0.01). Compared with the model group, the neurological deficit score, cerebral infarction size and the expressions of Axin2 protein and mRNA were significantly decreased on day 7, 14 and 21 (P<0.01), whereas the expression levels of VEGF, GFAP and NeuN and ß-catenin proteins and mRNAs were considerably up-regulated in the EA group on day 7, 14 and 21 (P<0.01). CONCLUSION: EA can protect the neurovascular units from injury, reduce the volume of cerebral infarction and improve the symptoms of neurological deficit in cerebral ischemic rats, which may be related to its effects in up-regulating ß-catenin expression and in down-regulating Axin2 expression to further activate classical Wnt/ ß-catenin signal pathway.

Towards the understanding of hyperthermophilic methanogenesis from waste activated sludge at 70 °C: Performance, stability, kinetic and microbial community analyses.

Anaerobic digestion is promising for waste activated sludge (WAS) degradation. However, conventional processes were generally stuck with limited hydrolysis and poor pathogen destruction. Hyperthermophilic digestion at 70 °C has drawn attention in overcoming those issues at a relatively low energy requirement and operating difficulties. In order to illuminate its operation characteristics, a single-stage hyperthermophilic digester was controlled at 70 °C and operated continuously to degrade WAS. 88.7 mL/g VSadded of methane yield could be achieved in the hyperthermophilic system, fourfold higher than that in the mesophilic system. Kinetic analysis revealed that hyperthermophilic digestion was advantageous in converting the non-degradable fraction. Consequently, hydrolysis under the hyperthermophilic condition was able to be significantly improved. Above 10 d was necessary for the hyperthermophilic system to gain such a high methane production. In the case of stability, the organic loading of higher than 10.2 g VS/L/d resulted in increasing limitation from methanogenesis and accumulation of propionic, butyric and valeric acids. In addition to the dominant acetoclastic genus Methanothrix for methane production in the hyperthermophilic system, two hydrogenotrophic methanogens Methanospirillum and Methanothermobacter reached 18.84% and 8.31%, respectively. The genus Coprothermobacter, affiliated with the phylum Firmicutes, made more contribution to protein hydrolysis in the hyperthermophilic digester.

ZBTB20 regulates WNT/CTNNB1 signalling pathway by suppressing PPARG during hepatocellular carcinoma tumourigenesis.

BACKGROUND & AIMS: Zinc finger and BTB domain containing 20 (ZBTB20) has been implicated as a potential oncogene in liver cancer. However, knockout studies have shown it to be a transcriptional repressor of the alpha-foetoprotein (Afp) gene in adult liver, and reduced levels of ZBTB20 allow for upregulation of AFP with increased tumour severity in certain cases of hepatocellular carcinoma (HCC). As there are many discrepancies in the literature regarding its role in liver tumourigenesis, the aim of this study was to elucidate the role of ZBTB20 in HCC tumourigenesis. METHODS: A reverse genetic study using the Sleeping Beauty (SB) transposon system in mice was performed to elucidate the role of ZBTB20 in HCC tumourigenesis. In vitro ZBTB20 gain- and loss-of-function experiments were used to assess the relationship amongst ZBTB20, peroxisome proliferator activated receptor gamma (PPARG) and catenin beta 1 (CTNNB1). RESULTS: Transgenic overexpression of ZBTB20 in hepatocytes and in the context of transformation related protein (T r p53) inactivation induced hepatic hypertrophy, activation of WNT/CTNNB1 signalling, and development of liver tumours. In vitro overexpression and knockout experiments using CRISPR/Cas9 demonstrated the important role for ZBTB20 in downregulating PPARG, resulting in activation of the WNT/CTNNB1 signalling pathway and its downstream effectors in HCC tumourigenesis. CONCLUSIONS: These findings demonstrate a novel interaction between ZBTB20 and PPARG, which leads to activation of the WNT/CTNNB1 signalling pathway in HCC tumourigenesis. LAY SUMMARY: ZBTB20 has been implicated as a potential oncogene in liver cancer. Herein, we uncover its important role in liver cancer development. We show that it interacts with PPARG to upregulate the WNT/CTNNB1 signalling pathway, leading to tumourigenesis.

Autophagy-dependent removal of α-synuclein: a novel mechanism of GM1 ganglioside neuroprotection against Parkinson's disease.

GM1 ganglioside is particularly abundant in the mammalian central nervous system and has shown beneficial effects on neurodegenerative diseases. In this study, we investigated the therapeutic effect of GM1 ganglioside in experimental models of Parkinson's disease (PD) in vivo and in vitro. Mice were injected with MPTP (30 mg·kg-1·d-1, i.p.) for 5 days, resulting in a subacute model of PD. PD mice were treated with GM1 ganglioside (25, 50 mg·kg-1·d-1, i.p.) for 2 weeks. We showed that GM1 ganglioside administration substantially improved the MPTP-induced behavioral disturbance and increased the levels of dopamine and its metabolites in the striatal tissues. In the MPP+-treated SH-SY5Y cells and α-synuclein (α-Syn) A53T-overexpressing PC12 (PC12α-Syn A53T) cells, treatment with GM1 ganglioside (40 µM) significantly decreased α-Syn accumulation and alleviated mitochondrial dysfunction and oxidative stress. We further revealed that treatment with GM1 ganglioside promoted autophagy, evidenced by the autophagosomes that appeared in the substantia nigra of PD mice as well as the changes of autophagy-related proteins (LC3-II and p62) in the MPP+-treated SH-SY5Y cells. Cotreatment with the autophagy inhibitor 3-MA or bafilomycin A1 abrogated the in vivo and in vitro neuroprotective effects of GM1 ganglioside. Using GM1 ganglioside labeled with FITC fluorescent, we observed apparent colocalization of GM1-FITC and α-Syn as well as GM1-FITC and LC3 in PC12α-Syn A53T cells. GM1 ganglioside significantly increased the phosphorylation of autophagy regulatory proteins ATG13 and ULK1 in doxycycline-treated PC12α-Syn A53T cells and the MPP+-treated SH-SY5Y cells, which was inhibited by 3-MA. Taken together, this study demonstrates that the anti-PD role of GM1 ganglioside resulted from activation of autophagy-dependent α-Syn clearance.

Synthesis of oleanolic acid analogues targeting PDGF receptor inhibitors and their antitumor biological activities.

The PDGF receptor is mock-coupled with a known active compound, and 14 novel skeleton candidate compounds were designed and synthesized. The structure was confirmed by 1H NMR, 13C NMR and MS. The in vitro cytotoxicity of the two cancer cell lines (SGC-7901 and A549) was evaluated by MTT assay. PDGF receptor protein inhibition assays were performed on I6 and II4 using fluorescence polarization immunoassay (FPIA). [Formula: see text].

Integrated Analyses of Mouse Stem Cell Transcriptomes Provide Clues for Stem Cell Maintenance and Transdifferentiation.

In vivo cell fate reprogramming has emerged as a new method for understanding cell plasticity and as potential treatment for tissue regeneration. Highly efficient and precise reprogramming requires fully understanding of the transcriptomes which function within different cell types. Here, we adopt weighted gene co-expression network analysis (WGCNA) to explore the molecular mechanisms of self-renewal in several well-known stem cell types, including embryonic stem cells (ESC), primordial germ cells (PGC), spermatogonia stem cells (SSC), neural stem cells (NSC), mesenchymal stem cells (MSC), and hematopoietic stem cells (HSC). We identified 37 core genes that were up-regulated in all of the stem cell types examined, as well as stem cell correlated gene co-expression networks. The validation of the co-expression genes revealed a continued protein-protein interaction network that included 823 nodes and 3113 edges. Based on the topology, we identified six densely connected regions within the continued protein-protein interaction network. The SSC specific genes Itgam, Cxcr6, and Agtr2 bridged four densely connected regions that consisted primarily of HSC-, NSC-, and MSC-correlated genes. The expression levels of identified stem cell related transcription factors were confirmed consistent with bioinformatics prediction in ESCs and NSCs by qPCR. Exploring the mechanisms underlying adult stem cell self-renewal will aid in the understanding of stem cell pool maintenance and will promote more accurate and efficient strategies for tissue regeneration and repair.

A Natural Flavone Tricin from Grains Can Alleviate Tumor Growth and Lung Metastasis in Colorectal Tumor Mice.

Tricin, a flavone isolated from rice bran, has been shown to be chemopreventive in a colorectal cancer (CRC) mouse model. This study aimed to illustrate the inhibitory activities of tricin in colon cancer cells and in a metastatic CRC mouse model. BALB/c mice injected with mouse Colon26-Luc cells into the rectum wall were treated with tricin (37.5 mg/kg) daily for 18 days. Orthotopic colon tumor growth and metastasis to lungs were assessed by in vivo bioluminescence imaging. Results showed that tricin suppressed Colon-Luc cells motility and downregulated phosphorylated Akt, Erk1/2 and NF-κB expressions of human colon cancer HT-29 cells. While tricin treatment suppressed tumor growth and lung metastasis as well as altered the populations of myeloid-derived suppressor cells and regulatory T cells in spleens. In summary, the tumor microenvironment modulatory and anti-metastatic effects of tricin in colon cancer mouse model were shown for the first time, suggesting the potential development of tricin-containing food supplements for CRC patients.

Schwann cell-specific Pten inactivation reveals essential role of the sympathetic nervous system activity in adipose tissue development.

There is increasing evidence that the sympathetic nervous system (SNS) plays an important role in adipose tissue development. However, the underlying molecular mechanism(s) associated with this remains unclear. SNS innervation of white adipose tissue (WAT) is believed to be necessary and sufficient to elicit WAT lipolysis. In this current study, mice with Schwann cell (SC)-specific inactivation of phosphatase and tensin homolog (Pten) displayed enlarged inguinal white adipose tissue (iWAT). This serendipitous observation implicates the role of SCs in mediating SNS activity associated with mouse adipose tissue development. Mice with SC-specific Pten inactivation displayed enlarged iWAT. Interestingly, the SNS activity in iWAT of SC-specific Pten-deficient mice was reduced as demonstrated by decreased tyrosine hydroxylase (TH) expression level and neurotransmitters, such as norepinephrine (NE) and histamine (H). The lipolysis related protein, phosphorylated hormone sensitive lipase (pHSL), was also decreased. As expected, AKT-associated signaling pathway was hyperactivated and hypothesized to induce enlarged iWAT in SC-specific Pten-deficient mice. Moreover, preliminary experiments using AKT inhibitor AZD5363 treatment ameliorated the enlarged iWAT condition in SC-specific Pten-deficient mice. Taken together, SCs play an essential role in the regulation of SNS activity in iWAT development via the AKT signaling pathway. This novel role of SCs in SNS function allows for better understanding into the genetic mechanisms of peripheral neuropathy associated obesity.

Correction to: The Protective Effects of Butorphanol on Pulmonary Function of Patients with Obesity Undergoing Laparoscopic Bariatric Surgery: A Double-Blind Randomized Controlled Trial.

In the original article some of the references were ordered incorrectly.