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Broccoli sprouts are promising functional food sources and their taste and flavor play a pivotal role in the acceptance of consumers. In this study, the flavor profiles of three varieties of broccoli sprouts, namely Bi Lv, You Xiu, and Lv Hua, were comprehensively characterized using HS-SPME-GC/MS analysis. A total of 364 volatile and flavor components across 15 chemical classes were successfully identified. The results revealed a majority of volatile metabolites exhibiting upregulation during the germination process, leading to an enhancement in taste intensity after germination, particularly for umami and sweet tastes, which was associated with an increase in associated amino acids and sugar content. Although the total glucosinolate content in broccoli sprouts has decreased compared to seeds, it remains the primary contributor to the bitterness of broccoli sprouts. The present study elaborated on the flavor contribution of broccoli sprouts, supporting the cultivation and consumption of them as a nutritious food.

Abstract Obesity/overweight and lipid metabolism disorders have become increased risk factors for lung cancer. Fatty acid translocase CD36 promotes cellular uptake of fatty acids. Whether and how CD36 facilitates lung adenocarcinoma (LUAD) growth in high-fat environment is unknown. Here, we demonstrated that palmitic acid (PA) or high-fat diet (HFD) promoted LUAD cell proliferation and metastasis in a CD36-dependent manner. Mechanistically, CD36 translocated from cytoplasm to cell membrane and interacted with Src kinase upon PA stimulation in human LUAD cells. Akt and ERK, downstream of Src, were then activated to mediate LUAD cell proliferation and metastasis. Furthermore, PA treatment promoted CD36 sarcolemmal translocation, where it activated Rac1 and upregulated MMP-9 through Src-Akt/ERK pathway, resulting in redistribution of cortactin, N-WASP and Arp2/3, and finally led to occurrence of finger-like protrusions of actin on cell surface to enhance cell metastasis. Compared with normal-chew diet (NCD) mice, the HFD group exhibited higher level of blood free fatty acid (FFA) and cholesterol (TC), developed larger xenograft LUAD tumors and enhanced tumor cell metastatic potential, which were accompanied by obvious sarcolemmal actin remodeling and were blocked by simultaneous CD36 knockdown in LUAD cells. Consistently, xenografted and tail vein-injected scramble-RNA-A549 cells but not CD36-shRNA-A549 in HFD mice formed metastatic LUAD tumors on the lung. CD36 inhibitor SSO significantly inhibited LUAD cell metastasis to the lung. Collectively, CD36 initiates Src signaling to promote LUAD cell proliferation and actin remodeling-involved metastasis under high-fat environment. Our study provides the new insights that CD36 is a valid target for LUAD therapy.

Summary: Smoking carcinogen nicotine-derived nitrosamine ketone (NNK) is the most potent contributor to lung adenocarcinoma (LUAD) development, but the mechanism has not been fully elucidated. Here, we reported that fatty acid translocase CD36 was significantly overexpressed in both human LUAD tissues and NNK-induced A/J mice LUAD tumors. The overexpressed CD36 was positively correlated with Src kinase activation, smoking status, metastasis, and worse overall survival of patients with smoking history. Upon NNK binding with α7 nicotinic acetylcholine receptor (α7nAChR), sarcolemmal CD36 was increased and it interacted with surface α7nAChR and cytosol Src simultaneously, which in turn activated Src and downstream pro-carcinogenic kinase ERK1/2 and Akt, and finally caused LUAD cells to form subcutaneous and pulmonary metastatic tumors. This process could be blocked by CD36 knockdown and CD36 irreversible inhibitor SSO. Furthermore, the effect of NNK was inhibited obviously in CD36−/− A/J mice. Thus, targeting CD36 may provide a breakthrough therapy of LUAD.

The artificial intelligence (AI) technology with supreme capacity of big data integration and management have been used in digital diagnosis and clinical treatment,which have greatly facilitated the development of clinical oncology and precision medicine. AI technology is far superior to human beings in big data integration and analysis, so has been widely applied in pathological image analysis, molecular marker discovery, clinical decision support, drug discovery and recommendation and so on. In recent years, many remarkable achievements have been made in the field. This review discussed the latest applications of AI-assisted precision cancer diagnosis and treatment, highlighted emerging challenges, and predicted the development trend in the future.

Partial substitution of chemical fertilizers by organic amendments is adopted widely for promoting the availability of soil phosphorus (P) in agricultural production. However, few studies have comprehensively evaluated the effects of long-term organic substitution on soil P availability and microbial activity in greenhouse vegetable fields. A 10-year (2009–2019) field experiment was carried out to investigate the impacts of organic fertilizer substitution on soil P pools, phosphatase activities and the microbial community, and identify factors that regulate these soil P transformation characteristics. Four treatments included 100% chemical N fertilizer (4CN), 50% substitution of chemical N by manure (2CN+2MN), straw (2CN+2SN), and combined manure with straw (2CN+1MN+1SN). Compared with the 4CN treatment, organic substitution treatments increased celery and tomato yields by 6.9−13.8% and 8.6−18.1%, respectively, with the highest yields being in the 2CN+1MN+1SN treatment. After 10 years of fertilization, organic substitution treatments reduced total P and inorganic P accumulation, increased the concentrations of available P, organic P, and microbial biomass P, and promoted phosphatase activities (alkaline and acid phosphomonoesterase, phosphodiesterase, and phytase) and microbial growth in comparison with the 4CN treatment. Further, organic substitution treatments significantly increased soil C/P, and the partial least squares path model (PLS-PM) revealed that the soil C/P ratio directly and significantly affected phosphatase activities and the microbial biomass and positively influenced soil P pools and vegetable yield. Partial least squares (PLS) regression demonstrated that arbuscular mycorrhizal fungi positively affected phosphatase activities. Our results suggest that organic fertilizer substitution can promote soil P transformation and availability. Combining manure with straw was more effective than applying these materials separately for developing sustainable P management practices.

IntroductionMicroorganisms play a critical role in soil biogeochemical cycles, but it is still debated whether they influence soil biogeochemical processes through community composition and diversity or not. This study aims to investigate variation in bacterial community structure across different soils and its correlation to soil multifunctionality. Soil samples were collected from five typical farmland zones along distinct climatic gradients in China.MethodsThe high-throughput sequencing (Illumina MiSeq) of 16S rRNA genes was employed to analyze bacterial community composition in each soil sample. Multivariate analysis was used to determine the difference in soil properties, microbial community and functioning, and their interactions.ResultsCluster and discrimination analysis indicated that bacterial community composition was similar in five tested soil samples, but bacterial richness combined with soil enzyme activities and potential nitrification rate (PNR) contributed most to the differentiations of soil samples. Mantel test analysis revealed that bacterial community composition and richness were more significantly shaped by soil nutrient conditions and edaphic variables than bacterial diversity. As for soil multifunctionality, soil microbial community level physiological profiles were little affected by abiotic and biotic factors, while soil enzymes and PNR were also significantly related to bacterial community composition and richness, in addition to soil N and P availability.ConclusionCumulatively, soil enzymes’ activities and PNR were greatly dependent on bacterial community composition and richness not diversity, which in turn were greatly modified by soil N and P availability. Therefore, in the future it should be considered for the role of fertilization in the modification of bacterial community and the consequent control of nutrient cycling in soil.

In our chemical investigation into Penicillium sp. UJNMF0740 derived from mangrove sediment, fourteen indole diterpene analogs, including four new ones, are purified by multiple chromatographic separation methods, with their structures being elucidated by the analyses of NMR, HR-ESIMS, and ECD data. The antibacterial and neuroprotective effects of these isolates were examined, and only compounds 6 and 9 exhibited weak antibacterial activity, while compounds 5, 8, and 10 showed protective effects against the injury of PC12 cells induced by 6-hydroxydopamine (6-OHDA). Additionally, compound 5 could suppress the apoptosis and production of reactive oxygen species (ROS) in 6-OHDA-stimulated PC12 cells as well as trigger the phosphorylation of PI3K and Akt. Taken together, our work enriches the structural diversity of indole diterpenes and hints that compounds of this skeleton can repress the 6-OHDA-induced apoptosis of PC12 cells via regulating the PI3K/Akt signaling pathway, which provides evidence for the future utilization of this fascinating class of molecules as potential neuroprotective agents.

Phosphorus (P) leaching is a major problem in greenhouse vegetable production with excessive P fertilizer application. Substitution of inorganic P fertilizer with organic fertilizer is considered a potential strategy to reduce leaching, but the effect of organic material addition on soil P transformation and leaching loss remains unclear. The X-ray absorption near-edge structure (XANES) spectroscopy technique can determine P speciation at the molecular level. Here, we integrated XANES and chemical methods to explore P speciation and transformation in a 10-year field experiment with four treatments: 100% chemical fertilizer (4CN), 50% chemical N and 50% manure N (2CN+2MN), 50% chemical N and 50% straw N (2CN+2SN), and 50% chemical N and 25% manure N plus 25% straw N (2CN+2MSN). Compared with the 4CN treatment, the organic substitution treatments increased the content of labile P by 13.7–54.2% in the 0–40 cm soil layers, with newberyite and brushite being the main constituents of the labile P. Organic substitution treatments decreased the stable P content; hydroxyapatite was the main species and showed an increasing trend with increasing soil depth. Straw addition (2CN+2SN and 2CN+2MSN) resulted in a higher moderately labile P content and a lower labile P content in the subsoil (60–100 cm). Moreover, straw addition significantly reduced the concentrations and amounts of total P, dissolved inorganic P (DIP), and particulate P in leachate. DIP was the main form transferred by leaching and co-migrated with dissolved organic carbon. Partial least squares path modeling revealed that straw addition decreased P leaching by decreasing labile P and increasing moderately labile P in the subsoil. Overall, straw addition is beneficial for developing sustainable P management strategies due to increasing labile P in the upper soil layer for the utilization of plants, and decreasing P migration and leaching.

Abstract Twenty-year-old Pinus radiata trees imported from New Zealand were investigated, and a comparison was made between the outerwood (rings 16–20) and corewood (rings 4–6) in terms of mechanical properties, anatomical characteristics, microfibril angle (MFA), relative crystallinity, crystallite size and lignin content to determine the relationship between their mechanical properties and microstructures. The results demonstrated that the mechanical properties of the Pinus radiata outerwood were significantly better than those of the corewood. The outerwood had a modulus of rupture (MOR) of 106 MPa, a modulus of elasticity (MOE) of 11.4 GPa, and compressive strength parallel to the grain of 38.7 MPa, and the MOR, MOE and compressive strength parallel to the grain of the corewood were 78.9 MPa, 7.12 GPa and 29.3 MPa, respectively. The observed microstructures of the Pinus radiata outerwood and corewood were different, mainly due to differences in cell wall thickness, MFA, and relative crystallinity. The double wall thickness of the tracheid cells of the corewood and outerwood were 3.65 and 5.02 µm, respectively. The MFA data indicated that the average MFA of the outerwood was 14.0°, which was smaller than that of the corewood (22.3°). With X-ray diffraction, the relative crystallinity of the corewood was determined to be 35.7%, while that of the outerwood was 40.2%. However, the crystallite size of the outerwood cell wall shows no obvious difference from that of the corewood. Imaging FTIR spectroscopy showed a slightly higher relative content of lignin in the cell wall of the outerwood. The correlation between the microstructures and mechanical properties showed that the corewood with a thin cell wall, large MFA and low relative crystallinity had poor mechanical properties, while the outerwood with a thicker tracheid, smaller MFA and higher relative crystallinity had better mechanical properties. This means that the MFA, relative crystallinity and cell wall thickness synergically affect the mechanical properties of Pinus radiata in different radial locations.

Sprouts are recognized as nutritional and functional vegetables. In this study, 17 selected seeds were germinated simultaneously. The antioxidant capacity and total phenolic content (TPC) were determined for seeds and sprouts of all species. Both seed and sprout of white radish, with the highest antioxidant capacity, and TPC among all the 17 species, were further determined for phenolic metabolomics. Four phenolic classes with 316 phenolic metabolites were identified. 198 significantly different metabolites with 146 up-regulated and 52 down-regulated were confirmed, and high amounts of phenolic acids and flavonoids were found to be accumulated in the sprout. Several metabolism and biosynthesis, including phenylpropanoid, favone and flavonol, phenylalanine, and various secondary metabolites, were significantly activated. Significant correlations were found among FRAP, DPPH, ABTS, TPC, and phenolic profiles. Therefore, white radish sprout could be served as antioxidant and could be a good source of dietary polyphenols.

Abstract Background Neuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer’s disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD. Methods Sixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers. Results Administration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS. Conclusions Colitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.

Background: Green tea, mulberry leaf and corn silk are traditional herbs used in the prevention and treatment of diabetes in China for a long time, but their synergistic hypoglycemic effects and mechanisms remain unclear. Methods: The effective components of green tea, mulberry leaf and corn silk were extracted and enriched. Mixture design of experiments was used to study the influences of different combinations on the cell viability and glucose uptake level of L6 myoblasts, so as to determine the optimal synergistic hypoglycemic combination. The possible hypoglycemic mechanism of the optimal synergistic combination was explored by cytotoxicity assay, glucose uptake assay, and western blot. Results: Three polyphenol enrichment fractions of the herbs, 30% ethanol elution fraction of green tea (GT), 50% ethanol elution fraction of mulberry leaf (ML) and 60% ethanol elution fraction of corn silk (CS) were obtained. The antioxidant activities of GT-30%, ML-50% and CS-60% were superior to those of crude extracts, and showed strong potential in a-amylase and a-glucosidase inhibition activities. The optimal synergistic combination of crude extracts G7 (crude extract of green tea:crude extract of mulberry leaf:crude extract of corn silk = 1:5:3), polyphenol enrichment fractions R3 (GT-30%:ML-50%:CS-60% = 1:7:1) and monomers X2 (epigallocatechin gallate:morusin:formononetin = 3:1:2) were selected, respectively. G7, R3, and X2 showed promoting effects on the cell viability and glucose uptake of L6 myoblasts within the detected concentration range. In addition, G7, R3, and X2 could increase the expression levels of p-PI3K/PI3K and p-Akt/Akt in L6 myoblasts, and promote the translocation of Glut4, but G7 and R3 showed more significant effects. Conclusion: The synergistic hypoglycemic effects of green tea, mulberry leaf and corn silk had the characteristics of multiple-components and multiple-targets with p-PI3K/PI3K, p-Akt/Akt and the translocation of Glut4 signal pathways involved. The three traditional herbs might have the potential to be combined used for the prevention and treatment of diabetes based on the synergistic hypoglycemic effects. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between erythrocyte (RBC) deformability and RBC energy metabolism in patients with type 2 diabetes mellitus (T2DM). Methods Totally 80 T2DM and 50 controls with age of 40 to 70 years were selected. Rough hematology laboratory test, ATP content, Hexokinase (HK) and Pyruvate kinase (PK) activity were detected.Results BMI, DBP and SBP of patients with T2DM were higher than those of control group (P＜0.05). T2DM of RBC deformation index (TK), rigidity index(IR), RBC distribution width (RDW) and average RBC volume (MCV) were higher than that of control group (P＜0.05); The content of ATP and PK activity in RBC of T2DM group were higher than that of control group (P＜0.05), while the activity of HK was lower than that of control group(P＜0.05). In the T2DM, TK was negatively correlated with ATP content and HK activity, and positively correlated with HbA1c. IR was negatively correlated with HK and PK values, and positively correlated with HbA1c (P＜0.05). Compared with Group A, the TK value of Group C increased (P＜0.05) in the HbA1c group. Compared with Group A, Group C had higher ATP, PK and HK (P＜0.05). Compared with Group A, ROS in Group C increased (P＜0.05). Results RCD damage in diabetic patients is closely related to HbA1c, and RBC energy metabolism plays an important role in maintaining RCD. In diabetic patients, ATP production in RBC increased, PK activity increased, and energy metabolism was vigorous, but this did not improve the reduced RCD status caused by high glucose. Conclusions The energy metabolism of erythrocytes in diabetic patients was more vigorous and is closely related to the decrease of RCD. RCD reduction is a risk factor for diabetic microangiopathy, so monitoring erythrocytes energy metabolism may provide a new basis for monitoring the progress of clinical diabetes patients and support clinical diagnosis and treatment.

Abstract Lung cancer is often diagnosed at an advanced stage and has a poor prognosis. Conventional treatments are not effective for metastatic lung cancer therapy. Although some of molecular targets have been identified with favorable response, those targets cannot be exploited due to the lack of suitable drug carriers. Lung cancer cell-derived exosomes (LCCDEs) receive recent interest in its role in carcinogenesis, diagnosis, therapy, and prognosis of lung cancer due to its biological functions and natural ability to carry donor cell biomolecules. LCCDEs can promote cell proliferation and metastasis, affect angiogenesis, modulate antitumor immune responses during lung cancer carcinogenesis, regulate drug resistance in lung cancer therapy, and be now considered an important component in liquid biopsy assessments for detecting lung cancer. Therapeutic deliverable exosomes are emerging as promising drug delivery agents specifically to tumor high precision medicine because of their natural intercellular communication role, excellent biocompatibility, low immunogenicity, low toxicity, long blood circulation ability, biodegradable characteristics, and their ability to cross various biological barriers. Several studies are currently underway to develop novel diagnostic and prognostic modalities using LCCDEs, and to develop methods of exploiting exosomes for use as efficient drug delivery vehicles. Current status of lung cancer and extensive applicability of LCCDEs are illustrated in this review. The promising data and technologies indicate that the approach on LCCDEs implies the potential application of LCCDEs to clinical management of lung cancer patients.

Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml. Compounds 8f and 9d showed the most potent inhibitory activities (MICs of 0.5–2 µg/ml). Furthermore, compounds 8b, 8d, 8f, 8k, 9b and 9e with antimicrobial activities were not cytotoxic to human gastric cancer cell lines (SGC-7901 and AGS) or a normal human liver cell line (L-02). Structure–activity relationship analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency and reducing the toxicity of the carbazole compounds. In vitro enzyme activity assays suggested that compound 8f binding to dihydrofolate reductase might account for the antimicrobial effect.

Tea (Camellia sinensis L.) is a very popular health drink and has attracted increasing attention in recent years due to its various bioactive substances. Among them, L-theanine, a unique free amino acid, is one of the most important substances in tea and endows tea with a special flavor. Moreover, L-theanine is also a bioactive compound with plenty of health benefits, including antioxidant, anti-inflammatory, neuroprotective, anticancer, metabolic regulatory, cardiovascular protective, liver and kidney protective, immune regulatory, and anti-obesity effects. Due to the unique characteristics and beneficial functions, L-theanine has potential applications in the development of functional foods. This review summarized the influencing factors of L-theanine content in teas, the main health benefits and related molecular mechanisms of L-theanine, and its applications in food, understanding of which can provide updated information for the further research of L-theanine.

Soil aggregation, microbial community, and functions (i.e., extracellular enzyme activities; EEAs) are critical factors affecting soil C dynamics and nutrient cycling. We assessed soil aggregate distribution, stability, nutrients, and microbial characteristics within >2, 0.25–2, 0.053–0.25, and 0.053 mm aggregates, but not in the 0.25, 0.25–0.053, and

Abstract Background Cerebral microinfarcts (MIs) lead to progressive cognitive impairments in the elderly, and there is currently no effective preventative strategy due to uncertainty about the underlying pathogenic mechanisms. One possibility is the dysfunction of GABAergic transmission and ensuing excitotoxicity. Dysfunction of GABAergic transmission induces excitotoxicity, which contributes to stroke pathology, but the mechanism has kept unknown. The secreted leucine-rich repeat (LRR) family protein slit homologue 2 (Slit2) upregulates GABAergic activity and protects against global cerebral ischemia, but the neuroprotective efficacy of Slit2 against MIs has not been examined. Methods Middle-aged Wild type (WT) and Slit2-Tg mice were divided into sham and MI treatment groups. MIs were induced in parietal cortex by laser-evoked arteriole occlusion. Spatial memory was then compared between sham and MI groups using the Morris water maze (MWM) task. In addition, neuronal activity, blood brain barrier (BBB) permeability, and glymphatic clearance in peri-infarct areas were compared using two-photon imaging, while GABAergic transmission, microglial activation, neuronal loss, and altered cortical connectivity were compared by immunofluorescent staining or western blotting. Results Microinfarcts increased the amplitude and frequency of spontaneous intracellular Ca2+ signals, reduced neuronal survival and connectivity within parietal cortex, decreased the number of GABAergic interneurons and expression of vesicular GABA transporter (VGAT), induced neuroinflammation, and impaired both glymphatic clearance and spatial memory. Alternatively, Slit2 overexpression attenuated dysfunctional neuronal Ca2+ signaling, protected against neuronal death in the peri-infarct area as well as loss of parietal cortex connectivity, increased GABAergic interneuron number and VGAT expression, attenuated neuroinflammation, and improved both glymphatic clearance and spatial memory. Conclusion Our results strongly suggest that overexpression of Slit2 protected against the dysfunction in MIs, which is a potential therapeutic target for cognition impairment in the elderly.

Objective To investigate the effect of stress hormones on cell cycle re-entry of G0 phase in mouse H22 hepatocarcinoma cells. Methods Flow cytometry antibody staining with CD44 and CD133 was used to determine the presence of cancer stem cells in H22 cells. In vitro, after treatment of H22 cells with stress hormone corticosterone (CORT), epinephrine (EPI) and norepinephrine (NE) for 48 h, the proportion changes of cells in G0 phase and cell cycle distribution were detected by Ki-67 and PI flow cytometry staining. The hormone receptor antagonists were used to verify the receptor subtypes that mediated the cell cycle re-entry of G0 phase cells. Results The proportion of cancer stem cells (CD44+CD133+) in H22 cells was 0.80%±0.15%. Compared with control group, the portion of G0 phase cells was unchanged after corticosterone treatment, but was decreased by 62.50% and 53.00% respectively after EPI and NE treatment. Meanwhile, the total cells, proportion of G2/M and S phase cells were increased compared to control group. The protein expression of Skp2 was increased and p27kip1 decreased significantly after EPI and NE treatment(P＜0.05). In addition, α1-adrenergic receptor antagonists terazosin and prazosin blocked the G0 phase cells cycle re-entry effect of EPI and NE. The protein expression of Skp2 was decreased and p27kip1 was increased significantly after prazosin treatment compared to EPI or NE group(P＜0.05). Conclusions Catecholamine stress hormones mediate the cell cycle re-entry of G0 phase cells in mouse H22 hepatocarcinoma cells by activating α1-adrenergic receptor,the mechanism of which may be associated with the Skp2 over-expression and the degradation of p27kip1 protein.

Abstract Background Translationally controlled tumor protein (TCTP) is linked to lung cancer. However, upon lung cancer carcinogens stimulation, there were no reports on the relationship between TCTP and lung cell carcinogenic epithelial–mesenchymal transition (EMT). This study was designed to investigate the molecular mechanism of regulation of TCTP expression and its role in lung carcinogens-induced EMT. Methods To study the role of TCTP in lung carcinogens [particulate matter 2.5 (PM2.5) or 4-methylnitrosamino-l-3-pyridyl-butanone (NNK)]-induced EMT, PM2.5/NNK-treated lung epithelial and non-small cell lung cancer (NSCLC) cells were tested. Cell derived xenografts, human lung cancer samples and online survival analysis were used to confirm the results. MassArray assay, Real-time PCR and Reporter assays were performed to elucidate the mechanism of regulation of TCTP expression. All statistical analyses were performed using GraphPad Prism version 6.0 or SPSS version 20.0. Results Translationally controlled tumor protein and vimentin expression were up-regulated in PM2.5/NNK-treated lung cells and orthotopic implantation tumors. TCTP expression was positively correlated with vimentin in human NSCLC samples. Patients with high expression of TCTP displayed reduced overall and disease-free survival. TCTP overexpression could increase vimentin expression and promote cell metastasis. Furthermore, PM2.5/NNK stimulation brought a synergistic effect on EMT in TCTP-transfected cells. TCTP knockdown blocked PM2.5/NNK carcinogenic effect. Mechanically, PM2.5/NNK-induced TCTP expression was regulated by one microRNA, namely miR-125a-3p, but not by methylation on TCTP gene promoter. The level of TCTP was regulated by its specific microRNA during the process of PM2.5/NNK stimulation, which in turn enhanced vimentin expression and played a permissive role in carcinogenic EMT. Conclusions Our results provided new insights into the mechanisms of TCTP regulatory expression in lung carcinogens-induced EMT. TCTP and miR-125a-3p might act as potential prognostic biomarkers and therapeutic targets for NSCLC.

Hepatocellular carcinoma results in a high risk of second primary malignancies and has prominent morbidity and mortality. There is a lack of effective treatment and prognosis is poor. Therefore, effective drugs need to be discovered. Carrimycin is a 16-member macrolide antibiotic with anticancer activity, and monomeric isovalerylspiramycin I is a main component. The aim of this study was to determine the anti-tumor effects of carrimycin and monomeric isovalerylspiramycin I on hepatocellular carcinoma through in vivo and in vitro experiments. In vitro, changes in cellular proliferation, migration, invasion, and apoptosis were analyzed by MTT, colony formation, EdU labeling, wound-healing, matrigel transwell invasion, and flow cytometric assays using SK-Hep1, Hep3B, SNU-354, SNU-387 hepatocellular carcinoma cell lines. Western blotting and RT-PCR were used to detect the effects of carrimycin and monomeric isovalerylspiramycin I on the expression levels of vascular endothelial growth factor (VEGF) and programmed death ligand 1 (PD-L1). Nude mice were subcutaneously transplanted with SK-Hep1 cells or C57BL/6J mice were orthotopically transplanted with hepatocarcinoma H22 cells. Tumor volume, pathological changes in tumor tissues, and the concentration of VEGF in mouse serum were measured after treatments. Carrimycin and monomeric isovalerylspiramycin I dose-dependently inhibited hepatocellular carcinoma cell viability, colony formation, and DNA replication. These agents markedly suppressed migration and invasion and promoted apoptosis of the cell lines. Western blotting and RT-PCR demonstrated that carrimycin and monomeric isovalerylspiramycin I reduced VEGF and PD-L1 protein and mRNA levels in a dose-dependent manner. In vivo studies further confirmed that carrimycin and monomeric isovalerylspiramycin I could significantly inhibit tumor growth, tumor histopathological alterations, and the concentration of VEGF in both mouse tumor models. These results show that carrimycin and monomeric isovalerylspiramycin I promoted apoptosis and inhibited proliferation, migration, and invasion of hepatocellular carcinoma cells. Therefore, our discovery suggests anti-tumor capacity for carrimycin and monomeric isovalerylspiramycin I and provides data on potential new drugs for inhibiting hepatocellular carcinoma.

(1) Background: Nuclear factor κB (NF-κB) is an important transcriptional regulator that regulates the inflammatory pathway and plays a key role in cellular inflammatory and immune responses. The presence of a high concentration of NF-κB is positively correlated with the severity of inflammation. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation; (2) Methods: we designed and synthesized 23 mollugin derivatives and evaluated their inhibitory activity against NF-κB transcription; (3) Results: Compound 6d exhibited the most promising inhibitory activity (IC50 = 3.81 µM) and did not show any significant cytotoxicity against the tested cell lines. Investigation of the mechanism of action indicated that 6d down-regulated NF-κB expression, possibly by suppressing TNF-α-induced expression of the p65 protein. Most of the compounds exhibited potent anti-inflammatory activity. Compound 4f was the most potent compound with 83.08% inhibition of inflammation after intraperitoneal administration, which was more potent than mollugin and the reference drugs (ibuprofen and mesalazine). ADMET prediction analysis indicated that compounds 6d and 4f had good pharmacokinetics and drug-like behavior; (4) Conclusions: Several series of mollugin derivatives were designed, synthesized, and evaluated for NF-κB inhibitory activity and toxicity. These results provide an initial basis for the development of 4f and 6d as potential anti-inflammatory agents.

Abstract Background Epidemiological observations have demonstrated that ambient fine particulate matter with d p

Stroke is one of the leading causes of long-term disabilities worldwide. Although exposure to an enriched environment (EE) initiated in the acute phase after stroke has neuroprotective effects and improves stroke outcome, it remains unclear whether EE has positive effects when started in a delayed time frame. Here we show that exposure to EE in the delayed phase notably ameliorates the ischemia-induced impairments in neurological functions and spatial learning and memory. In addition, delayed EE exposure after stroke significantly promotes the survival and neuronal fate choice of hippocampal newborn cells, increases synaptic density of hippocampal mature neurons, and enhances the migration of subventricular zone (SVZ)-derived cells towards the ischemic striatum. Histone deacetylase 2 (HDAC2), synapse-associated proteins and brain-derived neurotrophic factor (BDNF) may respectively mediate these roles of delayed EE. Our findings provide the suggestion that exposure to EE initiated in the delayed phase after stroke promotes plastic changes via affecting neurogenesis, synaptogenesis and neuronal migration, and thus improves stroke outcome. Because EE initiated earlier than 24 h is clinically feasible, our work could be introduced into clinical studies of stroke directly and may provide stroke survivors with a new strategy for their functional recovery. Keywords: Stroke, Enriched environment, Neurogenesis, Synaptogenesis, Neuronal migration

Objective: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality. T cell deficiency has recently been described, but the changes in T cell functionality during acute SFTS virus (SFTSV) infection and the mechanisms leading to T lymphocyte death remain largely unknown. This study was conducted to evaluate T cell functionality and the expression of apoptotic/proliferation and activation/inhibition markers during acute SFTSV infection. Methods: Twenty-eight surviving SFTS patients were sequentially sampled during their entire hospital stay. SFTSV RNA copies were investigated using real-time RT-PCR. The expression levels of apoptotic markers (annexin V and CD95) and proliferation and activation markers (Ki-67, HLA-DR, and CD25) and the expression levels of programmed cell death-1 (PD-1), interferon gamma (IFN-γ), and granzyme B in T cells were evaluated by flow cytometry for the SFTS patients. Results: In parallel with T cell depletion, higher annexin V and CD95 expression was observed in SFTS patients. Additionally, the expression levels of Ki-67, HLA-DR, CD25, and PD-1 and the levels of IFN-γ and granzyme B in T lymphocytes were markedly increased in the SFTS patients. Conclusions: T cell proliferation, activation, and functional enhancement were apparent despite the observation of T cell apoptosis, suggesting that these processes are involved in the complex protective response to SFTSV infection. Keywords: Severe fever with thrombocytopenia syndrome, T lymphocytes, Apoptosis, T cell proliferation, T cell activation, PD-1, T cell functionality

Abstract Background Previous studies have shown that acupuncture is beneficial for the alleviation of chemotherapy-induced nausea and vomiting. However, there is a lack of clinical evidence concerning the effects of acupoint-matching on chemotherapy-induced nausea and vomiting. Methods/design This is a parallel randomized controlled trial to evaluate the occurrence of nausea and vomiting after chemotherapy (the incidence of nausea and vomiting, frequency, VAS score, RINVR rating) as the main outcome for cancer. Quality of life, anxiety and depression scores are the secondary outcomes. Quality of life, anxiety and depression scores are the secondary phase. Use of remedy drugs, routine blood examination, and blood biochemical tests are the safety evaluation. We also compare the different effects of ST36 (single acupoint), CV12 (single acupoint), and ST36-CV12 matching groups. Discussion The results of this trial are expected to explore the effects of matching different acupoints and to offer biologic plausibility for the use of acupuncture in the treatment of chemotherapy-induced nausea and vomiting (CINV). Trial registration This trial is registered with clinicaltrials.gov NCT02195921 , The date of registration was 17 July 2014.

Abstract Background The role of cancer cell FOXP3 in tumorigenesis is conflicting. We aimed to study FOXP3 expression and regulation, function and clinical implication in human non-small cell lung cancer (NSCLC). Methods One hundred and six patients with histologically-confirmed NSCLC who underwent surgery were recruited for the study. Tumor samples and NSCLC cell lines were used to examine FOXP3 and its related molecules. Various cell functions related to tumorigenesis were performed. In vivo mouse tumor xenograft was used to confirm the in vitro results. Results NSCLC patients with the high level of FOXP3 had a significant decrease in overall survival and recurrence-free survival. FOXP3 overexpression significantly induced cell proliferation, migration, and invasion, whereas its inhibition impaired its oncogenic function. In vivo studies confirmed that FOXP3 promoted tumor growth and metastasis. The ectopic expression of FOXP3 induced epithelial–mesenchymal transition (EMT) with downregulation of E-cadherin and upregulation of N-cadherin, vimentin, snail, slug, and MMP9. The oncogenic effects by FOXP3 could be attributed to FOX3-mediated activation of Wnt/β-catenin signaling, as FOXP3 increased luciferase activity of Topflash reporter and upregulated Wnt signaling target genes including c-Myc and Cyclin D1 in NSCLC cells. Co-immunoprecipitation results further indicated that FOXP3 could physically interacted with β-catenin and TCF4 to enhance the functions of β-catenin and TCF4, inducing transcription of Wnt target genes to promote cell proliferation, invasion and EMT induction. Conclusions FOXP3 can act as a co-activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC.

Background: Early data showed that FOXP3 could induce epithelial-mesenchymal transition by stimulating the Wnt/β-catenin signaling pathway in non-small cell lung cancer (NSCLC). However, how the expression of FOXP3 is regulated in NSCLC remains unknown. We thus explored the impacts of the long noncoding RNA EGFR antisense RNA 1 (EGFR-AS1) and hypoxia-inducible factor-2A (HIF2A) on FOXP3 expression and the cancer stemness of NSCLC. Methods: Lung tissues samples from 87 patients with NSCLC and two NSCLC cell lines were used in this study. The regulation of FOXP3 and lung cancer cell stemness by EGFR-AS1 and HIF2A was determined at molecular levels in NSCLC tissue samples and cultured cells in the presence/absence of the smoking carcinogen, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (also known as nicotine-derived nitrosamine ketone). The results were confirmed in tumor xenograft models. Results: We found that NNK decreased the expression of EGFR-AS1 in the long term, but increased the expression of HIF2A and FOXP3 to stimulate lung cancer cell stemness. EGFR-AS1 significantly inhibited FOXP3 expression and NSCLC cell stemness, whereas HIF2A obviously promoted both. The enhancement of lung cancer stemness by FOXP3 was, at least partially, via stimulating Notch1, as the inhibition of Notch1 could markedly diminish the effect of FOXP3. Conclusions: FOXP3, the expression of which is under the fine control of EGFR-AS1, is a critical molecule that promotes NSCLC cancer cell stemness through stimulating the Notch1 pathway.

The poor clinical outcome of hepatocellular carcinoma (HCC) patients is ascribed to the resistance of HCC cells to traditional treatments and tumor recurrence after curative therapies. Cancer stem cells (CSCs) have been identified as a small subset of cancer cells which have high capacity for self-renewal, differentiation and tumorigenesis. Recent advances in the field of liver CSCs (LCSCs) have enabled the identification of CSC surface markers and the isolation of CSC subpopulations from HCC cells. Given their central role in cancer initiation, metastasis, recurrence and therapeutic resistance, LCSCs constitute a therapeutic opportunity to achieve cure and prevent relapse of HCC. Thus, it is necessary to develop therapeutic strategies to selectively and efficiently target LCSCs. Small molecular inhibitors targeting the core stemness signaling pathways have been actively pursued and evaluated in preclinical and clinical studies. Other alternative therapeutic strategies include targeting LCSC surface markers, interrupting the CSC microenvironment, and altering the epigenetic state. In this review, we summarize the properties of CSCs in HCC and discuss novel therapeutic strategies that can be used to target LCSCs.

Influence of meteorological variables on the transmission of bacillary dysentery (BD) is under investigated topic and effective forecasting models as public health tool are lacking. This paper aimed to quantify the relationship between meteorological variables and BD cases in Beijing and to establish an effective forecasting model.A time series analysis was conducted in the Beijing area based upon monthly data on weather variables (i.e. temperature, rainfall, relative humidity, vapor pressure, and wind speed) and on the number of BD cases during the period 1970-2012. Autoregressive integrated moving average models with explanatory variables (ARIMAX) were built based on the data from 1970 to 2004. Prediction of monthly BD cases from 2005 to 2012 was made using the established models. The prediction accuracy was evaluated by the mean square error (MSE).Firstly, temperature with 2-month and 7-month lags and rainfall with 12-month lag were found positively correlated with the number of BD cases in Beijing. Secondly, ARIMAX model with covariates of temperature with 7-month lag (β = 0.021, 95% confidence interval(CI): 0.004-0.038) and rainfall with 12-month lag (β = 0.023, 95% CI: 0.009-0.037) displayed the highest prediction accuracy.The ARIMAX model developed in this study showed an accurate goodness of fit and precise prediction accuracy in the short term, which would be beneficial for government departments to take early public health measures to prevent and control possible BD popularity.