Cinnamaldehyde Regulates the Migration and Apoptosis of Gastric Cancer Cells by Inhibiting the Jak2/Stat3 Pathway.

OBJECTIVE: Gastric cancer is a malignant tumor with high morbidity and mortality all around the world. Because of its poor prognosis and low survival rate, the treatment of gastric cancer has received extensive attention. Cinnamaldehyde (CA) is the main single active component of the Chinese herbal medicine cinnamon, which has a variety of pharmacological effects. The inhibitory effect of CA on the growth of some tumor cells has been proven, but its therapeutic effect on gastric cancer has rarely been reported. METHODS: Through network pharmacology, bioinformatics methods, and molecular docking technology, we predicted the interaction targets of CA and gastric cancer. Moreover, we found that apoptosis is an important mode of action of CA on gastric cancer cells. Subsequently, we validated it in gastric cancer cell lines cultured in vitro. RESULTS: The results showed that in the presence of CA, the Jak2/Stat3 pathway was inhibited, the ratio of Bcl-2/Bax decreased, and the apoptosis of gastric cancer cells was promoted in a concentration-dependent. CONCLUSION: In conclusion, CA can promote the apoptosis of gastric cancer cells by inhibiting the activity of the Jak2/Stat3 pathway, which may achieve the effect of treating gastric cancer.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model.

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aß plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aß clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-ß and Prevents Alzheimer's Disease-Type Pathology and Cognitive Deficits.

Deficiencies in the clearance of peripheral amyloid ß (Aß) play a crucial role in the progression of Alzheimer's disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aß is decreased in AD. However, the exact mechanism of Aß clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aß. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aß in vivo and in vitro. Moreover, enhancing blood monocyte Aß phagocytosis by improving energy metabolism alleviated brain Aß deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aß phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.

Rno_circRNA_006061 participates in apoptosis induced by formaldehyde via activating p38/ATF3 pathway.

Formaldehyde, a common indoor air pollutant, is significantly toxic to the respiratory system, whereas its mechanism is unclear. CircRNAs exert critical functions via sponging microRNAs (miRNAs). To evaluate the effect of long-term formaldehyde exposure on rno_circRNA_006061 expression profiles, the downstream targets and signaling pathways associated with rno_circRNA_006061 were predicted and validated using bioinformatics methods and dual-luciferase reporter assay. Previously, our circRNA microarray showed that rno_circRNA_006061 was up-regulated in the formaldehyde-exposed lung tissue. Subsequently, bioinformatics analysis predicted that rno_circRNA_006061 bound to rno-miR-128-3p and co-regulated the p38/ATF3 signaling pathway. Meanwhile, the expressions of rno_circRNA_006061, rno-miR-128-3p and p38 were correlated with the lung histomorphopathological injury assessment. Furthermore, TUNEL and Bax/Bcl-2 ratio results revealed that up-regulated rno_circRNA_00606 induced by formaldehyde stimulated apoptosis in the lung. After the knockdown of rno_circRNA_006061, the expression of rno-miR-128-3p increased and the expression of p38 decreased slightly, which partially restored formaldehyde-induced apoptosis in alveolar epithelial cells. In conclusion, our study hinted that the rno_circRNA_006061 might enhance p38/ATF3 pathway expression via sponging the rno-miR-128-3p, thus significantly promoting apoptosis in lung tissues, which may provide potential new targets for preventing and treating lung injury by formaldehyde inhalation.

Potential circRNA-Disease Association Prediction Using DeepWalk and Nonnegative Matrix Factorization.

Circular RNAs (circRNAs) are a category of noncoding RNAs that exist in great numbers in eukaryotes. They have recently been discovered to be crucial in the growth of tumors. Therefore, it is important to explore the association of circRNAs with disease. This paper proposes a new method based on DeepWalk and nonnegative matrix factorization (DWNMF) to predict circRNA-disease association. Based on the known circRNA-disease association, we calculate the topological similarity of circRNA and disease via the DeepWalk-based method to learn the node features on the association network. Next, the functional similarity of the circRNAs and the semantic similarity of the diseases are fused with their respective topological similarities at different scales. Then, we use the improved weighted K-nearest neighbor (IWKNN) method to preprocess the circRNA-disease association network and correct nonnegative associations by setting different parameters K1 and K2 in the circRNA and disease matrices. Finally, the L2,1-norm, dual-graph regularization term and Frobenius norm regularization term are introduced into the nonnegative matrix factorization model to predict the circRNA-disease correlation. We perform cross-validation on circR2Disease, circRNADisease, and MNDR. The numerical results show that DWNMF is an efficient tool for forecasting potential circRNA-disease relationships, outperforming other state-of-the-art approaches in terms of predictive performance.

Short daylight photoperiod alleviated alarm substance-stimulated fear response of zebrafish.

Photoperiod has been well-documented to be involved in regulating many activities of animals. However, whether photoperiod takes part in mood control, such as fear response in fish and the underlying mode(s) of action remain unclear. In this study, adult zebrafish males and females (Danio rerio) were exposed to different photoperiods, Blank (12 h light: 12 h dark), Control (12 h light: 12 h dark), Short daylight (SD, 6 h light: 18 h dark) and Long daylight (LD, 18 h light: 6 h dark) for 28 days. After exposure, fear response of the fish was investigated using a novel tank diving test. After alarm substance administration, the onset to higher half, total duration in lower half and duration of freezing in SD-fish were significantly decreased, suggesting that short daylight photoperiod is capable of alleviating fear response in zebrafish. In contrast, comparing with the Control, LD didn't show significant effect on fear response of the fish. Further investigation revealed that SD increased the levels of melatonin (MT), serotonin (5-HT) and dopamine (DA) in the brain while decreased the plasma level of cortisol comparing to the Control. Moreover, the expressions of genes in MT, 5-HT and DA pathways and HPI axis were also altered consistently. Our data indicated that short daylight photoperiod might alleviate fear response of zebrafish probably through interfering with MT/5-HT/DA pathways and HPI axis.

Chronic exposure to environmentally relevant concentrations of carbamazepine interferes with anxiety response of adult female zebrafish through GABA /5-HT pathway and HPI axis.

Carbamazepine (CBZ) is one of the widely distributed pharmaceutical residues in aquatic environments, yet few researches have addressed its chronic effect on the anxiety of fish, and the mechanisms possibly involved remained elusive. In this study, adult female zebrafish (Danio rerio) were exposed to environmental relevant concentrations of CBZ (CBZ-low, 10 µg/L; CBZ-high, 100 µg/L) for 28 days. After exposure, CBZ-high didn't affect the anxiety of fish. However, the onset time to the higher half of the tank was delayed and the total duration in the lower half of the tank was increased in CBZ-low fish, suggesting an increased anxiety. Further investigation indicated that CBZ-low significantly decreased the gamma-aminobutyric acid (GABA) level in the brain, while increased the serotonin (5-HT) level in the brain and cortisol level in plasma. Accordingly, the mRNA levels of genes in GABA (gad2, abat, gabrb2, gabrg2, gria1a and slc12a2) pathway and HPI (crha, actha, pc1 and pc2) axis were also altered. Despite the upregulation of tph2 was consistent with increased 5-HT level in the brain, significantly downregulated htr1aa and htr1b may indicate attenuated 5-HT potency. Although CBZ-high significantly reduced GABA level in the brain and increased cortisol level in plasma, the effects were dramatically alleviated than that of CBZ-low. Consistently, the expression of genes in HPI (crha, actha, pc1 and pc2) axis and GABA (gad2 and abat) pathway were also altered by CBZ-high, probably due to inconspicuous anxiety response of CBZ-high. Briefly, our data suggested that low concentration of CBZ disrupted zebrafish anxiety by interfering with neurotransmission and endocrine system, thereby bringing about adverse ecological consequences.

Novel hierarchical carbon microspheres@layered double hydroxides@copper lignosulfonate architecture for polypropylene with enhanced flame retardant and mechanical performances.

Due to the inherent defect of flammability of polypropylene (PP), a novel and highly efficient carbon microspheres@layered double hydroxides@copper lignosulfonate (CMSs@LDHs@CLS) flame retardant was designed and prepared, which was attributed to the strong electrostatic interaction between carbon microspheres (CMSs), layered double hydroxides (LDHs) and lignosulfonate as well as the chelation effect of lignosulfonate on copper ions, and then it was incorporated into the PP matrix. Significantly, CMSs@LDHs@CLS not only observably improved its dispersibility in PP matrix, but also simultaneously achieved excellent flame retardant properties for composites. With the addition of 20.0 % CMSs@LDHs@CLS, the limit oxygen index of CMSs@LDHs@CLS and PP composites (PP/CMSs@LDHs@CLS) reached 29.3 % and achieved the UL-94 V-0 rating. Cone calorimeter tests indicated that the peak heat release rate, total heat release and total smoke production of PP/CMSs@LDHs@CLS composites exhibited declines of 28.8 %, 29.2 % and 11.5 %, respectively, compared with those of PP/CMSs@LDHs composites. These advancements were attributed to the better dispersibility of CMSs@LDHs@CLS in PP matrix and illustrated that CMSs@LDHs@CLS observably reduced fire hazards of PP. The flame retardant property of CMSs@LDHs@CLS might relate to condensed phase flame retardant effect of char layer and catalytic charring of copper oxides.

Convolution Neural Networks Using Deep Matrix Factorization for Predicting Circrna-Disease Association.

CircRNAs have a stable structure, which gives them a higher tolerance to nucleases. Therefore, the properties of circular RNAs are beneficial in disease diagnosis. However, there are few known associations between circRNAs and disease. Biological experiments identify new associations is time-consuming and high-cost. As a result, there is a need of building efficient and achievable computation models to predict potential circRNA-disease associations. In this paper, we design a novel convolution neural networks framework(DMFCNNCD) to learn features from deep matrix factorization to predict circRNA-disease associations. Firstly, we decompose the circRNA-disease association matrix to obtain the original features of the disease and circRNA, and use the mapping module to extract potential nonlinear features. Then, we integrate it with the similarity information to form a training set. Finally, we apply convolution neural networks to predict the unknown association between circRNAs and diseases. The five-fold cross-validation on various experiments shows that our method can predict circRNA-disease association and outperforms state of the art methods.

Effects of Chemotherapy on Neuroinflammation, Neuronal Damage, Neurogenesis, and Behavioral Performance in Bone Marrow Transplantation Recipient Mice.

As bone marrow transplant (BMT) is gradually applied to the study of central nervous system (CNS) disease, it is needed to investigate the proper dose of chemotherapy to eradicate bone marrow cells while bringing little damage to brain. In the present study, we established a BMT model with varied busulfan and cyclophosphamide (Bu-Cy) dosages. The recipient mice's chimera rate, neuronal death, neuroinflammation, and behavioral functions were all investigated. Chimerism of peripheral blood cells was shown to rise with Bu-Cy treatment doses, with 60.7% in the Bu(20 mg/kg)/Cy(100 mg/kg) group and 93.0% in the Bu(35 mg/kg)/Cy(100 mg/kg) group. Recipients with Bu(35 mg/kg)/Cy(100 mg/kg) therapy had brain injury, increased neuroinflammation, diminished neurogenesis and cognitive abnormalities, whereas animals given a lesser dosage had no such brain damages. Conclusively, considering the chimerism and the possibility to damage brain, we recommend Bu(20 mg/kg)/Cy(100 mg/kg) is the ideal dose in BMT for studying CNS diseases in the C57/BL6 mouse strain.

Inhibiting α1-adrenergic receptor signaling pathway ameliorates AD-type pathologies and behavioral deficits in APPswe/PS1 mouse model.

The role of α1 adrenergic receptors (α1-ARs) signaling pathway in the pathogenesis of Alzheimer's disease (AD) has rarely been investigated. Clarifying the pathophysiological functions of α1-ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic targets of AD. This study included 2 arms of in vivo investigations: 1) 6-month-old female APPswe/PS1 mice were intravenously treated with AAV-PHP.eB-shRNA (α1-ARs)-GFP or AAV-PHP.eB-GFP for 3 months. 2) 3-month-old female APPswe/PS1 mice were daily treated with 0.5 mg/kg terazosin or an equal volume of saline for 6 months. SH-SY5Y cell lines bearing human amyloid precursor protein were treated with terazosin or saline for investigating possible mechanisms. α1-ARs knockdown mice exhibited improved behavioral performances in comparison with control mice. α1-ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aß species, compact and total Aß plaques, than control mice. α1-ARs inhibitor terazosin substantially reduced Aß deposition, attenuated downstream pathologies including tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction et al., and rescued behavioral deficits in APPswe/PS1 mice. In vitro investigation demonstrated that α1-ARs inhibition down-regulated BACE1 expression, and promoted ser9 phosphorylation of GSK-3ß, thus reducing Aß production. This study indicates that inhibition of α1-ARs signaling pathway might represent a promising therapeutic strategy for AD.

A type-2C protein phosphatase (GhDRP1) participates in cotton (Gossypium hirsutum) response to drought stress.

KEY MESSAGE: GhDRP1 acts as a negatively regulator to participate in response to drought stress possibly by modulating ABA signaling pathway and flavonoid biosynthesis pathway which affects stomata movement and thus water loss, ROS scavenging enzymes, and proline accumulation in cotton. Type-2C protein phosphatases (PP2C) may play important roles in plant stress signal transduction. Here, we show the evidence that a cotton PP2C protein GhDRP1 participates in plant response to drought stress. GhDRP1 gene encodes an active type-2C protein phosphatase (PP2C) and its expression is significantly induced in cotton by drought stress. Compared with wild type, the GhDRP1 overexpression (OE) transgenic cotton and Arabidopsis displayed reduced drought tolerance, whereas GhDRP1-silenced (RNAi) cotton showed enhanced drought tolerance. Under drought stress, malondialdehyde content was lower, whereas superoxide dismutase and peroxidase activities, proline content, stomata closure and relative water content were higher in GhDRP1 RNAi plants compared with those in wild type. In contrast, GhDRP1 OE plants showed the opposite phenotype under the same conditions. Expression levels of some stress-related and flavonoid biosynthesis-related genes were altered in GhDRP1 transgenic plants under drought stress. Additionally, GhDRP1 protein could interact with other proteins such as PYLs, SNF1-related protein kinase and GLK1-like protein. Collectively, these data suggest that GhDRP1 participates in plant response to drought stress possibly by modulating ABA signaling pathway and flavonoid biosynthesis pathway which affects stomata movement and thus water loss, ROS scavenging enzymes, and proline accumulation in cotton.

A novel fixed-dose combination treatment for chronic hepatitis C, based on NS5A inhibitor fopitasvir and NS5B inhibitor sofosbuvir.

Drug resistance caused by the extreme genetic variability of zhe hepatitis C virus has rendered effective combinations of drugs indispensable in the treatment of chronic hepatitis C (CHC). Herein, we developed a fixed-dose combination (FDC) treatment containing the NS5B inhibitor sofosbuvir (SOF) and the NS5A inhibitor fopitasvir (FOP). Then the dissolution behavior of FOP in FOP/SOF FDC was improved by co-micronizing FOP with lactose. The enhanced dissolution rate of FOP in the FDC was in good agreement with the behavior of the FOP singledrug tablet. In addition, pharmacokinetic studies showed that both FOP and SOF in the FDC exhibited similar characteristics (area under the curve, Cmax, Tmax, and T1/2) as those of tablets containing FOP or SOF alone. These results revealed that the FOP/SOF FDC represents a potential therapeutic option for the treatment of CHC.

Effect of glutamine on the growth performance, digestive enzyme activity, absorption function, and mRNA expression of intestinal transporters in heat-stressed chickens.

To explore the effect of glutamine (Gln) on the growth performance, digestive enzyme activity, absorption function and mRNA expression of intestinal transporters in heat-stressed chickens, 540 21-day-old Arbor Acres broilers were randomly assigned to a control group (no stress, NS), Gln group (Chickens were administered 0.5% and 1.0% Gln, respectively), heat stress group (HT), and Gln + HT group (Chickens were administered 0.5% and 1.0% Gln, respectively). The chickens in the HT and Gln + HT groups were reared under HT (36 ± 1 °C for 10 h/d and 22 ± 1 °C for 14 h/d), for 21 days. In contrast to the NS group, heat stress caused a reduction in the body weight gain (BWG); feed intake (FI); activity of trypsin, lipase, alkaline phosphatases, Ca2+ and Mg2+ adenosine triphosphatases, and Na+-K+-ATPase; and content of glutathione and d-xylose (P < 0.05) in the other groups. In addition, compared to the F:G and expression levels in the NS group, the heat stress increased the feed intake:body weight gain (F:G) and mRNA expression levels of SGLT1, CaBP-D28k, and L-GSBP (P < 0.05). Furthermore, HT-challenged birds were pretreated with Gln, the BWG; FI; activity of trypsin, lipase, alkaline phosphatase, Ca2+ and Mg2+ adenosine triphosphatases, and Na+-K+-ATPase; and content of glutathione and d-xylose (P < 0.05) were dramatically increased, but it decreased the F:G and mRNA expression levels of SGLT1, CaBP-D28k, and L-GSBP (P < 0.05) in the HT group. In summary, Gln can effectively improve growth performance and may promote digestion and absorption in the gastrointestinal tract by mediating the mRNA expression level of nutrient transporters and Gln metabolism in heat-stressed broilers.

Identification of a potent and selective phosphatidylinositol 3-kinase δ inhibitor for the treatment of non-Hodgkin's lymphoma.

PI3Kδ has proved to be an effective target for anti-lymphoma drugs. However, the application of current approved PI3Kδ inhibitors has been greatly limited due to their specific immune-mediated toxicity and increased risk of infection, it is necessary to develop more PI3Kδ inhibitors with new scaffold. In this study, SAR study with respect to piperazinone-containing purine derivatives led to the discovery of a potent and selective PI3Kδ inhibitor, 4-(cyclobutanecarbonyl)-1-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-2-one (WNY1613). WNY1613 exhibits good antiproliferative activity against a panel of non-Hodgkin's lymphoma (NHL) cell lines by inducing cancer cell apoptosis and inhibiting the phosphorylation of PI3K and MAPK downstream components. In addition, it can also prevent the tumor growth in both SU-DHL-6 and JEKO-1 xenograft models without observable toxicity. WNY1613 thus could be developed as a promising candidate for the treatment of NHL after subsequent extensive pharmacodynamics and pharmacokinetics investigation.