Translating mesenchymal stem cell and their exosome research into GMP compliant advanced therapy products: Promises, problems and prospects.

Mesenchymal stem cells (MSCs) are one of the few stem cell types used in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair, due to their unique paracrine capacity, multiple differentiation potential, active components in exosomes, and effective mitochondria donation. At present, MSCs derived from tissues such as bone marrow and umbilical cord are widely applied in preclinical and clinical studies. Nevertheless, there remain challenges to the maintenance of consistently good quality MSCs derived from different donors or tissues, directly impacting their application as advanced therapy products. In this review, we discuss the promises, problems, and prospects associated with translation of MSC research into a pharmaceutical product. We review the hurdles encountered in translation of MSCs and MSC-exosomes from the research bench to an advanced therapy product compliant with good manufacturing practice (GMP). These difficulties include how to set up GMP-compliant protocols, what factors affect raw material selection, cell expansion to product formulation, establishment of quality control (QC) parameters, and quality assurance to comply with GMP standards. To avoid human error and reduce the risk of contamination, an automatic, closed system that allows real-time monitoring of QC should be considered. We also highlight potential advantages of pluripotent stem cells as an alternative source for MSC and exosomes generation and manufacture.

Clinical plasma cells-related genes to aid therapy in colon cancer.

The tumor immune microenvironment (TIME) of colon cancer (CC) has been associated with extensive immune cell infiltration (IMI). Increasing evidence demonstrated that plasma cells (PC) have an extremely important role in advance of antitumor immunity. Nonetheless, there is a lack of comprehensive analyses of PC infiltration in clinical prognosis and immunotherapy in CC. This study systematically addressed the gene expression model and clinical information of CC patients. Clinical samples were obtained from the TCGA (The Cancer Genome Atlas) databases. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), GSVA, and the MAlignant Tumors using Expression data (ESTIMATE) algorithm were employed to research the potential mechanism and pathways. Immunophenoscore (IPS) was obtained to evaluate the immunotherapeutic significance of risk score. Half maximal inhibitory concentration (IC50) of chemotherapeutic medicine was predicted by employing the pRRophetic algorithm. A total of 513 CC samples (including 472 tumor samples and 41 normal samples) were collected from the TCGA-GDC database. Significant black modules and 313 candidate genes were considered PC-related genes by accessing WGCNA. Five pivotal genes were established through multiple analyses, which revealed excellent prognostic. The underlying correlation between risk score with tumor mutation burden (TMB) was further explored. In addition, the risk score was obviously correlated with various tumor immune microenvironment (TIME). Also, risk CC samples showed various signaling pathways activity and different pivotal sensitivities to administering chemotherapy. Finally, the biological roles of the CD177 gene were uncovered in CC.

Anti-Fatigue Effects of Lycium barbarum Polysaccharide and Effervescent Tablets by Regulating Oxidative Stress and Energy Metabolism in Rats.

The purpose of this study was to investigate the anti-fatigue effect of natural Lycium barbarum polysaccharide (LBP) during exercise, develop a functional anti-fatigue effervescent tablet by applying LBP to practical products, and help patients who have difficulty swallowing conventional tablets or capsules. LBP was extracted with water, and DEAE-52 cellulose was used for purification. The chemical structure and monosaccharide composition of LBP by Fourier transform infrared spectroscopy (FI-IR) and ion chromatography (IC). Lycium barbarum polysaccharide effervescent tablets (LBPT) were prepared by mixing LBP and an excipient. Animal experiments showed that LBP and LBPT significantly increased the exhaustive swimming time in rats. LBP and LBPT improved biochemical markers in rat serum, such as lactic acid and creatine kinase, enhanced the antioxidant capacity of rat muscle, and reversed the decrease in serum glucose, ATP and glycogen content caused by exercise. Transmission electron microscopy showed that LBP and LBPT increased the density of mitochondria in rat liver. In addition, molecular experiments showed that LBP and LBPT could improve oxidative stress caused by exercise by regulating the Nrf2/HO-1 signaling pathway and regulating energy metabolism via the AMPK/PGC-1α signaling pathway.

Click Chemistry-Actuated Digital DNA Walker Confined on a Single Particle toward Absolute MicroRNA Quantification.

A versatile single magnetic nanoparticle (MNP)-confined, click chemistry-actuated digital DNA walker (ddWalker) machine is devised for the absolute quantification of microRNA (miRNA). This delicate ddWalker allows one target molecule to fix one DNA walking leg on a single MNP, following the Poisson statistics through a specific click chemical DNA ligation, which will initiate single molecule DNA walking to stepwise cleave the molecular beacon tracks strictly constrained on the leg-hold MNP without cross-particle reaction, fluorescently "lighting up" the exact MNP. Accordingly, the initial miRNA input can be digitally and faithfully reflected by the number of fluorescent-positive MNPs counted by a total internal reflection fluorescent microscope, enabling the absolute and precise miRNA quantification down to the femtomolar level without external calibration. This flexible ddWalker design provides a new digital signaling concept and elegantly expands the toolbox for digital biosensing.

Molecular mechanisms of quinalizarin induces apoptosis and G0/G1 cell cycle of human esophageal cancer HCE-4 cells depends on MAPK, STAT3, and NF-κB signaling pathways.

Quinalizarin (Quina) is one of the main components of many herbal medicines and has good anti-tumor activity. However, the exact mode of cytotoxic action and signaling pathways on Quina in human esophageal cancer has not yet been confirmed. In this study, we explored the anticancer effect of Quina against human esophageal cancer HCE-4 cells and the underlying mechanisms. The results of the Cell Counting Kit-8 (CCK-8) assay showed that Quina inhibited the viability of human esophageal cancer HCE-4 cells in a dose-dependent and time-dependent manner. It also inhibited HCE-4 cells proliferation and induced apoptosis by increasing the levels of Bad, caspase-3, and PARP, decreasing the level of Bcl-2. The results of the cell cycle analysis suggested that Quina arrested HCE-4 cells in the G0/G1 cycle by downregulating cyclin-dependent (CDK) 2/4, cyclin D1/E and upregulating the levels of p21 and p27. We also found that Quina activated mitogen-activated protein kinase (MAPK) and inhibited the signal transducer and activator of transcription-3 (STAT3) and nuclear factor kappa B (NF-κB) signaling pathways. Furthermore, Quina significantly increased intracellular reactive oxygen species (ROS) level. The pretreatment of N-acetyl-L-cysteine (NAC) blocked the apoptosis induced by Quina and inhibited the activities of MAPK, STAT3, and NF-κB signaling pathways. These results indicate that Quina induces the apoptosis in HCE-4 cells, which is via accumulating ROS generation and regulating MAPK, STAT3, and NF-κB. In conclusion, this study demonstrated that Quina have good therapeutic effects on human esophageal cancer cells.

Glycitein induces reactive oxygen species-dependent apoptosis and G0/G1 cell cycle arrest through the MAPK/STAT3/NF-κB pathway in human gastric cancer cells.

Glycitein is an isoflavone that reportedly inhibits the proliferation of human breast cancer and prostate cancer cells. However, its anti-cancer molecular mechanisms in human gastric cancer remain to be defined. This study evaluated the antitumor effects of glycitein on human gastric cancer cells and investigated the underlying mechanisms. We used MTT assay, flow cytometry and western blotting to investigate its molecular mechanisms with focus on reactive oxygen species (ROS) production. Our results showed that glycitein had significant cytotoxic effects on human gastric cancer cells. Glycitein markedly decreased mitochondrial transmembrane potential (ΔΨm) and increased AGS cells mitochondrial-related apoptosis, and caused G0/G1 cell cycle arrest by regulating cycle-related protein. Mechanistically, accompanying ROS, glycitein can activate mitogen-activated protein kinase (MAPK) and inhibited the signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappaB (NF-κB) signaling pathways. Furthermore, the MAPK signaling pathway regulated the expression levels of STAT3 and NF-κB upon treatment with MAPK inhibitor and N-acetyl-L-cysteine (NAC). These findings suggested that glycitein induced AGS cell apoptosis and G0/G1 phase cell cycle arrest via ROS-related MAPK/STAT3/NF-κB signaling pathways. Thus, glycitein has the potential to a novel targeted therapeutic agent for human gastric cancer.

The Influence of Layer Stacking Method on the Mechanical Properties of Honeycomb Skeleton.

The performance of a multi-layer honeycomb skeleton can be significantly enhanced through tandem connection, while the structure's properties can be tailored by altering the layer stacking method of the honeycomb skeleton. To investigate the impact of layer stacking methods on the mechanical properties of multilayer honeycomb skeletons, 3D printing technology was used to prepare double-layer honeycomb skeleton tandem structures with different dislocation modes in compression testing. A finite element simulation model was established to conduct quasi-static simulation research. Compared to that of a single-layer honeycomb skeleton, the energy absorption of the honeycomb skeleton tandem structure increased. The optimal bearing capacity of the honeycomb skeleton was achieved when the upper and lower layers were precisely aligned. Once dislocation occurred, both the value of average platform stress and energy absorption decreased. Then, the bearing capacity of the honeycomb skeleton tandem structures increased with an enlargement of the dislocation, reaching its maximum at the half-dislocation period. An increase in the partition thickness and stiffness led to a reduction in the dislocation-induced effects on the mechanical properties. The research results can provide theoretical and data support for the engineering application of honeycomb skeleton tandem structures.

The impact of long-term orientation on compulsive buying behavior: A cross-cultural study.

The overall purpose of this study was to investigate the wider impacts of cultural values on consumer compulsive buying from a cross-cultural perspective. This study considers the long-term orientation as an extended antecedent to explore the moderating role of materialism value and money attitude on compulsive buying behavior in different cultures. Survey results from 313 Chinese and 309 U.S. consumers indicate that the higher materialistic values drive compulsive buying though some differences exist between consumers in both countries. To specify, American buyers had a higher materialistic orientation and higher compulsive buying tendencies than Chinese consumers. Furthermore, the results indicate that money attitudes are negatively related to compulsive buying behaviors among two countries' consumers. Lastly, this study found that long-term orientations were found to significantly influence money attitudes and compulsive buying among Chinese consumers.

The Association Between Serum Palmitic Acid and Thyroid Function.

Aim: Emerging evidence indicates that palmitic acid (PA) can regulate the progression and development of many diseases. However, the studies examining the association between PA and thyroid function remain sparse. We aimed to investigate the association between serum PA (sPA) and thyroid function in the US population. Methods: In this retrospective study, a cross-sectional analysis was performed using the data pooled from the database of the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2012. The thyroid parameters investigated were mainly free triiodothyronine (FT3), free thyroxine (FT4), total T3 (TT3), TT4, thyroglobulin (Tg), thyroid-stimulating hormone (TSH), anti-thyroglobulin antibody (TgAb), and anti-thyroperoxidase antibody (TPOAb). The central sensitivity to thyroid function was evaluated by the thyroid feedback quantile-based index (TFQI), thyrotrophin thyroxine resistance index (TT4RI), and thyrotropin index (TSHI). The FT3 to FT4 ratio (FT3/FT4) was employed to evaluate peripheral sensitivity to thyroid hormones. Multiple imputation was applied to handle the missing data, and weighted multivariable linear regression, subgroup, and interaction analyses were then employed to estimate the association between sPA and thyroid parameters. Results: In the 737 adults, after adjusting covariates, we demonstrated a significant negative association between sPA and FT4 [ß = -1.078, 95% confidence interval (CI): -1.729 to -0.427], as well as a positive relationship between sPA and FT3/FT4 ratio (ß = 0.073, 95% CI: 0.044 to 0.102). These results did not change on multiple imputations. In the subgroup analyses, the associations were more significant in male and obese subjects. Conclusion: This investigation demonstrated the significant correlation between sPA and thyroid dysfunction, which suggested the close relationship between lipotoxicity and hypothyroidism or subclinical hypothyroidism. Future research is required to confirm these findings.

Quinalizarin induces ROS­mediated apoptosis via the MAPK, STAT3 and NF­κB signaling pathways in human breast cancer cells.

Quinalizarin has been demonstrated to exhibit potent antitumor activities in lung cancer and gastric cancer cells, but currently, little is known regarding its anticancer mechanisms in human breast cancer cells. The aim of the present study was to investigate the apoptotic effects of quinalizarin in MCF­7 cells and to analyze its molecular mechanisms. The MTT assay was used to evaluate the viability of human breast cancer cells that had been treated with quinalizarin and 5­fluorouracil. Flow cytometric analyses and western blotting were used to investigate the effects of quinalizarin on apoptosis and cycle arrest in MCF­7 cells with focus on reactive oxygen species (ROS) production. The results demonstrated that quinalizarin exhibited significant cytotoxic effects on human breast cancer cells in a dose­dependent manner. Accompanying ROS, quinalizarin induced MCF­7 cell mitochondrial­associated apoptosis by regulating mitochondrial­associated apoptosis, and caused cell cycle arrest at the G2/M phase in a time­dependent manner. Furthermore, quinalizarin can activate p38 kinase and JNK, and inhibit the extracellular signal­regulated kinase, signal transducer and activator of transcription 3 (STAT3) and NF­κB signaling pathways. These effects were blocked by mitogen­activated protein kinase (MAPK) inhibitor and N­acetyl­L­cysteine. The results from the present study suggested that quinalizarin induced G2/M phase cell cycle arrest and apoptosis in MCF­7 cells through ROS­mediated MAPK, STAT3 and NF­κB signaling pathways. Thus, quinalizarin may be useful for human breast cancer treatment, as well as the treatment of other cancer types.

A Novel Cluster Head Selection Algorithm Based on Fuzzy Clustering and Particle Swarm Optimization.

An important objective of wireless sensor network is to prolong the network life cycle, and topology control is of great significance for extending the network life cycle. Based on previous work, for cluster head selection in hierarchical topology control, we propose a solution based on fuzzy clustering preprocessing and particle swarm optimization. More specifically, first, fuzzy clustering algorithm is used to initial clustering for sensor nodes according to geographical locations, where a sensor node belongs to a cluster with a determined probability, and the number of initial clusters is analyzed and discussed. Furthermore, the fitness function is designed considering both the energy consumption and distance factors of wireless sensor network. Finally, the cluster head nodes in hierarchical topology are determined based on the improved particle swarm optimization. Experimental results show that, compared with traditional methods, the proposed method achieved the purpose of reducing the mortality rate of nodes and extending the network life cycle.