As a widely used anticancer and immunosuppressive agent, methotrexate (MTX) can induce multiple adverse drug reactions (ADRs), such as gastrointestinal toxicity, the mechanisms are poorly understood. Gut microbiota has been widely reported to be associated with the onset of multiple diseases as well as treatment outcomes of different drugs. In this study, mucosal injury was observed in MTX-treated mice, leading to significant changes in macrophages (i.e., M1/M2 ratio, P < 0.05) but not in dendritic cells. Moreover, the population, diversity and principal components of the gut microbiota in mice were dramatically altered after MTX treatment in a time-dependent manner, and Bacteroidales exhibited the most distinct variation among all the taxa (P < 0.05). Bacteroides fragilis was significantly decreased with MTX treatment (P < 0.01) and tended to decrease proportionately with increasing macrophage density. Gavage of mice with B. fragilis ameliorated MTX-induced inflammatory reactions and modulate macrophage polarization. In conclusion, our results delineate a strong impact of the gut microbiota on MTX-induced intestinal mucositis and provide a potential method for the prevention of such ADRs.
A better understanding of hepatocyte senescence could be used to treat age-dependent disease processes of the liver. Whether continuously proliferating hepatocytes could avoid or reverse senescence has not yet been fully elucidated. We confirmed that the livers of aged mice accumulated senescent and polyploid hepatocytes, which is associated with accumulation of DNA damage and activation of p53-p21 and p16 ink4a -pRB pathways. Induction of multiple rounds continuous cell division is hard to apply in any animal model. Taking advantage of serial hepatocyte transplantation assays in the fumarylacetoacetate hydrolase-deficient (Fah 2/2 ) mouse, we studied the senescence of hepatocytes that had undergone continuous cell proliferation over a long time period, up to 12 rounds of serial transplantations. We demonstrated that the continuously proliferating hepatocytes avoided senescence and always maintained a youthful state. The reactivation of telomerase in hepatocytes after serial transplantation correlated with reversal of senescence. Moreover, senescent hepatocytes harvested from aged mice became rejuvenated upon serial transplantation, with full restoration of proliferative capacity. The same findings were also true for human hepatocytes. After serial transplantation, the high initial proportion of octoploid hepatocytes decreased to match the low level of youthful liver. Conclusion: These findings suggest that the hepatocyte "ploidy conveyer" is regulated differently during aging and regeneration. The findings of reversal of hepatocyte senescence could enable future studies on liver aging and cell therapy. (HEPATOLOGY 2014;60:349-361)
BackgroundHigh-intensity focused-ultrasound (HIFU) has been successfully employed for thermal ablation of tumors in clinical settings. Continuous- or pulsed-mode HIFU may also induce a host antitumor immune response, mainly through expansion of antigen-presenting cells in response to increased cellular debris and through increased macrophage activation/infiltration. Here we demonstrated that another form of focused ultrasound delivery, using low-pressure, pulsed-mode exposure in the presence of microbubbles (MBs), may also trigger an antitumor immunological response and inhibit tumor growth.MethodsA total of 280 tumor-bearing animals were subjected to sonographically-guided FUS. Implanted tumors were exposed to low-pressure FUS (0.6 to 1.4 MPa) with MBs to increase the permeability of tumor microvasculature.ResultsTumor progression was suppressed by both 0.6 and 1.4-MPa MB-enhanced FUS exposures. We observed a transient increase in infiltration of non-T regulatory (non-Treg) tumor infiltrating lymphocytes (TILs) and continual infiltration of CD8+ cytotoxic T-lymphocytes (CTL). The ratio of CD8+/Treg increased significantly and tumor growth was inhibited.ConclusionsOur findings suggest that low-pressure FUS exposure with MBs may constitute a useful tool for triggering an anticancer immune response, for potential cancer immunotherapy.
cTo design and discover new antimicrobial peptides (AMPs) with high levels of antimicrobial activity, a number of machinelearning methods and prediction methods have been developed. Here, we present a new prediction method that can identify novel AMPs that are highly similar in sequence to known peptides but offer improved antimicrobial activity along with lower host cytotoxicity. Using previously generated AMP amino acid substitution data, we developed an amino acid activity contribution matrix that contained an activity contribution value for each amino acid in each position of the model peptide. A series of AMPs were designed with this method. After evaluating the antimicrobial activities of these novel AMPs against both Gram-positive and Gram-negative bacterial strains, DP7 was chosen for further analysis. Compared to the parent peptide HH2, this novel AMP showed broad-spectrum, improved antimicrobial activity, and in a cytotoxicity assay it showed lower toxicity against human cells. The in vivo antimicrobial activity of DP7 was tested in a Staphylococcus aureus infection murine model. When inoculated and treated via intraperitoneal injection, DP7 reduced the bacterial load in the peritoneal lavage solution. Electron microscope imaging and the results indicated disruption of the S. aureus outer membrane by DP7. Our new prediction method can therefore be employed to identify AMPs possessing minor amino acid differences with improved antimicrobial activities, potentially increasing the therapeutic agents available to combat multidrug-resistant infections.A ntimicrobial peptides (AMPs) are produced by multicellular organisms to defend against microbial infections. Along with potent antimicrobial activity, many AMPs also have the ability to enhance immunity by functioning as immunomodulators (1-3). AMPs therefore have excellent therapeutic potential, especially in light of increased drug resistance to many conventional antibiotic therapies. A number of naturally occurring peptides and synthetic derivatives have been developed or are currently in development (2, 4-6). Although AMPs vary in length, amino acid composition, and structure, they share some similarities, such as electrical charge and amphipathicity (3, 7). To determine the characteristics that are important in antimicrobial activity, bioinformatic tools and prediction methods have been developed (8), all based to some extent on the sequence similarities between peptides (9-11).To optimize the antimicrobial activity of identified AMPs and to predict novel peptide sequences, we present a machine-learning method based on the concept of an antimicrobial activity contribution score for each amino acid. Here, we consider that each amino acid in a peptide sequence possesses a different level of importance for the biological activity of that peptide, and this is represented by an assigned score. By calculation of each amino acid's contribution score, we can predict the antimicrobial activity of an AMP.To verify our results, we tested some of our designed AMPs ...
A novel transparent electrode composed of alginate/silver nanowire (AgNW) with high conductivity and low roughness is fabricated via a solution process at room temperature. The sol-gel transition of the alginate triggered by CaCl solution bonds the AgNWs to the substrate tightly. Meanwhile, Cl in the solution can renovate the cracks on the AgNW surfaces created during the mechanical pressing, resulting in a great increase of the electrical conductivity. The alginate/AgNW composite film can reach a sheet resistance of 2.3 Ω/sq with a transmittance of 83% at 550 nm. The conductivity of the composite film remains stable after bending and tape tests, demonstrating excellent flexibility and great adhesion of AgNWs to the substrate. Moreover, the composite film shows better stability to resist longtime storage than conventional annealed-AgNW film. The organic light emitting diode using such alginate/AgNW composite film as anode presents current densities and luminances comparable to those of indium tin oxide (ITO) anode, and higher efficiencies are obtained due to the better charge balance.
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