A serious problem currently facing the field of wound healing is bacterial infection, especially
(
) infection. Although the application of antibiotics has achieved good effects, their irregular use ...has resulted in the emergence of drug-resistant strains. It is thus the purpose of this study to analyze whether the naturally extracted phenolic compound, juglone, can inhibit
in wound infection. The results show that the minimum inhibitory concentration (MIC) of juglone against
was 1000 μg/mL. Juglone inhibited the growth of
by inhibiting membrane integrity and causing protein leakage. At sub-inhibitory concentrations, juglone inhibited biofilm formation, the expression of α-hemolysin, the hemolytic activity, and the production of proteases and lipases of
. When applied to infected wounds in Kunming mice, juglone (50 μL juglone with a concentration of 1000 μg/mL) significantly inhibited the number of
and had a significant inhibitory effect on the expression of inflammatory mediators (TNF-α, IL-6 and IL-1β). Moreover, the juglone-treated group promoted wound healing. At the same time, in animal toxicity experiments, juglone had no obvious toxic effects on the main tissues and organs of mice, indicating that juglone has good biocompatibility and has the potential to be used in the treatment of wounds infected with
.
Heme oxygenase-1 (HO-1) is one of the most powerful cytoprotective proteins known. The goal of this study was to explore the effects of HO-1 in c-kit-positive cardiac cells (CPCs). Lin
/c-kit
CPCs ...were isolated and expanded from wild-type (WT), HO-1 transgenic (TG), or HO-1 knockout (KO) mouse hearts. Compared with WT CPCs, cell proliferation was significantly increased in HO-1
CPCs and decreased in HO-1
CPCs. HO-1
CPCs also exhibited a marked increase in new DNA synthesis during the S-phase of cell division, not only under normoxia (21% O
) but after severe hypoxia (1% O
for 16 h). These properties of HO-1
CPCs were associated with nuclear translocation (and thus activation) of Nrf2, a key transcription factor that regulates antioxidant genes, and increased protein expression of Ec-SOD, the only extracellular antioxidant enzyme. These data demonstrate that HO-1 upregulates Ec-SOD in CPCs and suggest that this occurs via activation of Nrf2, which thus is potentially involved in the crosstalk between two antioxidants, HO-1 in cytoplasm and Ec-SOD in extracellular matrix. Overexpression of HO-1 in CPCs may improve the survival and reparative ability of CPCs after transplantation and thus may have potential clinical application to increase efficacy of cell therapy.
Heme oxygenase-1 (HO-1) is an inducible stress-response protein that imparts antioxidant and antiapoptotic effects. However, its pathophysiological role in cardiac remodeling and chronic heart ...failure (HF) is unknown. We hypothesized that induction of HO-1 in HF alleviates pathological remodeling.
Adult male nontransgenic and myocyte-restricted HO-1 transgenic mice underwent either sham operation or coronary ligation to induce HF. Four weeks after ligation, nontransgenic HF mice exhibited postinfarction left ventricular (LV) remodeling and dysfunction, hypertrophy, fibrosis, oxidative stress, apoptosis, and reduced capillary density, associated with a 2-fold increase in HO-1 expression in noninfarcted myocardium. Compared with nontransgenic mice, HO-1 transgenic HF mice exhibited significantly (P<0.05) improved postinfarction survival (94% versus 57%) and less LV dilatation (end-diastolic volume, 46+/-8 versus 85+/-32 microL), mechanical dysfunction (ejection fraction, 65+/-9% versus 49+/-16%), hypertrophy (LV/tibia length 4.4+/-0.4 versus 5.2+/-0.6 mg/mm), interstitial fibrosis (11.2+/-3.1% versus 18.5+/-3.5%), and oxidative stress (3-fold reduction in tissue malondialdehyde). Moreover, myocyte-specific HO-1 overexpression in HF promoted tissue neovascularization and ameliorated myocardial p53 expression (2-fold reduction) and apoptosis. In isolated mitochondria, mitochondrial permeability transition was inhibited by HO-1 in a carbon monoxide (CO)-dependent manner and was recapitulated by the CO donor tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). HO-1-derived CO also prevented H2O2-induced cardiomyocyte apoptosis and cell death. Finally, in vivo treatment with CORM-3 alleviated postinfarction LV remodeling, p53 expression, and apoptosis.
HO-1 induction in the failing heart is an important cardioprotective adaptation that opposes pathological LV remodeling, and this effect is mediated, at least in part, by CO-dependent inhibition of mitochondrial permeability transition and apoptosis. Augmentation of HO-1 or its product, CO, may represent a novel therapeutic strategy for ameliorating HF.
Ruddlesden–Popper (R–P) phase layered chalcogenide perovskites had attracted broad interest as potential lead-free high-performance photovoltaic absorbers. Ca3Sn2S7 is a graphene-like RP phase ...perovskite with a ultrahigh carrier mobility and a more significant absorption coefficient in the visible light region than those of the classic hybrid halide perovskite MAPbI3. However, the ultra-low direct bandgap of Ca3Sn2S7 is unfavorable for the photovoltaic application. In this work, we addressed these issues by designing an anion-mixed RP phase perovskite with an appropriate direct bandgap. The idea was to adjust its bandgap with different O proportions from 7.14% to 35.71%. We considered more than 3000 derivative structures of Ca6Sn4S14−xOx (x = 1–5) that were related to the arrangement of mixed S/O atoms. To ensure that the computational models were based on the screened optimal structures, we found that Ca6Sn4S14−xOx (x = 4 and 5) could increase the bandgap of Ca3Sn2S7 into the range of 1.19 eV–1.64 eV and 1.02 eV–1.47 eV, respectively. Meanwhile, Ca6Sn4S14−xOx also had absorption coefficients beyond 105 cm−1. These results made them possible candidates as new-generation photovoltaic absorbers. We also trained the supervised graph convolutional network and the unsupervised Mat-generative adversarial networks (GAN) for accelerating the density functional theory (DFT) calculation of over 3000 structures. Even if considering the time to generate the training samples by DFT, we prove that the Mat-GAN strategy could reduce the DFT calculation consumption by more than 99%. In order to reveal the distributive characteristics of the arrangement of mixed S/O, we adopted active machine learning to analyze the differences of these structures. We found that the O atom would preferentially replace the S in the Sn–S–Sn position.
Autologous transplantation of cardiac progenitor cells (CPCs) alleviates myocardial dysfunction in the damaged heart; however, the mechanisms that contribute to their reparative qualities remain ...poorly understood. In this study, we examined CPC metabolism to elucidate the metabolic pathways that regulate their proliferative capacity. In complete growth medium, undifferentiated CPCs isolated from adult mouse heart proliferated rapidly (Td = 13.8 hours). CPCs expressed the Glut1 transporter and their glycolytic rate was increased by high extracellular glucose (Glc) concentration, in the absence of insulin. Although high Glc concentrations did not stimulate proliferation, glutamine (Gln) increased CPC doubling time and promoted survival under conditions of oxidative stress. In comparison with Glc, pyruvate (Pyr) or BSA‐palmitate, Gln, when provided as the sole metabolic substrate, increased ATP‐linked and uncoupled respiration. Although fatty acids were not used as respiratory substrates when present as a sole carbon source, Gln‐induced respiration was doubled in the presence of BSA‐palmitate, suggesting that Gln stimulates fatty acid oxidation. Additionally, Gln promoted rapid phosphorylation of the mTORC1 substrate, p70S6k, as well as retinoblastoma protein, followed by induction of cyclin D1 and cdk4. Inhibition of either mTORC1 or glutaminolysis was sufficient to diminish CPC proliferation, and provision of cell permeable α‐ketoglutarate in the absence of Gln increased both respiration and cell proliferation, indicating a key role of Gln anaplerosis in cell growth. These findings suggest that Gln, by enhancing mitochondrial function and stimulating mTORC1, increases CPC proliferation, and that interventions to increase Gln uptake or oxidation may improve CPC therapy. Stem Cells 2015;33:2613—2627
Alpha-hemolysin (Hla) is one of the important exotoxins of
(
and can be used as a target to reduce the virulence of
. This study explored the inhibitory effect of Lysine (Lys) on Hla and its ...application in food safety. Lys significantly inhibited the expression of Hla at sub-inhibitory concentrations and directly interacted with Hla to interfere with its oligomerization and thus significantly inhibited its hemolytic activity. Notably, Lys attenuated
damage to mouse small intestine and Caco-2 cells and delayed mouse mortality. In the food model, Lys inhibited the expression of Hla of
and had no significant effect on the sensory score. Moreover, Lys had no obvious damage effect on the main organs of mice, which indicated that Lys has good biocompatibility and has the potential to be used in the food industry as an anti-
preparation.
Abstract Background The authors previously reported that the c-kit–positive (c-kitPOS ) cells isolated from slowly adhering (SA) but not from rapidly adhering (RA) fractions of cardiac mesenchymal ...cells (CMCs) are effective in preserving left ventricular (LV) function after myocardial infarction (MI). Objectives This study evaluated whether adherence to plastic alone, without c-kit sorting, was sufficient to isolate reparative CMCs. Methods RA and SA CMCs were isolated from mouse hearts, expanded in vitro, characterized, and evaluated for therapeutic efficacy in mice subjected to MI. Results Morphological and phenotypic analysis revealed that murine RA and SA CMCs are indistinguishable; nevertheless, transcriptome analysis showed that they possess fundamentally different gene expression profiles related to factors that regulate post-MI LV remodeling and repair. A similar population of SA CMCs was isolated from porcine endomyocardial biopsy samples. In mice given CMCs 2 days after MI, LV ejection fraction 28 days later was significantly increased in the SA CMC group (31.2 ± 1.0% vs. 24.7 ± 2.2% in vehicle-treated mice; p < 0.05) but not in the RA CMC group (24.1 ± 1.2%). Histological analysis showed reduced collagen deposition in the noninfarcted region in mice given SA CMCs (7.6 ± 1.5% vs. 14.5 ± 2.8% in vehicle-treated mice; p < 0.05) but not RA CMCs (11.7 ± 1.7%), which was associated with reduced infiltration of inflammatory cells (14.1 ± 1.6% vs. 21.3 ± 1.5% of total cells in vehicle and 19.3 ± 1.8% in RA CMCs; p < 0.05). Engraftment of SA CMCs was negligible, which implies a paracrine mechanism of action. Conclusions We identified a novel population of c-kit–negative reparative cardiac cells (SA CMCs) that can be isolated with a simple method based on adherence to plastic. SA CMCs exhibited robust reparative properties and offered numerous advantages, appearing to be more suitable than c-kitPOS cardiac progenitor cells for widespread clinical therapeutic application.
Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 × 10
c-kit positive cardiac cells (CPCs) are more ...effective than a single dose of 1 × 10
cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 × 10
cells each) can be fully replicated by a single combined dose of 3 × 10
CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle × 3; (2) one combined dose of CPCs (3 × 10
) and vehicle × 2; or (3) three doses of CPCs (1 × 10
each). In the combined-dose group, left ventricular ejection fraction (LVEF) improved after the 1st CPC infusion, but not after the 2nd and 3rd (vehicle) infusions. In contrast, in the multiple-dose group, LVEF increased after each CPC infusion; at the final echo, LVEF averaged 35.2 ± 0.6% (
< 0.001 vs. the vehicle group, 27.3 ± 0.2%). At the end of the study, the total cumulative change in EF from pretreatment values was numerically greater in the multiple-dose group (6.6 ± 0.6%) than in the combined-dose group (4.8 ± 0.8%), although the difference was not statistically significant (
= 0.08). Hemodynamic studies showed that several parameters of LV function in the multiple-dose group were numerically greater than in the combined-dose group (
= 0.08 for the difference in LVEF). Compared with vehicle, cardiomyocyte cross-sectional area was reduced only in the multiple-dose group (-32.7%, 182.6 ± 15.1 µm
vs. 271.5 ± 27.2 µm
,
< 0.05, in the risk region and -28.5%, 148.5 ± 12.1 µm
vs. 207.6 ± 20.5 µm
,
< 0.05, in the noninfarcted region). LV weight/body weight ratio and LV weight/tibia length ratios were significantly reduced in both cell treated groups vs. the vehicle group, indicating the attenuation of LV hypertrophy; however, the lung weight/body weight ratio was significantly reduced only in the multiple-dose group, suggesting decreased pulmonary congestion. Taken together, these results indicate that in mice with chronic ischemic cardiomyopathy, the beneficial effects of three doses of CPCs on LV function and hypertrophy cannot be fully replicated with a single dose, notwithstanding the fact that the total number of cells delivered with one or three doses is the same. Thus, it is the multiplicity of doses, and not the total number of cells, that accounts for the superiority of the repeated-dose paradigm. This study supports the idea that the efficacy of cell therapy in heart failure can be augmented by repeated administrations.
Background
We have recently found that 3 repeated doses (12×106 each) of c‐kitPOS cardiac progenitor cells (CPCs) were markedly more effective than a single dose of 12×106 cells in alleviating ...postinfarction left ventricular dysfunction and remodeling. However, since the single‐dose group received only one third of the total number of CPCs given to the multiple‐dose group, it is unknown whether the superior therapeutic efficacy was caused by repeated treatments per se or by administration of a higher total number of CPCs. This issue has major clinical implications because multiple cell injections in patients pose significant challenges, which would be obviated by using 1 large injection. Accordingly, we determined whether the beneficial effects of 3 repeated CPC doses can be recapitulated by 1 large dose containing the same total number of cells.
Methods and Results
Rats with a 30‐day‐old myocardial infarction received 3 echo‐guided intraventricular infusions, 35 days apart, of vehicle‐vehicle‐vehicle, 36×106 CPCs‐vehicle‐vehicle, or 3 equal doses of 12×106 CPCs. Infusion of a single, large dose of CPCs (36×106 cells) produced an initial improvement in left ventricular function, but no further improvement was observed after the second and third infusions (both vehicle). In contrast, each of the 3 doses of CPCs (12×106) caused a progressive improvement in left ventricular function, the cumulative magnitude of which was greater than with a single dose. Unlike the single dose, repeated doses reduced collagen content and immune cell infiltration.
Conclusions
Three repeated doses of CPCs are superior to 1 dose even though the total number of cells infused is the same, possibly because of greater antifibrotic and anti‐inflammatory actions.
A model of intracoronary stem cell delivery that enables transgenesis/gene targeting would be a powerful tool but is still lacking. To address this gap, we compared intracoronary and intramyocardial ...delivery of lin
−
/c-kit
+
/GFP
+
cardiac stem cells (CSCs) in a murine model of reperfused myocardial infarction (MI). Lin
−
/c-kit
+
/GFP
+
CSCs were successfully expanded from GFP transgenic hearts and cultured with no detectable phenotypic change for up to ten passages. Intracoronary delivery of CSCs 2 days post-MI resulted in significant alleviation of adverse LV remodeling and dysfunction, which was at least equivalent, if not superior, to that achieved with intramyocardial delivery. Compared with intramyocardial injection, intracoronary infusion was associated with a more homogeneous distribution of CSCs in the infarcted region and a greater increase in viable tissue in this region, suggesting greater formation of new cardiomyocytes. Intracoronary CSC delivery resulted in improved function in the infarcted region, as well as in improved global LV systolic and diastolic function, and in decreased LV dilation and LV expansion index; the magnitude of these effects was similar to that observed after intramyocardial injection. We conclude that, in the murine model of reperfused MI, intracoronary CSC infusion is at least as effective as intramyocardial injection in limiting LV remodeling and improving both regional and global LV function. The intracoronary route appears to be superior in terms of uniformity of cell distribution, myocyte regeneration, and amount of viable tissue in the risk region. To our knowledge, this is the first study to report that intracoronary infusion of stem cells in mice is feasible and effective.
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