Flavonoids are well-known antioxidants and have shown the ability to prevent tumor formation and recurrence. Especially in dietary flavonoids, they have provided convenience and consistence of intake ...for long-term prevention of tumor formation. Previous reports suggested that S100 calcium-binding protein A7 (S100A7) might activate epithelial-mesenchymal transition (EMT) signaling and promote the metastasis of tumor cells; however, the regulatory signaling was unclear. In this study, we found that S100A7 was highly expressed in cancer cells and could be reduced by luteolin (Lu) and quercetin (Qu) through Src/Stat3 signaling. We found that the protein levels of S100A7, phosphorylated Src (p-Src), and p-Stat3 were increased in A431-III cells. Flavonoids Lu and Qu reduce protein levels of p-Src, p-Stat3 and S100A7 in A431-III cells. Treatment of A431-III cells with Src inhibitor SU6656 and Stat3 inhibitor S3I-201 also reduced the protein levels of S100A7. Transactivation activity of 5'-upstream regions of
was activated by Stat3 but was reduced by treatment with Lu, Qu, SU6656 and S3I-201. The treatment also reduced the migratory and invasive abilities of A431-III cells. In a further analysis of EMT markers, the protein level of E-cad increased and that of Twist decreased after treatment with the inhibitors and flavonoids. Overexpression of S100A7 decreased the protein level of E-cad and increased the Twist level, whereas knockdown of S100A7 had the opposite effects. Treatment with S3I-201, Lu and Qu, compared to the control, were found to decrease metastasis of tumor cells in zebrafish larvae. These results suggest that Lu and Qu may inhibit Src/Stat3/S100A7 signaling to reduce tumorigenesis of cancer cells.
The immune system plays an important role in maintaining body homeostasis. Recent studies on the immune-enhancing effects of ginseng saponins have revealed more diverse mechanisms of action. Maillard ...reaction that occurs during the manufacturing processes of red ginseng produces a large amount of Amadori rearrangement compounds (ARCs), such as arginyl-fructose (AF). The antioxidant and anti-hyperglycemic effects of AF have been reported. However, the possible immune enhancing effects of non-saponin ginseng compounds, such as AF, have not been investigated. In this study the effects of AF and AF-enriched natural product (Ginofos, GF) on proliferation of normal mouse splenocytes were evaluated in vitro and male BALB/c mice models. The proliferation of splenocytes treated with mitogens (concanavalin A, lipopolysaccharide) were further increased by addition of AF (
< 0.01) or GF (
< 0.01), in a dose dependent manner. After the 10 days of oral administration of compounds, changes in weights of spleen and thymus, serum immunoglobulin, and expression of cytokines were measured as biomarkers of immune-enhancing potential in male BALB/c mice model. The AF or GF treated groups had higher weights of the thymus (0.94 ± 0.25 and 0.86 ± 0.18,
< 0.05, respectively) than that of cyclophosphamide treated group (0.59 ± 0.18). This result indicates that AF or AF-enriched extract (GF) increased humoral immunity against CY-induced immunosuppression. In addition, immunoglobulin contents and expression of cytokines including IgM (
< 0.01), IgG (
< 0.05), IL-2 (
< 0.01), IL-4 (
< 0.01), IL-6 (
< 0.01), and IFN-γ (
< 0.05) were also significantly increased by supplementation of AF or GF. These results indicate that AF has immune enhancing effects by activation of adaptive immunity via increase of expression of immunoglobulins and cytokines such as IgM, IgG, IL-2, IL-4, IL-6 and thereby proliferating the weight of thymus. Our findings provide a pharmacological rationale for AF-enriched natural products such as ginseng and red ginseng that can possibly have immune-enhancement potential and should be further evaluated.
(
), a rapidly growing nontuberculous mycobacterium (NTM), can infect humans (posttraumatic wound infections and catheter-related sepsis). Similar to other NTM species,
exhibits colony morphologies ...of rough (
-R) and smooth (
-S) types. Although there are several case reports on
infection, no experimental evidence supports that the R-type is more virulent. In addition, the immune response and metabolic reprogramming of
have not been studied on the basis of morphological characteristics. Thus, a standard ATCC
strain and two clinical strains were analyzed, and macrophages were generated from mouse bone marrow. Cytokines and cell death were measured by ELISA and FACS, respectively. Mitochondrial respiration and glycolytic changes were measured by XF seahorse. Higher numbers of intracellular bacteria were found in
-R-infected macrophages than in
-S-infected macrophages. Additionally,
-R induced higher levels of the cytokines TNF-α, IL-6, IL-12p40, and IL-10 and induced more BMDM necrotic death. Furthermore, our metabolic data showed marked glycolytic and respiratory differences between the control and each type of
infection, and changes in these parameters significantly promoted glucose metabolism, extracellular acidification, and oxygen consumption in BMDMs. In conclusion, at least in the strains we tested,
-R is more virulent, induces a stronger immune response, and shifts bioenergetic metabolism more extensively than the S-type. This study is the first to report differential immune responses and metabolic reprogramming after
infection and might provide a fundamental basis for additional studies on
pathogenesis.
Future changes in the stratospheric circulation could have an important impact on northern winter tropospheric climate change, given that sea level pressure (SLP) responds not only to tropospheric ...circulation variations but also to vertically coherent variations in troposphere‐stratosphere circulation. Here we assess northern winter stratospheric change and its potential to influence surface climate change in the Coupled Model Intercomparison Project‐Phase 5 (CMIP5) multimodel ensemble. In the stratosphere at high latitudes, an easterly change in zonally averaged zonal wind is found for the majority of the CMIP5 models, under the Representative Concentration Pathway 8.5 scenario. Comparable results are also found in the 1% CO2 increase per year projections, indicating that the stratospheric easterly change is common feature in future climate projections. This stratospheric wind change, however, shows a significant spread among the models. By using linear regression, we quantify the impact of tropical upper troposphere warming, polar amplification, and the stratospheric wind change on SLP. We find that the intermodel spread in stratospheric wind change contributes substantially to the intermodel spread in Arctic SLP change. The role of the stratosphere in determining part of the spread in SLP change is supported by the fact that the SLP change lags the stratospheric zonally averaged wind change. Taken together, these findings provide further support for the importance of simulating the coupling between the stratosphere and the troposphere, to narrow the uncertainty in the future projection of tropospheric circulation changes.
Key Points
Stratospheric easterly change is common feature in future climate projections
Significant intermodel spread in stratospheric northern winter climate change
Importance of stratospheric easterly change to narrow uncertainty in SLP change
In this study, we investigate metallic nanocomposites to elucidate the properties of nanostructured conventional superconductors. Liquid tin, indium, and mercury are loaded into opal matrices by high ...pressure up to 10 kbar. The opal templates preserve the 3D dendritic morphology of confined superconducting metals to model a dendritic second phase with particular grain shape in bulk superconductors observed by a DualBeam microscope. We carry out measurements of the dc and ac magnetizations to study the superconducting phase diagrams, vortex dynamics, and impact of grain morphology in the opal composites. Besides, we apply the small-angle neutron scattering (SANS) to deny a regular vortex structure. The phase diagrams reveal an enhanced upper critical field H
(0) and curvature crossover in the upper critical field line. We also calculate the vortex activation barriers U
and observe a transformation in the vortex system. According to the field dependence of U
, the vortex structure transformation highly correlates with the curvature crossover in the upper critical field line. Our observations suggest that the similarity in the normalized phase diagrams and field dependences of U
in the three nanocomposites is owing to their particular morphology of confinement.
Ulcerative colitis is a complex inflammatory bowel disorder disease that can induce rectal and colonic dysfunction. Although the prevalence of IBD in Western countries is almost 0.5% of the general ...population, genetic causes are still not fully understood. In a recent discovery, itaconate was found to function as an immune-modulating metabolite in mammalian immune cells, wherein it is synthesized as an antimicrobial compound from the citric acid cycle intermediate cis-aconitic acid. However, the association between the Acod1 (Aconitate decarboxylase 1)-itaconate axis and ulcerative colitis has rarely been studied. To elucidate this, we established a DSS-induced colitis model with Acod1-deficient mice and then measured the mouse body weights, colon lengths, histological changes, and cytokines/chemokines in the colon. We first confirmed the upregulation of Acod1 RNA and protein expression levels in DSS-induced colitis. Then, we found that colitis symptoms, including weight loss, the disease activity index, and colon shortening, were worsened by the depletion of Acod1. In addition, the extent of intestinal epithelial barrier breakdown, the extent of immune cell infiltration, and the expression of proinflammatory cytokines and chemokines in Acod1-deficient mice were higher than those in wild-type mice. Finally, we confirmed that 4-octyl itaconate (4-OI) alleviated DSS-induced colitis in Acod1-deficient mice and decreased the expression of inflammatory cytokines and chemokines. To our knowledge, this study is the first to elucidate the role of the Acod1-itaconate axis in colitis. Our data clearly showed that Acod1 deletion resulted in severe DSS-induced colitis and substantial increases in inflammatory cytokine and chemokine levels. Our results suggest that Acod1 may normally play an important regulatory role in the pathogenesis of colitis, demonstrating the potential for novel therapies using 4-OI.
Original analytical data on trace elements and radiogenic Nd and Pb isotopes in the volcanic rocks of the Southern and southwestern part of the Northern plateaus of the underwater Vityaz Ridge are ...presented. Interpretation of these data and a comparison with published materials on the volcanic rocks from the southern and northern parts of the Kuril Island Arc (KIA), which formed on two basement blocks of different genetic nature, allow us to draw the following conclusions. The tholeiite varieties of volcanic rocks of the Southern Plateau and the southern part of the KIA have similar isotope-geochemical features, which point to the similar geodynamic conditions of the formation and the identical influence of low-temperature fluid on magma-generating processes. The geochemistry of the volcanic rocks of the Northern Plateau, which are mainly represented by subalkaline varieties, indicates a more pronounced contribution of the mantle component to the magmagenesis and a greater degree of influence of high-temperature melt compared to the rocks of the Southern Plateau, but a lesser degree compared to the rocks of the northern part of the arc. The volcanics of both plateaus are derivatives of a single mantle source, the MORB of the Indian Ocean (Indian MORB), and were formed together with the rocks of the southern part of the KIA within the lithospheric block transformed by tectonomagmatic processes that accompanied the opening of the Kuril Basin.
Although the incidence of
infection has recently increased significantly, treatment is difficult because this bacterium is resistant to most anti-tuberculosis drugs. In particular,
is often resistant ...to available macrolide antibiotics, so therapeutic options are extremely limited. Hence, there is a pressing demand to create effective drugs or therapeutic regimens for
infections. The aim of the investigation was to assess the capability of isoegomaketone (iEMK) as a therapeutic option for treating
infections. We determined the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of iEMK for both reference and clinically isolated
strains. In addition to time-kill and biofilm formation assays, we evaluated iEMK's capability to inhibit
growth in macrophages using an intracellular colony counting assay. iEMK inhibited the growth of reference and clinically isolated
strains in macrophages and demonstrated effectiveness at lower concentrations against macrophage-infected
than when used to treat the bacteria directly. Importantly, iEMK also exhibited anti-biofilm properties and the potential to mitigate macrolide-inducible resistance, underscoring its promise as a standalone or adjunctive therapeutic agent. Overall, our results suggest that further development of iEMK as a clinical drug candidate is promising for inhibiting
growth, especially considering its dual action against both planktonic bacteria and biofilms.
•LMWCS damages cell membrane of ZFL cells reducing cell viability.•LMWCS damages yolk of zebrafish larvae and gill filaments of adult zebrafish inducing death.•Purification and neutralization with ...Na2HPO4 could eliminate toxicity of LMWCS nanoparticle.
Chitosan is suggested as no or low toxicity and biocompatible biomaterial. Digestion of chitosan to reduce molecular weight and formulate nanoparticle was generally used to improve efficiency for DNA or protein delivery. However, the toxicity of low-molecular-weight chitosan (LMWCS) towards freshwater fishes has not been well evaluated. Here, we reported the toxic mechanism of LMWCS using zebrafish (Danio rerio) liver (ZFL) cell line, zebrafish larvae, and adult fish. LMWCS rapidly induced cytotoxicity of ZFL cells and death of zebrafish. Cell membrane damaged by LMWCS reduced cell viability. Damaged membrane of epithelial cell in zebrafish larvae induced breakage of the yolk. Adult fish exhibited hypoxia before death due to multiple damages induced by LMWCS. Although the toxicity of LMWCS was revealed in zebrafish model, the toxicity was only present in pH < 7 and easy be neutralized by other negative ions. Collectively, these data improved a new understanding of LMWCS properties.
Currently there is no neuroprotective or neurorestorative therapy for Parkinson's disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous ...production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP(+)-lesioned or adeno-associated virus α-synuclein rat models of Parkinson's disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson's disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRα on dopamine neurons) might have relevance to human Parkinson's disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson's disease.
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