Using an inducible, inflammatory model of breast cellular transformation, we describe the transcriptional regulatory network mediated by STAT3, NF-κB, and AP-1 factors on a genomic scale. These ...proinflammatory regulators form transcriptional complexes that directly regulate the expression of hundreds of genes in oncogenic pathways via a positive feedback loop. This transcriptional feedback loop and associated network functions to various extents in many types of cancer cells and patient tumors, and it is the basis for a cancer inflammation index that defines cancer types by functional criteria. We identify a network of noninflammatory genes whose expression is well correlated with the cancer inflammatory index. Conversely, the cancer inflammation index is negatively correlated with the expression of genes involved in DNA metabolism, and transformation is associated with genome instability. We identify drugs whose efficacy in cell lines is correlated with the cancer inflammation index, suggesting the possibility of using this index for personalized cancer therapy. Inflammatory tumors are preferentially associated with infiltrating immune cells that might be recruited to the site of the tumor via inflammatory molecules produced by the cancer cells.
There are global concerns about heavy metal (HM) contamination in soils, which in turn has produced an increased demand for soil remediation. Biochar has been widely documented to effectively ...immobilize metals in contaminated soils and has received increasing attention for use in soil remediation. Here, we review recent progresses in understanding metal-biochar interactions in soils, potential risks associated with biochar amendment, and application of biochar in soil remediation in China. These recent studies indicate that: (1) the remediation effect depends on the characteristics of both biochar and soil and their interactions; (2) biochar applications could decrease the mobility/bioavailability of HMs in soils and HM accumulation in plants; and (3) despite its advantages, biochar applications could pose ecological and health risks, e.g., by releasing toxic substances into soils or by inhalation of biochar dust. Research gaps still exist in the development of practical methods for preparing and applying different biochars that target specific HMs. In the future, the long term effects and security of biochar applications on soil remediation, soil organisms and plant growth need to be considered.
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•The metal-biochar interactions and mechanisms in soils were reviewed.•Potential risks associated with biochar amendment were discussed.•Cases of biochar application in soils in China were summarized.•Long term effects of biochar on soil remediation need further investigation.
The remediation of heavy metal contaminated soils by biochar in China was reviewed, including metal-biochar interactions and mechanisms, its application risk and status.
After wounding, multiple cell types interact to form a fibrovascular scar; the formation and cellular origins of these scars are incompletely understood. We used a laser-injury wound model of ...choroidal neovascularization in the eye to determine the spatiotemporal cellular events that lead to formation of a fibrovascular scar. After laser injury, F4/80+ myeloid cells infiltrate the wound site and induce smooth muscle actin (SMA) expression in adjacent retinal pigment epithelial cells, with subsequent formation of a SMA+ NG2+ myofibroblastic scaffold, into which endothelial cells then infiltrate to form a fibrovascular lesion. Cells of the fibrovascular scaffold express the proangiogenic factor IL-1β strongly, whereas retinal pigment epithelial cells are the main source of VEGF-A. Subsequent choroidal neovascularization is limited to the area demarcated by this myofibroblastic scaffold and occurs independently of epithelial- or myeloid-derived VEGF-A. The SMA+ NG2+ myofibroblastic cells, F4/80+ macrophages, and adjacent epithelial cells actively proliferate in the early phase of the wound healing response. Cell-lineage tracing experiments suggest that the SMA+ NG2+ myofibroblastic scaffold originates from choroidal pericyte-like cells. Targeted ablation of macrophages inhibits the formation of this fibrovascular scaffold, and expression analysis reveals that these macrophages are Arg1+ YM1+ F4/80+ alternatively activated M2-like macrophages, which do not require IL-4/STAT6 or IL-10 signaling for their activation. Thus, macrophages are essential for the early wound healing response and the formation of a fibrovascular scar.
Based on ozone (O
3
) monitoring data for Xiangtan and meteorological observation data for 2020–2022, we examined ozone pollution characteristics and the effects of meteorological factors on daily ...maximum 8-h average ozone (O
3-8h
) concentrations in Xiangtan. Thus, we observed significant increases as well as notable seasonal variations in O
3-8h
concentrations in Xiangtan during the period considered. The ozone and temperature change response slope (
K
O3-T
) indicated that local emissions had no significant effect on O
3-8h
generation. Further, average O
3-8h
concentration and maximum temperature (
T
max
) values showed a polynomial distribution. Specifically, at
T
max
< 27 °C, it increased almost linearly with increasing temperature, and at
T
max
between 27 and 37 °C, it showed an upward curvilinear trend as temperature increased, but at a much lower rate. Then, at
T
max
> 37 °C, it decreased with increasing temperature. With respect to relative humidity (RH), the average O
3-8h
concentration primarily exceeded the standard value when RH varied in the range of 45–65%, which is the key humidity range for O
3
pollution, and the inflection point for the correlation curve between O
3-8h
concentration and RH appeared at ~55%. Furthermore, at wind speeds (WSs) below 1.5 m∙s
−1
, O
3-8h
concentration increased rapidly, and at WSs in the 1.5–2 m∙s
−1
range, it increased at a much faster rate. However, at WSs > 2 m∙s
−1
, it decreased slowly with increasing WS. O
3-8h
concentration also showed the tendency to exceed the standard value when the dominant wind directions in Xiangtan were easterly or southeasterly.
Biochar is a carbon-rich solid material derived from the pyrolysis of agricultural and forest residual biomass. Previous studies have shown that biochar is suitable as an adsorbent for soil ...contaminants such as heavy metals and consequently reduces their bioavailability. However, the long-term effect of different biochars on metal extractability or soil health has not been assessed. Therefore, a 1-year incubation experiment was carried out to investigate the effect of biochar produced from bamboo and rice straw (at temperatures ≥500 °C) on the heavy metal (cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn)) extractability and enzyme activity (urease, catalase, and acid phosphatase) in a contaminated sandy loam paddy soil. Three rates (0, 1, and 5 %) and two mesh sizes (<0.25 and <1 mm) of biochar applications were investigated. After incubation, the physicochemical properties, extractable heavy metals, available phosphorus, and enzyme activity of soil samples were analyzed. The results demonstrated that rice straw biochar significantly (P < 0.05) increased the pH, electrical conductivity, and cation exchange capacity of the soil, especially at the 5 % application rate. Both bamboo and rice straw biochar significantly (P < 0.05) decreased the concentration of CaCl₂-extractable heavy metals as biochar application rate increased. The heavy metal extractability was significantly (P < 0.01) correlated with pH, water-soluble organic carbon, and available phosphorus in soil. The 5 % application rate of fine rice straw biochar resulted in the greatest reductions of extractable Cu and Zn, 97.3 and 62.2 %, respectively. Both bamboo and rice straw biochar were more effective at decreasing extractable Cu and Pb than removing extractable Cd and Zn from the soil. Urease activity increased by 143 and 107 % after the addition of 5 % coarse and fine rice straw biochars, respectively. Both bamboo and rice straw biochars significantly (P < 0.05) increased catalase activity but had no significant impact on acid phosphatase activity. In conclusion, the rice straw biochar had greater potential as an amendment for reducing the bioavailability of heavy metals in soil than that of the bamboo biochar. The impact of biochar treatment on heavy metal extractability and enzyme activity varied with the biochar type, application rate, and particle size.
Macrophages occur along a continuum of functional states between M1-type polarized macrophages with antiangiogenic and antitumor activity and M2-type polarized macrophages, which have been implicated ...to promote angiogenesis and tumor growth. Proangiogenic M2-type macrophages promote various pathologic conditions, including choroidal neovascularization in models of neovascular age-related macular degeneration, or certain cancers, such as glioblastoma multiforme. Thus, a potential novel therapeutic approach to target pathological angiogenesis in these conditions would be to inhibit the polarization of macrophages toward the proangiogenic M2-type. However, no pharmacological inhibitors of M2-type macrophage polarization have been identified yet. Here we performed an unbiased pharmacological and small chemical screen to identify drugs that inhibit proangiogenic M2-type macrophage polarization and block pathologic macrophage-driven neovascularization. We identified the well tolerated and commonly used antibiotic doxycycline as a potent inhibitor of M2-type polarization of macrophages. Doxycycline inhibited, in a dose-dependent manner, M2-type polarization of human and bone marrow-derived mouse macrophages without affecting cell viability. Furthermore, doxycycline inhibited M2-type macrophage polarization and subsequent neovascularization in vivo in a laser injury model of choroidal neovascularization. Thus, doxycycline could be used to enhance current antiangiogenic treatment approaches in various conditions that are promoted by proangiogenic M2-type macrophages, including neovascular age-related macular degeneration and certain cancers.
Background: M2-type macrophages are proangiogenic and protumorigenic, whereas M1-type macrophages are antiangiogenic.
Results: Doxycycline is a potent inhibitor of M2-type macrophage polarization in both human and mouse macrophages in vitro and in vivo.
Conclusion: Preventing M2-type macrophage polarization correlates with inhibition of pathological angiogenesis.
Significance: Doxycycline may be used to enhance current antiangiogenic treatment approaches in neovascular age-related macular degeneration and in certain cancers.
Phthalic acid esters have been used as plasticizers in numerous products and classified as endocrine-disrupting compounds. As China is one of the largest consumers of phthalic acid esters, some human ...activities may lead to the accumulation of phthalic acid esters in soil and result in contamination. Therefore, it is necessary for us to understand the current contamination status and to identify appropriate remediation technologies. Here, we reviewed the potential sources, distribution, and contamination status of phthalic acid esters in soil. We then described the ecological effect and human risk of phthalic acid esters and finally provided technologies to remediate phthalic acid esters. We found that (1) the application of plastic agricultural films, municipal biosolids, agricultural chemicals, and wastewater irrigation have been identified as the main sources for phthalic acid ester contamination in agricultural soil; (2) the distribution of phthalic acid esters in soils is determined by factors such as anthropogenic behaviors, soil type, properties of phthalic acid esters, seasonal variation, etc.; (3) the concentrations of phthalic acid esters in soil in most regions of China are exceeding the recommended values of soil cleanup guidelines used by the US Environmental Protection Agency (US EPA), causing phthalic acid ester in soils to contaminate vegetables; (4) phthalic acid esters are toxic to soil microbes and enzymes; and (5) phthalic acid ester-contaminated soil can be remedied by degradation, phytoremediation, and adsorption.
Macrophages undergoing M1- versus M2-type polarization differ significantly in their cell metabolism and cellular functions. Here, global quantitative time-course proteomics and phosphoproteomics ...paired with transcriptomics provide a comprehensive characterization of temporal changes in cell metabolism, cellular functions, and signaling pathways that occur during the induction phase of M1- versus M2-type polarization. Significant differences in, especially, metabolic pathways are observed, including changes in glucose metabolism, glycosaminoglycan metabolism, and retinoic acid signaling. Kinase-enrichment analysis shows activation patterns of specific kinases that are distinct in M1- versus M2-type polarization. M2-type polarization inhibitor drug screens identify drugs that selectively block M2- but not M1-type polarization, including mitogen-activated protein kinase kinase (MEK) and histone deacetylase (HDAC) inhibitors. These datasets provide a comprehensive resource to identify specific signaling and metabolic pathways that are critical for macrophage polarization. In a proof-of-principle approach, we use these datasets to show that MEK signaling is required for M2-type polarization by promoting peroxisome proliferator-activated receptor-γ (PPARγ)-induced retinoic acid signaling.
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•Time-course quantitative proteomics/phosphoproteomics of polarizing macrophages•Distinct changes in cell metabolism and signaling in M1- and M2-type macrophages•Chemical screens identify pharmacologic M2-type macrophage polarization inhibitors•MEK induces PPARγ that promotes M2-type polarization by activating RA signaling
He et al. provide a detailed characterization of dynamic temporal changes in cell signaling and metabolism during macrophage polarization by using quantitative time-course proteomics and phosphoproteomics and identify pharmacologic inhibitors of M2-type macrophage polarization. These data uncover a critical role of MEK/ERK signaling for PPARγ/retinoic acid-induced M2-type macrophage polarization.
The YAP and TAZ paralogs are transcriptional co-activators recruited to target sites by TEAD proteins. Here, we show that YAP and TAZ are also recruited by JUNB (a member of the AP-1 family) and ...STAT3, key transcription factors that mediate an epigenetic switch linking inflammation to cellular transformation. YAP and TAZ directly interact with JUNB and STAT3 via a WW domain important for transformation, and they stimulate transcriptional activation by AP-1 proteins. JUNB, STAT3, and TEAD co-localize at virtually all YAP/TAZ target sites, yet many target sites only contain individual AP-1, TEAD, or STAT3 motifs. This observation and differences in relative crosslinking efficiencies of JUNB, TEAD, and STAT3 at YAP/TAZ target sites suggest that YAP/TAZ is recruited by different forms of an AP-1/STAT3/TEAD complex depending on the recruiting motif. The different classes of YAP/TAZ target sites are associated with largely non-overlapping genes with distinct functions. A small minority of target sites are YAP- or TAZ-specific, and they are associated with different sequence motifs and gene classes from shared YAP/TAZ target sites. Genes containing either the AP-1 or TEAD class of YAP/TAZ sites are associated with poor survival of breast cancer patients with the triple-negative form of the disease.
MafB (a bZIP transcription factor), ß-catenin (the ultimate target of the Wnt signal transduction pathway that acts as a transcriptional co-activator of LEF/TCF proteins), and WDR77 (a ...transcriptional co-activator of multiple hormone receptors) are important for breast cellular transformation. Unexpectedly, these proteins interact directly with each other, and they have similar genomic binding profiles. Furthermore, while some of these common target sites coincide with those bound by LEF/TCF, the majority are located just downstream of transcription initiation sites at a position near paused RNA polymerase (Pol II) and the +1 nucleosome. Occupancy levels of these factors at these promoter-proximal sites are strongly correlated with the level of paused Pol II and transcriptional activity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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