Elucidating distinct roles of chemical reduction and autotrophic denitrification driven by three iron-based materials in nitrate removal from low carbon-to-nitrogen ratio wastewater.

Effective nitrate removal is a key challenge when treating low carbon-to-nitrogen ratio wastewater. How to select an effective inorganic electron donor to improve the autotrophic denitrification of nitrate nitrogen has become an area of intense research. In this study, the nitrate removal mechanism of three iron-based materials in the presence and absence of microorganisms was investigated with Fe2+/Fe0 as an electron donor and nitrate as an electron acceptor, and the relationship between the iron materials and denitrifying microorganisms was explored. The results indicated that the nitrogen removal efficiency of each iron-based material coupled sludge systems was higher than that of iron-based material. Furthermore, compared with the sponge iron coupled sludge system (60.6%-70.4%) and magnetite coupled sludge (56.1%-65.3%), the pyrite coupled sludge system had the highest removal efficiency of TN, and the removal efficiency increased from 62.5% to 82.1% with time. The test results of scanning electron microscope, X-ray photoelectron spectroscopy and X-ray diffraction indicated that iron-based materials promoted the attachment of microorganisms and the chemical reduction of nitrate in three iron-based material coupled sludge systems. Furthermore, the pyrite coupled sludge system had the highest nitrite reductase activity and can induce microorganisms to secrete more extracellular polymer substances. Combined with high-throughput sequencing and PICRUSt2 functional predictive analysis software, the total relative abundance of the dominant bacterial in pyrite coupled sludge system was the highest (72.06%) compared with the other iron-based material systems, and the abundance of Blastocatellaceae was relatively high. Overall, these results suggest that the pyrite coupled sludge system was more conducive to long-term stable nitrate removal.

The role of FERMT2 in the tumor microenvironment and immunotherapy in pan-cancer using comprehensive single-cell and bulk sequencing.

FERMT2 has been identified as a participant in integrin-linked kinase signaling pathways, influencing epithelial-mesenchymal transition and thereby affecting tumor initiation, progression, and invasion. While the character of FERMT2 in the tumor microenvironment (TME) as well as its implications for immunotherapy remain unclear. Thus, we conducted a comprehensive analysis to assess the prognostic significance of FERMT2 using Kaplan-Meier analysis. In addition, we employed enrichment analysis to uncover potential underlying molecular mechanisms. Using "Immunedeconv" package, we evaluated the immune characteristics of FERMT2 within TME. Furthermore, we determined the expression levels of FERMT2 in various cell types within TME, based on single-cell sequencing data. To confirm the co-expression of FERMT2 and markers of cancer-associated fibroblasts (CAFs), we performed multiplex immunofluorescence staining on tissue paraffin sections across various cancer types. Our analysis disclosed a significant correlation between elevated FERMT2 expression and unfavorable prognosis in specific cancer types. Furthermore, we identified a strong correlation between FERMT2 expression and diverse immune-related factors, including immune checkpoint molecules, immune cell infiltration, microsatellite instability (MSI), and tumor mutational burden (TMB). Additionally, there was a significant correlation between FERMT2 expression and immune-related pathways, particularly those associated with activating, migrating, and promoting the growth of fibroblasts in diverse cancer types. Interestingly, we observed consistent co-expression of FERMT2 in both malignant tumor cells and stromal cells, particularly within CAFs. Notably, our findings also indicated that FERMT2, in particular, exhibited elevated expression levels within tumor tissues and co-expressed with α-SMA in CAFs based on the multiplex immunofluorescence staining results.

Toxic effects of nanoplastics on biological nitrogen removal in constructed wetlands: Evidence from iron utilization and metabolism.

Nanoplastics (NPs) in wastewaters may present a potential threat to biological nitrogen removal in constructed wetlands (CWs). Iron ions are pivotal in microbially mediated nitrogen metabolism, however, explicit evidence demonstrating the impact of NPs on nitrogen removal regulated by iron utilization and metabolism remains unclear. Here, we investigated how NPs disturb intracellular iron homeostasis, consequently interfering with the coupling mechanism between iron utilization and nitrogen metabolism in CWs. Results indicated that microorganisms affected by NPs developed a siderophore-mediated iron acquisition mechanism to compensate for iron loss. This deficiency resulted from NPs internalization limited the activity of the electron transport system and key enzymes involved in nitrogen metabolism. Microbial network analysis further suggested that NPs exposure could potentially trigger destabilization in microbial networks and impair effective microbial communication, and ultimately inhibit nitrogen metabolism. These adverse effects, accompanied by the dominance of Fe3+ over certain electron acceptors engaged in nitrogen metabolism under NPs exposure, were potentially responsible for the observed significant deterioration in nitrogen removal (decreased by 30 %). This study sheds light on the potential impact of NPs on intracellular iron utilization and offers a substantial understanding of the iron-nitrogen coupling mechanisms in CWs.

Efficient stabilization of arsenic migration and conversion in soil with surfactant-modified iron-manganese oxide: Environmental effects and mechanistic insights.

The use of iron-manganese oxide (FMO) as a promising amendment for remediating arsenic (As) contamination in soils has gained attention, but its application is limited owing to agglomeration issues. This study aims to address agglomeration using surfactant-modified FMO and investigate their stabilization behavior towards As and resulting environmental changes upon amendments. The results confirmed the efficacy of surfactants and demonstrated that cetyltrimethylammonium-bromide-modified FMO significantly reduced the leaching concentration of As by 92.5 % and effectively suppressed the uptake of As by 85.8 % compared with the control groups. The ratio of the residual fraction increased from 30.5-41.6 % in unamended soil to 67.9-69.2 %. The number of active sites was through the introduction of surfactants and immobilized As via complexation, ion exchange, and redox reactions. The study also revealed that amendments and the concentration of As influenced the soil physicochemical properties and enriched bacteria associated with As and Fe reduction and changed the distribution of C, N, Fe, and As metabolism genes, which promoted the stabilization of As. The interactions among cetyltrimethylammonium bromide, FMO, and microorganisms were found to have the greatest effect on As immobilization.

Releasing and Assessing the Toxicity of Polycyclic Aromatic Hydrocarbons from Biochar Loaded with Iron.

Iron (Fe)-loaded biochar has garnered attention for its potential applications in recent years. However, the pyrolysis process of Fe-loaded biochar generates polycyclic aromatic hydrocarbons (PAHs), which can have adverse effects on both human health and the environment. This study explored the correlation between Fe loading and PAH production in Fe-loaded biochar. The results indicate that increasing Fe loading in biochar reduces the PAH concentration, with the most significant decrease observed in naphthalene (0.02-0.08 mg/kg). This reduction can be attributed to the decrease in precursor compounds (e.g., C2H2), substitution of the C=O bond by Fe-O, and a decrease in the dissolved organic matter concentration (3.19-10.76 mg/L) with Fe loading. When Fe loading increased from 0 to 10%, the ecological toxicity of biochar increased by 33.48% due to an elevated production of dibenzo[a,h]anthracene, which poses a significant risk to human health. Therefore, it is imperative to take into consideration the ecological risk of PAHs prior to the application of Fe-loaded biochar. This study presents a comprehensive risk assessment of Fe-loaded biochar and provides valuable insights into the optimization of its production and safe application.

Highly efficient phosphorous removal in constructed wetland with iron scrap: Insights into the microbial removal mechanism.

Excessive phosphorus (P) in surface water can lead to serious eutrophication and economic losses. Iron-based constructed wetland (CW) is considered as a promising solution to eliminate P effectively due to the advantage of low-cost. However, there is limited available information on the microbial removal mechanism of P in iron-based CW up to now. Therefore, CW with iron scrap was constructed to investigate the treatment performance and microbial removal mechanism in this study. Results showed that efficient and stable P removal (97.09 ± 1.90%) was achieved in iron scrap-based CW during the experiment period, which was attributed to the precipitation of iron and P and improved microbially mediated P removal. Metagenomic analysis showed that microbial diversity was enhanced and phosphate accumulating organisms (e.g., Dechloromonas and Tetrasphaera) were enriched in CW with iron scrap, which explained higher P removal reasonably. In addition, the abundance of genes involved in the P starvation (e.g., phoB), uptake and transport (e.g., pstB) were enhanced in iron scrap-based CW. Enrichment analysis demonstrated that phosphotransferase pathway was also significantly up-regulated in CW with iron scraps, indicating that the energy supply of microbial P removal was enhanced. These findings provide a better understanding of the microbial removal mechanism of P in iron-based CW.

Effects of multiple key factors on the performance of petroleum coke-based constructed wetland-microbial fuel cell.

In this study, two constructed wetland-microbial fuel cells (CW-MFC), including a closed-circuit system (CCW-MFC) and an open-circuit system (OCW-MFC) with petroleum coke as electrode and substrate, were constructed to explore the effect of multiple key factors on their operation performances. Compared to a traditional CW, the CCW-MFC system showed better performance, achieving an average removal efficiency of COD, NH4+-N, and TN of 94.49 ± 1.81%, 94.99 ± 4.81%, and 84.67 ± 5.6%, respectively, when the aeration rate, COD concentration, and hydraulic retention time were 0.4 L/min, 300 mg/L, and 3 days. The maximum output voltage (425.2 mV) of the CCW-MFC system was achieved when the aeration rate was 0.2 L/min. In addition, the CCW-MFC system showed a greater denitrification ability due to the higher abundance of Thiothrix that might attract other denitrifying bacteria, such as Methylotenera and Hyphomicrobium, to participate in the denitrifying process, indicating the quorum sensing could be stimulated within the denitrifying microbial community.

Heparin-binding protein as a biomarker of severe sepsis in the pediatric intensive care unit: A multicenter, prospective study.

OBJECTIVES: The aim of this study is to assess Heparin-binding protein (HBP) as a diagnostic and prognostic biomarker of severe sepsis in the pediatric intensive care unit (PICU). METHODS: A multicenter, prospective study was conducted among children with sepsis in nine PICUs in China from October 2019 to June 2021. Plasma levels of HBP, procalcitonin (PCT), C-reactive protein (CRP), lactate, and white blood cell (WBC) count were determined at enrollment and 72 h after enrollment. RESULTS: Of 355 included patients, 132 patients were diagnosed with non-severe sepsis (referred to as sepsis), 223 patients had severe sepsis. Patients with severe sepsis had significantly elevated levels of HBP compared with sepsis (median 170.5 vs. 74.1 ng/mL, P < 0.001). Adding HBP to a diagnostic model with PCT and lactate could significantly improve the diagnostic capability for severe sepsis. The plasma levels of HBP correlated positively with the number of dysfunctional organs. After adjusting for confounding factors, the declined levels of HBP at 72 h had a significant association with decreased in-hospital mortality (adjusted odds ratio (aOR) 0.242, P < 0.001). The levels of HBP showed weak positive correlations with PCT, CRP, WBC, and no correlation to lactate. CONCLUSIONS: HBP at enrollment can be an independent indicator for severe sepsis and the dynamic changes at 72 h can be a predictor for in-hospital mortality in PICU.

Water-energy-greenhouse gas nexus of a novel high-rate activated sludge-two-stage vertical up-flow constructed wetland system for low-carbon wastewater treatment.

Municipal wastewater treatment which is associated with high energy consumption and excessive greenhouse gas (GHG) emissions, has been facing severe challenges toward carbon emissions. In this study, a high-rate activated sludge-two-stage vertical up-flow constructed wetland (HRAS-TVUCW) system was developed to reduce carbon emissions during municipal wastewater treatment. Through carbon management, optimized mass and energy flows were achieved, resulting in high treatment efficiency and low operational energy consumption. The carbon emission of the HRAS-TVUCW system (i.e., 0.21 kg carbon dioxide equivalent/m3 wastewater) was 4.1-folds lower than that of the conventional anaerobic/anoxic/aerobic (A2O) process. Meanwhile, the recovered energy from the HRAS-TVUCW system increased its contribution to carbon neutrality to 40.2%, 4.6-folds higher than that of the A2O process. Results of functional microbial community analysis at the genus level revealed that the controlled dissolved oxygen allocation led to distinctive microbial communities in each unit of HRAS-TVUCW system, which facilitated denitrification efficiency increase and carbon emissions reduction. Overall, the HRAS-TVUCW system could be considered as a cost-effective and sustainable low-carbon technology for municipal wastewater treatment.

Enhanced benzofluoranthrene removal in constructed wetlands with iron- modified biochar: Mediated by dissolved organic matter and microbial response.

Polycyclic aromatic hydrocarbons (PAHs) pose a high risk to ecosystems owing to their adverse environmental effects. The use of biochar in constructed wetlands (CWs) to remove PAH has received increased interest, but is frequently challenging because of saturation adsorption. To enhance the microbial degradation, electron acceptors are provided. This study aimed to remove a representative PAH, benzofluoranthrene (BbF), using iron-modified biochar as a supplement to the CW substrate. Results revealed that iron-mediated biochar based CWs increased the removal of BbF by 20.4 % and ammonium by 25.6 %. The BbF retained in substrate with biochar (36.6 % higher content) and further removed with iron modification (40.6 % lower content). Iron-modified biochar increased dissolved organic carbon content, particularly low-aromaticity, and low-molecular-weight organic matters (25.7 % higher tryptophan-like material), which contributed to PAH degradation by microorganisms. Microbial analysis confirmed that iron-mediated biochar enriched the abundance of microbes (e.g., Cellulomonas, Actinotalea, and Sphingomonas) and key enzymes (e.g., catA, lipV, and sdhA) that are involved in PAH degradation. Higher proportion of iron-reducing bacteria (e. g., Thiobacillus, Rhodobacter) played a significant role in driving microbial iron cycle, which was beneficial for PAHs removal. Based on the results, we confirmed that the use of iron-modified biochar in CWs enhance PAH removal.

Crizotinib Shows Antibacterial Activity against Gram-Positive Bacteria by Reducing ATP Production and Targeting the CTP Synthase PyrG.

Infections caused by drug-resistant bacteria are a serious threat to public health worldwide, and the discovery of novel antibacterial compounds is urgently needed. Here, we screened an FDA-approved small-molecule library and found that crizotinib possesses good antimicrobial efficacy against Gram-positive bacteria. Crizotinib was found to increase the survival rate of mice infected with bacteria and decrease pulmonary inflammation activity in an animal model. Furthermore, it showed synergy with clindamycin and gentamicin. Importantly, the Gram-positive bacteria showed a low tendency to develop resistance to crizotinib. Mechanistically, quantitative proteomics and biochemical validation experiments indicated that crizotinib exerted its antibacterial effects by reducing ATP production and pyrimidine metabolism. A drug affinity responsive target stability study suggested crizotinib targets the CTP synthase PyrG, which subsequently disturbs pyrimidine metabolism and eventually reduces DNA synthesis. Subsequent molecular dynamics analysis showed that crizotinib binding occurs in close proximity to the ATP binding pocket of PyrG and causes loss of function of this CTP synthase. Crizotinib is a promising antimicrobial agent and provides a novel choice for the development of treatment for Gram-positive infections. IMPORTANCE Infections caused by drug-resistant bacteria are a serious problem worldwide. Therefore, there is an urgent need to find novel drugs with good antibacterial activity against multidrug-resistant bacteria. In this study, we found that a repurposed drug, crizotinib, exhibits excellent antibacterial activity against drug-resistant bacteria both in vivo and in vitro via suppressing ATP production and pyrimidine metabolism. Crizotinib was found to disturb pyrimidine metabolism by targeting the CTP synthase PyrG, thus reducing DNA synthesis. This unique mechanism of action may explain the decreased development of resistance by Staphylococcus aureus to crizotinib. This study provides a potential option for the treatment of drug-resistant bacterial infections in the future.

Iron ore or manganese ore filled constructed wetlands enhanced removal performance and changed removal process of nitrogen under sulfamethoxazole and trimethoprim stress.

Iron ore and manganese ore were used as substrate of constructed wetlands (CWs) to enhance nitrogen (N) removal. However, the N purification performance in CWs filled with iron or manganese ore under antibiotics stress needs further study. In this study, three groups of CWs filled with river sand, limonite (a kind of iron ore), and manganese ore sand were constructed, which were named as C-CWs, Fe-CWs, and Mn-CWs, respectively. The effect and mechanism of the composite antibiotics sulfamethoxazole (SMX) and trimethoprim (TMP) on N removal in CWs were investigated. While the addition of SMX and TMP inhibited about 40% nitrification and promoted about 25% denitrification in all CWs, Fe-CWs and Mn-CWs always had better N removal performance than C-CWs. Changes in microbial community structure in CWs indicated that the better N removal performance in Fe-CWs and Mn-CWs was attributed to the presence of more abundant and diverse N-associated bacteria, especially Fe- and Mn-driven autotrophic denitrifying bacteria. What's more, the addition of iron ore or manganese ore contributed to the better N removal performance with highest relative abundance of N-transferring bacteria under antibiotics stress.

TNFα antagonist in combination with PD-1 blocker to prevent or retard malignant transformation of B[a]P-induced chronic lung inflammation.

Benzo[a]pyrene (B[a]P) is a typical complete carcinogen in tobacco, but its mechanism of inducing the development of chronic pneumonia and consequent lung cancer is unclear. Here we elucidated the role of myeloid-derived suppressor cells (MDSCs) in developing B[a]P-induced chronic lung inflammation and efficacy of immunotherapy in preventing subsequent malignant transformation. Our study showed that as B[a]P could induce the accumulation of MDSCs in lung tissues and enhance the immunosuppressive effect regulated by cytokines and metabolites, thereby promoting the formation of immunosuppressive microenvironment, where effector T cells were exhausted, NK cells were dysfunctional, regulatory T (Treg) cells were expanded, polarized alveolar macrophages were transformed from M1 to M2. Subsequently, we performed the immunotherapy to block TNFɑ only or both TNFɑ and PD-1 at the early- or middle-stage of B[a]P-induced chronic lung inflammation to ameliorate the immunosuppressive microenvironment. We found that TNFɑ antagonist alone or with PD-1 blocker was shown to exert therapeutic effects on malignant transformation at the early stage of B[a]P-induced chronic lung inflammation. Taken together, our findings demonstrated that B[a]P-induced chronic lung inflammation resulted in the accumulation of MDSCs in lung tissues and exercise their immunosuppressive functions, thereby developing an immunosuppressive microenvironment, thus TNFɑ antagonist alone or with PD-1 blocker could prevent or retard the malignant transformation of B[a]P-induced chronic lung inflammation.

Human in silico trials for parametric computational fluid dynamics investigation of cerebrospinal fluid drug delivery: impact of injection location, injection protocol, and physiology.

BACKGROUND: Intrathecal drug delivery has a significant role in pain management and central nervous system (CNS) disease therapeutics. A fluid-physics based tool to assist clinicians in choosing specific drug doses to the spine or brain may help improve treatment schedules. METHODS: This study applied computational fluid dynamics (CFD) and in vitro model verification to assess intrathecal drug delivery in an anatomically idealized model of the human CSF system with key anatomic features of the CNS. Key parameters analyzed included the role of (a) injection location including lumbar puncture (LP), cisterna magna (CM) and intracerebroventricular (ICV), (b) LP injection rate, injection volume, and flush volume, (c) physiologic factors including cardiac-induced and deep respiration-induced CSF stroke volume increase. Simulations were conducted for 3-h post-injection and used to quantify spatial-temporal tracer concentration, regional area under the curve (AUC), time to maximum concentration (Tmax), and maximum concentration (Cmax), for each case. RESULTS: CM and ICV increased AUC to brain regions by ~ 2 logs compared to all other simulations. A 3X increase in bolus volume and addition of a 5 mL flush both increased intracranial AUC to the brain up to 2X compared to a baseline 5 mL LP injection. In contrast, a 5X increase in bolus rate (25 mL/min) did not improve tracer exposure to the brain. An increase in cardiac and respiratory CSF movement improved tracer spread to the brain, basal cistern, and cerebellum up to ~ 2 logs compared to the baseline LP injection. CONCLUSION: The computational modeling approach provides ability to conduct in silico trials representative of CSF injection protocols. Taken together, the findings indicate a strong potential for delivery protocols to be optimized to reach a target region(s) of the spine and/or brain with a needed therapeutic dose. Parametric modification of bolus rate/volume and flush volume was found to have impact on tracer distribution; albeit to a smaller degree than injection location, with CM and ICV injections resulting in greater therapeutic dose to brain regions compared to LP. CSF stroke volume and frequency both played an important role and may potentially have a greater impact than the modest changes in LP injection protocols analyzed such as bolus rate, volume, and flush.

By restoring autophagic flux and improving mitochondrial function, corosolic acid protects against Dox-induced cardiotoxicity.

Despite effective anticancer effects, the use of doxorubicin (Dox) is limited due to its side effects as cardiotoxicity. Corosolic acid (CRA) is a pentacyclic triterpene acid isolated from Lagerstroemia speciosa L. (Banaba) leaves, and it has also been shown to improve myocardial hypertrophy and myocardial infarction which expected to be used in clinical pharmaceuticals. The purpose of this study was to explore whether CRA can improve myocardial injury caused by Dox and to clarify potential mechanisms. C57 BL/6J mice and AMPKα2 knockout mice were given a single intraperitoneal (i.p.) injection of Dox (5 mg/kg) every week for 4 weeks, while normal saline (NS) was used as control. Mice were given CRA (10 mg/kg or 20 mg/kg) or equal volumes of normal saline daily after the first time i.p. injection of Dox. After 4 weeks, echocardiography, gravimetric, hemodynamic, histological, and biochemical analyses were conducted. After Dox injury, compared with the control group, CRA increased the survival rate of mice, improved the cardiac function, decreased the oxidative stress, and reduced the apoptosis. CRA may function by promoting transcription factor EB (TFEB) nuclear translocation and thus restoring autophagic flux. We also observed that CRA protected mitochondrial structure and function, which may benefit from oxidative stress reduction or TFEB activation. In vitro, the protective effect of CRA is reversed by TFEB deletion. Then, we evaluated the expression of AMPKα2/mTOR C1 signaling pathway, the main pathway of TFEB activation. In vivo and in vitro, CRA promoted TFEB nuclear translocation by activating AMPKα2/mTOR C1 signaling, while ablating AMPKα2 reversed these results and accompanied with a decrease in the ability of CRA to resist Dox-induced cardiotoxicity. Thus, we suggested that CRA activated TFEB in an AMPKα2-dependent manner to protect against Dox cardiotoxicity. This study confirms the role and mechanism of CRA in the treatment of Dox-induced cardiac injury. Dox-induced damage to autophagy includes autophagosomes maturation disorders and autophagolysosomes acidification defects, CRA restored autophagic flux, and promoted lysosomal degradation by activating TFEB in an AMPKα2-depended manner, stabilized mitochondrial function, ultimately protected against Dox-induced cardiotoxicity.

Fabrication of polypyrrole nanowire arrays-modified electrode for point-of-use water disinfection via low-voltage electroporation.

Still ∼10% of world's population has no sustainable access to centralized water supply system, causing millions of deaths annually by waterborne diseases. Here, we develop polypyrrole nanowire arrays (PPyNWs)-modified electrodes by polymerization of pyrrole on graphite felt for point-of-use water disinfection via low-voltage electroporation. A flow-through mode is specially applied to alleviate diffusion barrier of pyrrole in the porous graphite felt for uniform PPyNWs growth. The flow-through disinfection device using the optimized PPyNWs electrode achieves above 4-log removal for model virus (MS2) and gram-positive/negative bacteria (E. faecalis and E. coli) at applied voltage of 1.0 V and fluxes below 1000 and 2500 L/m2/h. Electroporation is recognized as the dominant disinfection mechanism by using square-wave alternating voltage of ±1.0 V to eliminate the electrochemical reactions. In-situ sampling experiments reveal that anode acts as the main disinfection function due to its electric field attraction with negatively charged E. coli cells. The live/dead baclight staining experiments indicate an adsorption-desorption process of E. coli cells on anode, and the adsorption-desorption balance determines the disinfection abilities of PPyNWs anode. Under 1.0 V and 2000 L/m2/h, the disinfection device enables above 4-log E. coli removal in tap water within 7-day operation with energy consumption below 20 mJ/L, suggesting its sound application potential for point-of-use water disinfection.

Cardiomyocyte-Specific RIP2 Overexpression Exacerbated Pathologic Remodeling and Contributed to Spontaneous Cardiac Hypertrophy.

This study aimed to investigate the role and mechanisms of Receptor interacting protein kinase 2 (RIP2) in pressure overload-induced cardiac remodeling. Human failing or healthy donor hearts were collected for detecting RIP2 expression. RIP2 cardiomyocyte-specific overexpression, RIP2 global knockout, or wild-type mice were subjected to sham or aortic banding (AB) surgery to establish pressure overload-induced cardiac remodeling in vivo. Phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) were used for further investigation in vitro. The expression of RIP2 was significantly upregulated in failing human heart, mouse remodeling heart, and Ang II-treated NRCMs. RIP2 overexpression obviously aggravated pressure overload-induced cardiac remodeling. Mechanistically, RIP2 overexpression significantly increased the phosphorylation of TAK1, P38, and JNK1/2 and enhanced IκBα/p65 signaling pathway. Inhibiting TAK1 activity by specific inhibitor completely prevented cardiac remodeling induced by RIP2 overexpression. This study further confirmed that RIP2 overexpression in NRCM could exacerbate PE-induced NRCM hypertrophy and TAK1 silence by specific siRNA could completely rescue RIP2 overexpression-mediated cardiomyocyte hypertrophy. Moreover, this study showed that RIP2 could bind to TAK1 in HEK293 cells, and PE could promote their interaction in NRCM. Surprisingly, we found that RIP2 overexpression caused spontaneous cardiac remodeling at the age of 12 and 18 months, which confirmed the powerful deterioration of RIP2 overexpression. Finally, we indicated that RIP2 global knockout attenuated pressure overload-induced cardiac remodeling via reducing TAK1/JNK1/2/P38 and IκBα/p65 signaling pathways. Taken together, RIP2-mediated activation of TAK1/P38/JNK1/2 and IκBα/p65 signaling pathways played a pivotal role in pressure overload-induced cardiac remodeling and spontaneous cardiac remodeling induced by RIP2 overexpression, and RIP2 inhibition might be a potential strategy for preventing cardiac remodeling.

Insight into heavy metals (Cr and Pb) complexation by dissolved organic matters from biochar: Impact of zero-valent iron.

In this study, batch experiments were conducted to investigate the immobilization of HMs (Cr and Pb) by DOM derived from biochar in the presence and absence of zero-valent iron (Fe) in nitrate and HMs co-contaminated groundwater. Both Cr and Pb were removed effectively in biochar-Fe aqueous systems, while only Pb could be mitigated in biochar systems. Excitation-emission spectrophotometry combined with parallel factor analysis (EEM-PARAFAC) revealed that DOM released from biochar mainly contained human-like and tryptophan-like substances. Moreover, the fluorescence of hemic-like components could be quenched differently by the complexation of HMs, which proved the different removal efficiencies of Cr and Pb in biochar aqueous phase. In biochar-Fe aqueous systems, Fe-C micro-electrolysis was formed in prior to the complexation of DOM-Fe hydroxides. Thus, the chemical reduction was the primary way to removal HMs in batch-Fe systems, which was corresponding with the less variation of DOM components when adding Cr and Pb into aqueous systems. Besides, the observed DOM components with higher aromaticity and humification after adding Cr and Pb, further indicated the complexation of DOM-HMs through the analysis of adsorption and fluorescence indices. These results will provide new insights into the HMs retention on biochar, particularly for the role of Fe on the complexation process.

Isoquercitrin protects HUVECs against high glucose­induced apoptosis through regulating p53 proteasomal degradation.

High glucose (HG)­induced endothelial apoptosis serves an important role in the vascular dysfunction associated with diabetes mellitus (DM). It has been reported that isoquercitrin (IQC), a flavonoid glucoside, possesses an anti­DM effect, but the mechanism requires further investigation. The present study investigated the effect of IQC against HG­induced apoptosis in human umbilical vein endothelial cells (HUVECs) and explored its molecular mechanism. HUVECs were treated with 5 or 30 mM glucose for 48 h. Endothelial cell viability was monitored using the Cell Counting Kit­8 assay. Mitochondrial membrane potential was detected by JC­1 staining. Apoptosis was observed by TUNEL staining and flow cytometry. Western blotting was used for the analysis of apoptosis­associated proteins Bax, Bcl­2, cleaved (C)­caspase3, total­caspase3, p53 and phosphorylated p53. Reverse transcription­quantitative PCR was used to analyze the mRNA expression levels of Bax, Bcl­2 and p53. Immunofluorescence staining was utilized to detect the expression levels and distribution of p53 and ubiquitin specific peptidase 10 (USP10) in HUVECs. The results revealed that IQC significantly attenuated HG­induced endothelial apoptosis, as shown by decreased apoptotic cells observed by TUNEL, JC­1 staining and flow cytometry. Moreover, under HG stress, IQC treatment markedly inhibited the increased expression levels of the pro­apoptotic proteins p53, Bax and C­caspase3, and increased the expression levels of the anti­apoptotic protein Bcl­2 in HUVECs. However, the anti­apoptotic effect of IQC against HG was partially blunted by increasing p53 protein levels in vitro. IQC influenced the mRNA expression levels of Bax and Bcl­2 in response to HG, but it did not affect the transcription of p53. Notably, IQC inhibited the HG­induced phosphorylation of p53 at Ser15 and the nuclear transport of USP10, destabilizing p53 and increasing the proteasomal degradation of the p53 protein. The current findings revealed that IQC exerted a protective effect against the HG­induced apoptosis of endothelial cells by regulating the proteasomal degradation of the p53 protein, suggesting that IQC may be used as a novel therapeutic compound to ameliorate DM­induced vascular complications.

6-Gingerol protects against cardiac remodeling by inhibiting the p38 mitogen-activated protein kinase pathway.

6-Gingerol, a pungent ingredient of ginger, has been reported to possess anti-inflammatory and antioxidant activities, but the effect of 6-gingerol on pressure overload-induced cardiac remodeling remains inconclusive. In this study, we investigated the effect of 6-gingerol on cardiac remodeling in in vivo and in vitro models, and to clarify the underlying mechanisms. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 6-gingerol (20 mg/kg, ig) three times a week (1 week in advance and continued until the end of the experiment). Four weeks after TAC surgery, the mice were subjected to echocardiography, and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes and cardiac fibroblasts were used to validate the protective effects of 6-gingerol in response to phenylephrine (PE) and transforming growth factor-ß (TGF-ß) challenge. We showed that 6-gingerol administration protected against pressure overload-induced cardiac hypertrophy, fibrosis, inflammation, and dysfunction in TAC mice. In the in vitro study, we showed that treatment with 6-gingerol (20 µM) blocked PE-induced-cardiomyocyte hypertrophy and TGF-ß-induced cardiac fibroblast activation. Furthermore, 6-gingerol treatment significantly decreased mitogen-activated protein kinase p38 (p38) phosphorylation in response to pressure overload in vivo and extracellular stimuli in vitro, which was upregulated in the absence of 6-gingerol treatment. Moreover, transfection with mitogen-activated protein kinase kinase 6 expressing adenoviruses (Ad-MKK6), which specifically activated p38, abolished the protective effects of 6-gingerol in both in vitro and in vivo models. In conclusion, 6-gingerol improves cardiac function and alleviates cardiac remodeling induced by pressure overload in a p38-dependent manner. The present study demonstrates that 6-gingerol is a promising agent for the intervention of pathological cardiac remodeling.