Propionate outperforms conventional acetate as electron donors for highly-sensitive electrochemical active biofilm sensors in water biotoxicity early-warning.

With the ability to generate in situ real-time electric signals, electrochemically active biofilm (EAB) sensors have attracted wide attention as a promising water biotoxicity early-warning device. Organic matters serving as the electron donors potentially affect the electric signal's output and the sensitivity of the EAB sensor. To explore the influence of organic matters on EAB sensor's performance, this study tested six different organic matters during the sensor's inoculation. Besides the acetate, a conventional and widely used organic matter, propionate and lactate were also found capable of starting up the sensor. Moreover, the propionate-fed (PF) sensor delivered the highest sensitivity, which are respectively 1.4 times and 2.8 times of acetate-fed (AF) sensor and lactate-fed (LF) sensor. Further analysis revealed that EAB of PF sensor had more vulnerable intracellular metabolism than the others, which manifested as the most severe energy metabolic suppression and reactive oxygen species attack. Regarding the microbial function, a two-component system that was deemed as an environment awareness system was found in the EAB of PF, which also contributed to its high sensitivity. Finally, PF sensor was tested in real water environment to deliver early-warning signals.

Updating vehicle VOCs emissions characteristics under clean air actions in a tropical city of China.

In the context of clean air actions in China, vehicle emission limits have been continuously tightened, which has facilitated the reduction of volatile organic compounds (VOCs) emissions. However, the characteristics of VOC emissions from vehicles with strict emission limits are poorly understood. This study investigated the VOC emission characteristics from vehicles under the latest standards based on tunnel measurements, and identified future control strategies for vehicle emissions. The results showed that the highest percentage of VOCs from vehicle consisted of alkanes (80.9 %), followed by aromatics (15.8 %) and alkenes (3.1 %). Alkanes had the most significant ozone formation potential due to their high concentrations, in contrast to the aromatics that have been dominant in previous studies. The measured fleet-average VOC emission factor was 71.3 mg·km-1, including tailpipe emissions of 39.6 mg·km-1 and evaporative emissions of 31.7 mg·km-1. The VOC emission factors of the subgroups were obtained. The emission of evaporated VOCs accounted for 44.5 % of the total vehicle VOC emissions, which have increased substantially from previous studies. In addition, the emission characteristics of vehicles that are under the latest emission threshold values have changed significantly, and the mixing ratio of toluene/benzene (T/B) has been updated to 3:1. This study updates the VOCs emission factors of vehicles under clean air actions and highlights the future mitigation policies should focus on reducing evaporative VOC emissions.

Light-induced degradation of dimethylmercury in different natural waters.

Photo-induced degradation of dimethylmercury (DMHg) is considered to be an important source for the generation of methylmercury (MMHg). However, studies on DMHg photodegradation are scarce, and it is even debatable about whether DMHg can be degraded in natural waters. Herein, we found that both DMHg and MMHg could be photodegraded in three natural waters collected from the Yellow River Delta, while in pure water only DMHg photodegradation occurred under visible light irradiation. The effects of different environmental factors on DMHg photodegradation were investigated, and the underlying mechanisms were elucidated by density functional theory calculations and a series of control experiments. Our findings revealed that the DMHg degradation rate was higher in the tidal creek water compared to Yellow River, Yan Lake, and purified water. NO3-, NO2-, and DOM could promote the photodegradation with DOM and NO3- showing particularly strong positive effects. Different light sources were employed, and UV light was found to be more effective in DMHg photodegradation. Moreover, MMHg was detected during the photodegradation of DMHg, confirming that the photochemical demethylation of DMHg is a source of MMHg in sunlit water. This work may provide a novel mechanistic insight into the DMHg photodegradation in natural waters and enrich the study of the global biogeochemical cycle of Hg.

Whole-cell biophotovoltaic systems for renewable energy generation: A systematic analysis of existing knowledge.

The development of carbon-neutral fuel sources is an essential step in addressing the global fossil energy crisis. Whole-cell biophotovoltaic systems (BPVs) are a renewable, non-polluting energy-generating device that utilizes oxygenic photosynthetic microbes (OPMs) to split water molecules and generate bioelectricity under the driving of light energy. Since 2006, BPVs have been widely studied, with the order magnitudes of power density increasing from 10-4 mW/m2 to 103 mW/m2. This review examines the extracellular electron transfer (EET) mechanisms and regulation techniques of BPVs from biofilm to external environment. It is found that the EET of OPMs is mainly mediated by membrane proteins, with terminal oxidase limiting the power output. Synechocystis sp. PCC6803 and Chlorella vulgaris are two species that produce high power density in BPVs. The use of metal nanoparticles mixing, 3D pillar array electrodes, microfluidic technology, and transient-state operation models can significantly enhance power density. Challenges and potential research directions are discussed, including a deeper analysis of EET mechanisms and dynamics, the development of modular devices, integration of multiple regulatory components, and the exploration of novel BPV technologies.

Deep learning model to differentiate Crohn's disease from intestinal tuberculosis using histopathological whole slide images from intestinal specimens.

Crohn's disease (CD) and intestinal tuberculosis (ITB) share similar histopathological characteristics, and differential diagnosis can be a dilemma for pathologists. This study aimed to apply deep learning (DL) to analyze whole slide images (WSI) of surgical resection specimens to distinguish CD from ITB. Overall, 1973 WSI from 85 cases from 3 centers were obtained. The DL model was established in internal training and validated in external test cohort, evaluated by area under receiver operator characteristic curve (AUC). Diagnostic results of pathologists were compared with those of the DL model using DeLong's test. DL model had case level AUC of 0.886, 0.893 and slide level AUC of 0.954, 0.827 in training and test cohorts. Attention maps highlighted discriminative areas and top 10 features were extracted from CD and ITB. DL model's diagnostic efficiency (AUC = 0.886) was better than junior pathologists (*1 AUC = 0.701, P = 0.088; *2 AUC = 0.861, P = 0.788) and inferior to senior GI pathologists (*3 AUC = 0.910, P = 0.800; *4 AUC = 0.946, P = 0.507) in training cohort. In the test cohort, model (AUC = 0.893) outperformed senior non-GI pathologists (*5 AUC = 0.782, P = 0.327; *6 AUC = 0.821, P = 0.516). We developed a DL model for the classification of CD and ITB, improving pathological diagnosis accuracy effectively.

Schaumann bodies deposited along myenteric plexus of the muscularis propria is a unique histopathological feature of Crohn's disease.

AIMS: Schaumann bodies were first identified in sarcoidosis by Dr Schaumann in 1941. They were also detected in 10% of Crohn's disease (CD) cases in a study involving patients with surgically resected CD. However, the characteristics and significance of Schaumann bodies in CD have yet to be fully elucidated. This study aimed to determine the pathological features and diagnostic significance of Schaumann bodies in various bowel diseases. METHODS: Overall, 278 bowel specimens were collected from patients with CD, intestinal tuberculosis, ulcerative colitis, intestinal schistosomiasis, diverticulosis and idiopathic mesenteric vasculopathy. The frequency, pathology and clinical features of patients with Schaumann bodies were studied. RESULTS: Schaumann bodies were present exclusively in CD (27.0%, 38 of 141) and were not detected in other intestinal diseases within the series. In CD, Schaumann bodies were deposited along the myenteric plexus of the muscularis propria (84.2%, 32 of 38). These bodies were small (diameter: 60.3±32.7 µm) and exhibited a low density in the intestinal wall (1.1±0.4 per low-power field). The majority were located within the cytoplasm of multinucleated giant cells (84.2%, 32 of 38) and were not found within or adjacent to granulomas. Notably, the number of female patients with CD and Schaumann bodies was higher than that of males. CONCLUSION: Schaumann bodies are common in resected CD specimens, and their characteristic deposition pattern may serve as a diagnostic indication for CD.

Corrigendum: Systems pharmacology approach to investigate the mechanism of Kai-Xin-San in Alzheimer's disease.

[This corrects the article DOI: 10.3389/fphar.2020.00381.].

Luteolin overcomes acquired resistance to osimertinib in non-small cell lung cancer cells by targeting the HGF-MET-Akt pathway.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has overcome the acquired resistance of first- and second-generation EGFR-TKIs due to the EGFR T790M mutation in non-small cell lung cancer (NSCLC). However, acquired resistance to osimertinib remains a significant clinical challenge. Luteolin, a natural flavonoid from traditional Chinese medicine, has exerted antitumor effects in various tumors. In this study, we investigated whether the natural flavonoid luteolin can enhance the antitumor effects of osimertinib in NSCLC cells. We established an acquired osimertinib-resistant cell line, H1975/OR, and evaluated the effects of luteolin and osimertinib alone and in combination on proliferation, migration, invasion, and apoptosis of H1975/OR cells. The potential mechanisms by which the combination of luteolin and osimertinib exert their effects were investigated by PCR, western blot, gene silencing, molecular docking, SPR and kinase activity analysis. The combination of luteolin and osimertinib inhibited the proliferation, migration, and invasion of H1975/OR cells and promoted apoptosis. We identified mesenchymal-epithelial transition factor (MET) amplification and overactivation as important resistance mechanisms of H1975/OR cells. The combination downregulated the gene and protein expression of MET and inhibited its protein phosphorylation, thereby blocking the activation of the downstream Akt pathway. Additionally, the mediated effects of MET on the synergistic effect of luteolin and osimertinib were confirmed by silencing of MET. Luteolin strongly bound with nonphosphorylated MET by occupying the active pocket of MET and inhibiting its activation. Notably, the combination also downregulated the expression of autocrine hepatocyte growth factor (HGF), the sole ligand of MET. In conclusion, luteolin can synergize with osimertinib to overcome MET amplification and overactivation-induced acquired resistance to osimertinib by suppressing the HGF-MET-Akt pathway, suggesting the clinical potential of combining luteolin with osimertinib in NSCLC patients with acquired resistance.

Titanium mesh as the anode of electrochemically active biofilm sensor for improved sensitivity in water toxicity real-time early-warning.

As serious water ecological pollution caused by toxicant leakage occurs frequently, early-warning for toxicity presented in water environment attracts increasing attentions as it saves time to retain water safety and human health. Electrochemically active biofilm (EAB) sensor is a promising device for in situ real-time water toxicity early-warning. To improve the sensitivity of EAB sensor particularly for low-concentration toxicity warning, this study employed titanium mesh (TiM) as the anode to construct an EAB sensor. Compared to traditional EAB sensor with carbon felt (CF) anode, the sensitivity of the TiM sensor was increased up to 37.4 times. The effects of mesh size (TiM50, TiM100, TiM150) and operation mode (flow-by and flow-through) on the sensitivity of TiM sensors were further investigated. Results showed the sensor with TiM100 anode had the highest inhibition rate (IR) in flow-by mode, attributed to low charge transfer resistance (Rct) and fast mass transfer. Flow-through operation could further enhance TiM100 sensor's sensitivity from flow-by operation and succeeded to signal as low as 0.0025% formaldehyde, the lowest so far tested in EAB sensor with sensing anode. Multiple toxicity shocks on flow-through TiM100 sensor revealed its good recoverability towards all tested formaldehyde concentration from 0.01% to 0.0025%, during which electrochemical activity degradation and biomass accumulation partially impaired the repeatability. This work highlights the great improvement of EAB sensors by utilizing titanium mesh as EAB carrier and provides a reference for the practical application of metallic materials for EAB sensors.

Raman Spectroscopy Combined with Malaria Protein for Early Capture and Recognition of Broad-Spectrum Circulating Tumor Cells.

Early identification of tumors can significantly reduce the mortality rate. Circulating tumor cells (CTCs) are a type of tumor cell that detaches from the primary tumor and circulates through the bloodstream. Monitoring CTCs may allow the early identification of tumor progression. However, due to their rarity and heterogeneity, the enrichment and identification of CTCs is still challenging. Studies have shown that Raman spectroscopy could distinguish CTCs from metastatic cancer patients. VAR2CSA, a class of malaria proteins, has a strong broad-spectrum binding effect on various tumor cells and is a promising candidate biomarker for cancer detection. Here, recombinant malaria VAR2CSA proteins were synthesized, expressed, and purified. After confirming that various types of tumor cells can be isolated from blood by recombinant malaria VAR2CSA proteins, we further proved that the VAR2CSA combined with Raman spectroscopy could be used efficiently for tumor capture and type recognition using A549 cell lines spiked into the blood. This would allow the early screening and detection of a broad spectrum of CTCs. Finally, we synthesized and purified the malaria protein fusion antibody and confirmed its in vitro tumor-killing activity. Herein, this paper exploits the theoretical basis of a novel strategy to capture, recognize, and kill broad-spectrum types of CTCs from the peripheral blood.

Integration analysis using bioinformatics and experimental validation on the clinical and biological significance of TSLP in cancers.

Thymic stromal lymphopoietin (TSLP) has significantly impacted the development and progression of various neoplastic disorders. To comprehensively evaluate the diverse significance of TSLP in malignant tumors, we first integrative analyze the TSLP expression level in paired and unpaired pan-cancer tissue and cell line, compared against the normal tissue. The correlation between TSLP expression, molecular subtypes, immune subtypes, diagnostic value, and prognostic value in pan-cancer was also investigated. We then explored the impact of TSLP expression on multifaced immune cell infiltration and subsequent clinical outcomes in lung adenocarcinoma (LUAD) patients. and conducted cellular experiments to functionally examine the effect of TSLP on cell proliferation, apoptosis, cell cycle, migration, and invasion in LUAD. The anti-neoplastic mechanism of TSLP was further investigated by qRT-PCR and western blotting. Our findings reveal that TSLP expression is abnormally low in various cancers compared to normal tissue and is associated with different molecular and immune subtypes of cancers. Moreover, ROC and survival analysis results suggest that TSLP expression is correlated with the diagnostic, prognostic, clinical features, and immune cells of LUAD patients. Cell experiments showed that overexpression of TSLP elicited a significant reduction in LUAD cell viability, promoted cell apoptosis, impeded cell cycle progression in the G2/M phase, and inhibited cell migration and invasion. In addition, TSLP inhibited LUAD progression through the JAK1/STAT3 signaling pathway. Therefore, targeting TSLP shows potential as a therapeutic strategy for pan-cancer, particularly for LUAD, and as a biomarker for predicting the prognosis of this malignancy.

Deep insight into oriented propionate production from food waste: Microbiological interpretation and design practice.

Using mixed microbial cultures (MMCs) for oriented volatile fatty acids (VFAs) refining in an open environment is a typical challenge due to the microbial diversiform and the process complexity. Especially for carbohydrate-rich waste (such as food waste), butyrate-type fermentation is usually dominant in a single-stage MMCs anaerobic process, while the production of odd-carbon VFAs (such as propionate) is difficult although it plays a significant role in chemicals industries. In this study, firstly, we gave a new perspective on the rationality of the oriented propionate production using MMCs with lactate as feedstock by conducting in-depth microbial informatics and reaction analysis. Secondly, we verified the feasibility of the "food waste-lactate-propionate" route to reverse the original butyrate-type fermentation situation and explore mechanisms for maintaining stability. In the first stage, a defined lactate fermentation microbiome was used to produce lactate-containing broth (80% of total chemical oxygen demand) at pH=4. In the second stage, an undomesticated undefined anaerobic microbiome was used to drive propionate production (45.26% ± 2.23% of total VFAs) under optimized conditions (C/N = 100:1-200:1 and pH=5.0). The low pH environment in the first stage enhanced the lactic acid bacteria to resist the invasion of non-functional flanking bacteria, making the community stable. In the second stage, the system maintained the propionate-type fermentation due to the absence of the ecological niche of the invasive lactic acid bacteria; The selection of propionate-producing specialists was a necessary but not sufficient condition for propionate-type fermentation. At last, this study proposed an enhanced engineering strategy framework for understanding elaborate MMCs fermentation.

Regioselective oxidation of heterocyclic aromatic hydrocarbons catalyzed by cytochrome P450: A case study of carbazole.

Recently there are increasing interests in accurately evaluating the health effects of heterocyclic PAHs. However, the activation mechanism and possible metabolites of heterocyclic PAHs catalyzed by human CYP1A1 is still elusive to a great extent. Here, leveraged to high level QM/MM calculations, the corresponding activation pathways of a representative heterocyclic PAHs, carbazole, were systematically explored. The first stage is electrophilic addition or hydrogen abstraction from N-H group. Electrophilic addition was evidenced to be more feasible and regioselectivity at C3 and C4 sites were identified. Correlations between energy barriers and key structural/electrostatic parameters reveal that O-Cα distance and Fe-O-Cα angle are the main origin for the catalytic regioselectivity. Electrophilic addition was determined as the rate-determining step and the subsequent possible reactions include epoxidation, NIH shift (the hydrogen migration from the site of hydroxylation to the adjacent carbon) and proton shuttle. The corresponding products are epoxides, ketones and hydroxylated carbazoles, respectively. The main metabolites (hydroxylated carbazoles) are estimated to be more toxic than carbazole. The regioselectivity of carbazole activated by CYP1A1 is different from the environmental processes (gas and aqueous phase). Collectively, these results will inform the in-depth understanding the metabolic processes of heterocyclic PAHs and aid the accurate evaluation of their health effects.

Dasabuvir suppresses esophageal squamous cell carcinoma growth in vitro and in vivo through targeting ROCK1.

Esophageal squamous cell carcinoma (ESCC) is an upper gastrointestinal cancer with high morbidity and mortality. New strategies are urgently needed to prolong patients' survival. Through screening FDA-approved drugs, we found dasabuvir, a drug approved for hepatitis C virus (HCV) treatment, suppressed ESCC proliferation. Dasabuvir could inhibit the growth of ESCC cells in a time and dose-dependent manner and arrested cell cycle at the G0/G1 phase. The antitumor activity was further validated in vivo using patient-derived xenograft tumor models. In terms of mechanism, we unveil that dasabuvir is a Rho-associated protein kinase 1 (ROCK1) inhibitor. Dasabuvir can bind to ROCK1 and suppress its kinase activity, thus downregulating the phosphorylation of ERK1/2 by ROCK1 and the expression of cyclin-dependent kinase 4 (CDK4) and cyclin D1. These results provide evidence that dasabuvir suppresses ESCC growth in vivo and in vitro through blocking ROCK1/ERK signaling pathway.

Comprehensive Techno-environmental Evaluation of a Pilot-Scale PHA Production from Food Waste in China.

Polyhydroxyalkanoates (PHAs), a biodegradable plastic that might replace petroleum-based plastics, can be recovered from organic waste using mixed microbial cultures (MMCs). Research in this field has been ongoing for about 25 years and is now in a critical commercialization period. However, few pilot-scale studies are available to analyze its technical feasibility and environmental impact. We ran an MMC PHA production pilot plant for 6 months using local food waste as the feedstock. The traditional three-stage process achieved PHA content of 47.91 ± 1.91% dry cell weight and volumetric productivity of 9.94 ± 0.01 g/L·d, while a novel rapid proliferation stage was built in, the PHA content and productivity could reach 41.39 ± 2.39% cell dry weight and 20.02 ± 0.01 g/L·d, respectively. Life cycle assessment using field data showed that greenhouse warming potential was much more than five times that of the known literature, and the fossil depletion potential was 10.30 (scenario #1)/7.59 (scenario #2) times higher than petroleum-based polyethylene (PE) plastic. However, establishing a resource-energy-water union instead of an isolated plant could achieve environmental benefits compared to PE plastic. This techno-environmental analysis provides emerging MMC PHA producers worldwide with a valuable reference for further development opportunities and market planning.

Protein tyrosine phosphatase PTPL1 suppresses lung cancer through Src/ERK/YAP1 signaling.

BACKGROUND: To reveal the function of protein tyrosine phosphatase-L1 (PTPL1) in lung adenocarcinoma. METHODS: Lung cancer cell lines were transfected with short hairpin RNA against PTPL1 (shPTPL1 group) or negative control (shmock group). Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to verify the transfection efficacy. Cell proliferation was analyzed by ethynyldeoxyuridine (EdU), Cell counting kit 8 (CCK8), and colony formation assay after PTPL1 or PTPL1 and yes-associated protein (YAP1) knockdown. The effect of PTPL1 on tumor growth was examined in a xenograft lung cancer model. RESULTS: PTPL1 was downregulated in various types of lung cancer cell lines. The EdU, CCK8, colony formation assays and investigation using a xenograft lung cancer model indicated that PTPL1 knockdown increased the proliferation of lung cancer cells. Mechanistically, PTPL1 knockdown induced the activation of the Proto-oncogene tyrosine-protein kinase SRC (Src)/Extracellular regulated MAP kinase (ERK) pathway and thereby promoted yes-associated protein (YAP1) nuclear translocation and activation. CONCLUSIONS: In our study, PTPL1 played a crucial suppressive role in the pathogenesis of lung cancer potentially through counteracting the Src/ERK/YAP1 pathway.

Transmissible ER stress between macrophages and tumor cells configures tumor microenvironment.

Endoplasmic reticulum (ER) stress initiates the unfolded protein response (UPR) and is decisive for tumor cell growth and tumor microenvironment (TME) maintenance. Tumor cells persistently undergo ER stress and could transmit it to the neighboring macrophages and surroundings. Tumor infiltrating macrophages can also adapt to the microenvironment variations to fulfill their highly energy-demanding and biological functions via ER stress. However, whether the different macrophage populations differentially sense ER stress and transmit ER stress to surrounding tumor cells has not yet been elucidated. Here, we aimed to investigate the role of transmissible ER stress, a novel regulator of intercellular communication in the TME. Murine bone marrow-derived macrophage (BMDM) can be polarized toward distinct functional endpoints termed classical (M1) and alternative (M2) activation, and their polarization status has been shown to be tightly correlated with their functional significance. We showed that tumor cells could receive the transmissible ER stress from two differentially polarized macrophage populations with different extent of ER stress activation. The proinflammatory M1-like macrophages respond to ER stress with less extent, however they could transmit more ER stress to tumor cells. Moreover, by analyzing the secreted components of two ER-stressed macrophage populations, we identified certain damage-associated molecular patterns (DAMPs), including S100A8 and S100A9, which are dominantly secreted by M1-like macrophages could lead to significant recipient tumor cells death in synergy with transferred ER stress.

Design, synthesis, and bioactivity study on Lissodendrins B derivatives as PARP1 inhibitor.

Poly(ADP-ribose) polymerase-1 (PARP1) is an enzyme that catalyzes the polymerization of ADP-ribose units to target proteins, and it is a potential target for anti-cancer drug discovery, especially for BRAC1/2 mutated tumors. In this study, a series of 2-aminoimidazole Lissodendrins B derivatives were designed, synthesized, and evaluated as PARP1 inhibitors. We found that compound D3 is better due to its PARP enzyme inhibitory activity and in vitro anti-cancer activity compared with other tested compounds. It could inhibit PARP1 enzymatic activity (IC50 = 17.46 µM) in the non-cell system and BRCA1-deficient HCC1937 and MDA-MB-436 cells growth (IC50 = 17.81 and 12.63 µM, respectively). Further study demonstrated that compound D3 inhibits tumor growth through multiple mechanisms, such as reduction of PARylation, accumulation of cellular DNA double-strand breaks, induction of G2/M cell cycle arrest, and subsequent apoptosis of BRCA1-deficient cells. Besides, the molecular docking study also confirmed that compound D3 could effectively occupy the active pocket of PARP1. Our findings provide a new skeleton structure for PARP1 inhibitor, and the results suggested that the compound D3 may serve as a potential lead compound to develop novel PARP1 inhibitors for cancer therapy.

Interaction Structure and Affinity of Zwitterionic Amino Acids with Important Metal Cations (Cd2+, Cu2+, Fe3+, Hg2+, Mn2+, Ni2+ and Zn2+) in Aqueous Solution: A Theoretical Study.

Heavy metals are non-biodegradable and carcinogenic pollutants with great bio-accumulation potential. Their ubiquitous occurrence in water and soils has caused serious environmental concerns. Effective strategies that can eliminate the heavy metal pollution are urgently needed. Here the adsorption potential of seven heavy metal cations (Cd2+, Cu2+, Fe3+, Hg2+, Mn2+, Ni2+ and Zn2+) with 20 amino acids was systematically investigated with Density Functional Theory method. The binding energies calculated at B3LYP-D3/def2TZVP level showed that the contribution order of amino acid side chains to the binding affinity was carboxyl > benzene ring > hydroxyl > sulfhydryl > amino group. The affinity order was inversely proportional to the radius and charge transfer of heavy metal cations, approximately following the order of: Ni2+ > Fe3+ > Cu2+ > Hg2+ > Zn2+ > Cd2+ > Mn2+. Compared to the gas-phase in other researches, the water environment has a significant influence on structures and binding energies of the heavy metal and amino acid binary complexes. Collectively, the present results will provide a basis for the design of a chelating agent (e.g., adding carboxyl or a benzene ring) to effectively remove heavy metals from the environment.

Mxi1-0 Promotes Hypoxic Pulmonary Hypertension Via ERK/c-Myc-dependent Proliferation of Arterial Smooth Muscle Cells.

Background: Hypoxic pulmonary hypertension (HPH) is a challenging lung arterial disorder with remarkably high incidence and mortality, and so far patients have failed to benefit from therapeutics clinically available. Max interacting protein 1-0 (Mxi1-0) is one of the functional isoforms of Mxi1. Although it also binds to Max, Mxi1-0, unlike other Mxi1 isoforms, cannot antagonize the oncoprotein c-Myc because of its unique proline rich domain (PRD). While Mxi1-0 was reported to promote cell proliferation via largely uncharacterized mechanisms, it is unknown whether and how it plays a role in the pathogenesis of HPH. Methods: GEO database was used to screen for genes involved in HPH development, and the candidate players were validated through examination of gene expression in clinical HPH specimens. The effect of candidate gene knockdown or overexpression on cultured pulmonary arterial cells, e.g., pulmonary arterial smooth muscle cells (PASMCs), was then investigated. The signal pathway(s) underlying the regulatory role of the candidate gene in HPH pathogenesis was probed, and the outcome of targeting the aforementioned signaling was evaluated using an HPH rat model. Results: Mxi1 was significantly upregulated in the PASMCs of HPH patients. As the main effector isoform responding to hypoxia, Mxi1-0 functions in HPH to promote PASMCs proliferation. Mechanistically, Mxi1-0 improved the expression of the proto-oncogene c-Myc via activation of the MEK/ERK pathway. Consistently, both a MEK inhibitor, PD98059, and a c-Myc inhibitor, 10058F4, could counteract Mxi1-0-induced PASMCs proliferation. In addition, targeting the MEK/ERK signaling significantly suppressed the development of HPH in rats. Conclusion: Mxi1-0 potentiates HPH pathogenesis through MEK/ERK/c-Myc-mediated proliferation of PASMCs, suggesting its applicability in targeted treatment and prognostic assessment of clinical HPH.