Recalcification stabilizes cadmium but magnifies phosphorus limitation in wastewater-irrigated calcareous soil.

Long-term wastewater irrigation leads to the loss of calcium carbonate (CaCO3) in the tillage layer of calcareous land, which irreversibly damages the soil's ability to retain cadmium (Cd). In this study, we selected calcareous agricultural soil irrigated with wastewater for over 50 years to examine the recalcification effects of sugar beet factory lime (SBFL) at doses of 0%, 2.5%, 5%, and 10%. We found that SBFL promoted Cd transformation in the soil from active exchangeable species to more stable carbonate-bonded and residual species, which the X-ray diffraction patterns also confirmed results that CdSO4 reduced while CdS and CaCdCO3 increased. Correspondingly, the soil bioavailable Cd concentration was significantly reduced by 65.6-84.7%. The Cd concentrations in maize roots and shoots were significantly reduced by 11.7-50.6% and 13.0-70.0%, respectively, thereby promoting maize growth. Nevertheless, SBFL also increased the proportion of plant-unavailable phosphorus (P) in Ca8-P and Ca10-P by 4.3-13.0% and 10.7-25.9%, respectively, reducing the plant-available P (Olsen P) content by 5.2-22.1%. Consequently, soil P-acquiring associated enzyme (alkaline phosphatase) activity and microbial (Proteobacteria, Bacteroidota, and Actinobacteria) community abundance significantly increased. Our findings showed that adding SBFL to wastewater-irrigated calcareous soil stabilized Cd, but exacerbated P limitation. Therefore, it is necessary to alleviate P limitations in the practice of recalcifying degraded calcareous land.

Engineering biomimetic nanosystem targeting multiple tumor radioresistance hallmarks for enhanced radiotherapy.

Tumor cells establish a robust self-defense system characterized by hypoxia, antioxidant overexpression, DNA damage repair, and so forth to resist radiotherapy. Targeting one of these features is insufficient to overcome radioresistance due to the feedback mechanisms initiated by tumor cells under radiotherapy. Therefore, we herein developed an engineering biomimetic nanosystem (M@HHPt) masked with tumor cell membranes and loaded with a hybridized protein-based nanoparticle carrying oxygens (O2) and cisplatin prodrugs (Pt(IV)) to target multiple tumor radioresistance hallmarks for enhanced radiotherapy. After administration, M@HHPt actively targeted and smoothly accumulated in tumor cells by virtue of its innate homing abilities to realize efficient co-delivery of O2 and Pt(IV). O2 introduction induced hypoxia alleviation cooperated with Pt(IV) reduction caused glutathione consumption greatly amplified radiotherapy-ignited cellular oxidative stress. Moreover, the released cisplatin effectively hindered DNA damage repair by crosslinking with radiotherapy-produced DNA fragments. Consequently, M@HHPt-sensitized radiotherapy significantly suppressed the proliferation of lung cancer H1975 cells with an extremely high sensitizer enhancement ratio of 1.91 and the progression of H1975 tumor models with an excellent tumor inhibition rate of 94.7%. Overall, this work provided a feasible strategy for tumor radiosensitization by overcoming multiple radioresistance mechanisms.

Glucopeptide Superstructure Hydrogel Promotes Surgical Wound Healing Following Neoadjuvant Radiotherapy by Producing NO and Anticellular Senescence.

Neoadjuvant radiotherapy, a preoperative intervention regimen for reducing the stage of primary tumors and surgical margins, has gained increasing attention in the past decade. However, radiation-induced skin damage during neoadjuvant radiotherapy exacerbates surgical injury, remarkably increasing the risk of refractory wounds and compromising the therapeutic effects. Radiation impedes wound healing by increasing the production of reactive oxygen species and inducing cell apoptosis and senescence. Here, a self-assembling peptide (R-peptide) and hyaluronic-acid (HA)-based and cordycepin-loaded superstructure hydrogel is prepared for surgical incision healing after neoadjuvant radiotherapy. Results show that i) R-peptide coassembles with HA to form biomimetic fiber bundle microstructure, in which R-peptide drives the assembly of single fiber through π-π stacking and other forces and HA, as a single fiber adhesive, facilitates bunching through electrostatic interactions. ii) The biomimetic superstructure contributes to the adhesion and proliferation of cells in the surgical wound. iii) Aldehyde-modified HA provides dynamic covalent binding sites for cordycepin to achieve responsive release, inhibiting radiation-induced cellular senescence. iv) Arginine in the peptides provides antioxidant capacity and a substrate for the endogenous production of nitric oxide to promote wound healing and angiogenesis of surgical wounds after neoadjuvant radiotherapy.

CD58 alterations govern antitumor immune responses by inducing PD-L1 and IDO in diffuse large B-cell lymphoma.

Recurrent abnormalities in immune surveillance-related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and natural killer (NK) cells and is recurrently mutated and deleted in DLBCL, suggesting it may play a role in regulating antitumor immunity. Herein, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA-sequencing, whole-exome sequencing, and single-cell RNA-sequencing in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled DLBCL patients. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free and overall survival. Single-cell RNA sequencing revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the Lyn/CD22/SHP1 axis, thereby limiting PD-L1 and IDO expression. Elevated PD-L1 and IDO expression in CD58 deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to CAR T-cell therapy. Direct activation of CD58-CD2 costimulatory signaling in combination with anti-PD-L1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to CAR T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL.

NAT10-mediated mRNA N4-acetylcytidine modification of MDR1 and BCRP promotes breast cancer progression.

BACKGROUND: N-acetyltransferase 10 (NAT10) serves as a critical enzyme in mediating the N4-acetylcytidine (ac4C) that ensures RNA stability and effective translation processes. The role of NAT10 in driving the advancement of breast cancer remains uninvestigated. METHODS: We observed an increase in NAT10 expression, both at mRNA level through the analysis of the Cancer Genome Atlas (TCGA) database and at the protein level of tumor tissues from breast cancer patients. We determined that a heightened expression of NAT10 served as a predictor of an unfavorable clinical outcome. By screening the Cancer Cell Line Encyclopedia (CCLE) cell bank, this expression pattern of NAT10 was consistency found across almost all the classic breast cancer cell lines. RESULTS: Functionally, interference of NAT10 expression exerts an inhibitory effect on proliferation and invasion of breast cancer cells. By using ac4C RNA immunoprecipitation (ac4c-RIP) and acRIP-qPCR assays, we identified a reduction of ac4C enrichment within the ATP binding cassette (ABC) transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), consequent to NAT10 suppression. Expressions of MDR1 and BCRP exhibited a positive correlation with NAT10 expression in tumor tissues, and the inhibition of NAT10 in breast cancer cells resulted in a decrease of MDR1 and BCRP expression. Therefore, the overexpressing of MDR1 and BCRP could partially rescue the adverse consequences of NAT10 depletion. In addition, we found that, remodelin, a NAT10 inhibitor, reinstated the susceptibility of capecitabine-resistant breast cancer cells to the chemotherapy, both in vitro and in vivo. CONCLUSION: The results of our study demonstrated the essential role of NAT10-mediated ac4c-modification in breast cancer progression and provide a novel strategy for overcoming chemoresistance challenges.

ABAG-docking benchmark: a non-redundant structure benchmark dataset for antibody-antigen computational docking.

Accurate prediction of antibody-antigen complex structures is pivotal in drug discovery, vaccine design and disease treatment and can facilitate the development of more effective therapies and diagnostics. In this work, we first review the antibody-antigen docking (ABAG-docking) datasets. Then, we present the creation and characterization of a comprehensive benchmark dataset of antibody-antigen complexes. We categorize the dataset based on docking difficulty, interface properties and structural characteristics, to provide a diverse set of cases for rigorous evaluation. Compared with Docking Benchmark 5.5, we have added 112 cases, including 14 single-domain antibody (sdAb) cases and 98 monoclonal antibody (mAb) cases, and also increased the proportion of Difficult cases. Our dataset contains diverse cases, including human/humanized antibodies, sdAbs, rodent antibodies and other types, opening the door to better algorithm development. Furthermore, we provide details on the process of building the benchmark dataset and introduce a pipeline for periodic updates to keep it up to date. We also utilize multiple complex prediction methods including ZDOCK, ClusPro, HDOCK and AlphaFold-Multimer for testing and analyzing this dataset. This benchmark serves as a valuable resource for evaluating and advancing docking computational methods in the analysis of antibody-antigen interaction, enabling researchers to develop more accurate and effective tools for predicting and designing antibody-antigen complexes. The non-redundant ABAG-docking structure benchmark dataset is available at https://github.com/Zhaonan99/Antibody-antigen-complex-structure-benchmark-dataset.

Computational methods for in situ structural studies with cryogenic electron tomography.

Cryo-electron tomography (cryo-ET) plays a critical role in imaging microorganisms in situ in terms of further analyzing the working mechanisms of viruses and drug exploitation, among others. A data processing workflow for cryo-ET has been developed to reconstruct three-dimensional density maps and further build atomic models from a tilt series of two-dimensional projections. Low signal-to-noise ratio (SNR) and missing wedge are two major factors that make the reconstruction procedure challenging. Because only few near-atomic resolution structures have been reconstructed in cryo-ET, there is still much room to design new approaches to improve universal reconstruction resolutions. This review summarizes classical mathematical models and deep learning methods among general reconstruction steps. Moreover, we also discuss current limitations and prospects. This review can provide software and methods for each step of the entire procedure from tilt series by cryo-ET to 3D atomic structures. In addition, it can also help more experts in various fields comprehend a recent research trend in cryo-ET. Furthermore, we hope that more researchers can collaborate in developing computational methods and mathematical models for high-resolution three-dimensional structures from cryo-ET datasets.

VEGF-modified PLA/HA nanocomposite fibrous membrane for cranial defect repair in rats.

A major obstacle to bone tissue repair is the difficulty in establishing a rapid blood supply areas of bone defects. Vascular endothelial growth factor (VEGF)-infused tissue-engineered scaffolds offer a possible therapeutic option for these types of injuries. Their role is to accelerate angiogenesis and improve bone healing. In this study, we used electrostatic spinning and biofactor binding to construct polylactic acid (PLA)/hydroxyapatite (HA)-VEGF scaffold materials and clarify their pro-vascular role in bone defect areas for efficient bone defect repair. PLA/HA nanocomposite fibrous membranes were manufactured by selecting suitable electrostatic spinning parameters. Heparin and VEGF were bound sequentially, and then the VEGF binding and release curves of the fiber membranes were calculated. A rat cranial defect model was constructed, and PLA/HA fiber membranes bound with VEGF and unbound with VEGF were placed for treatment. Finally, we compared bone volume recovery and vascular recovery in different fibrous membrane sites. A VEGF concentration of 2.5 µg/mL achieved the maximum binding and uniform distribution of PLA/HA fibrous membranes. Extended-release experiments showed that VEGF release essentially peaked at 14 days. In vivo studies showed that PLA/HA fibrous membranes bound with VEGF significantly increased the number of vessels at the site of cranial defects, bone mineral density, bone mineral content, bone bulk density, trabecular separation, trabecular thickness, and the number of trabeculae at the site of defects in rats compared with PLA/HA fibrous membranes not bound with VEGF. VEGF-bound PLA/HA fibrous membranes demonstrate the slow release of VEGF. The VEGF binding process does not disrupt the morphology and structure of the fibrous membranes. The fibrous membranes could stimulate both osteogenesis and angiogenesis. Taken together, this research provides a new strategy for critical-sized bone defects repairing.

[Retracted] Increased resistin suggests poor prognosis and promotes development of lung adenocarcinoma.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the colony formation assay data shown in Fig. 3A on p. 3399 were strikingly similar to data that were already under consideration for publication in another article written by different authors at different research institutes. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 40: 3392­3404, 2018; DOI: 10.3892/or.2018.6736].

TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in allergic airway inflammation.

As a pattern recognition receptor which activates innate immune system, toll-like receptor 2 (TLR2) has been reportedly mediates allergic airway inflammation (AAI), yet the underlying mechanism remains elusive. Here, in a murine AAI model, TLR2-/- mice showed decreased airway inflammation, pyroptosis and oxidative stress. RNA-sequencing revealed that allergen-induced hif1 signaling pathway and glycolysis were significantly downregulated when TLR2 was deficient, which were confirmed by lung protein immunoblots. Glycolysis inhibitor 2-Deoxy-d-glucose (2-DG) inhibited allergen-induced airway inflammation, pyroptosis, oxidative stress and glycolysis in wild type (WT) mice, while hif1α stabilizer ethyl 3,4-dihydroxybenzoate (EDHB) restored theses allergen-induced changes in TLR2-/- mice, indicating TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in AAI. Moreover, upon allergen challenge, lung macrophages were highly activated in WT mice but were less activated in TLR2-/- mice, 2-DG replicated while EDHB reversed such effect of TLR2 deficiency on lung macrophages. Likewise, both in vivo and ex vivo WT alveolar macrophages (AMs) exhibited higher TLR2/hif1α expression, glycolysis and polarization activation in response to ovalbumin (OVA), which were all inhibited in TLR2-/- AMs, suggesting AMs activation and metabolic switch are dependent on TLR2. Finally, depletion of resident AMs in TLR2-/- mice abolished while transfer of TLR2-/- resident AMs to WT mice replicated the protective effect of TLR2 deficiency on AAI when administered before allergen challenge. Collectively, we suggested that loss of TLR2-hif1α-mediated glycolysis in resident AMs ameliorates allergic airway inflammation that inhibits pyroptosis and oxidative stress, therefore the TLR2-hif1α-glycolysis axis in resident AMs may be a novel therapeutic target for AAI.

Diagnosis value of 18F-Fluoro-D-glucose positron emission tomography-computed tomography in pulmonary hamartoma: a retrospective study and systematic review.

PURPOSE: The diagnosis of pulmonary hamartoma (PH) based on computed tomography (CT) is a challenge, especially in patients with atypical imaging characteristics. This study was aimed at summarizing the imaging characteristic of 18F-Fluoro-D-glucose positron emission tomography-computed tomography (18F-FDG PET-CT) in PH and exploring the application value of PET-CT in the diagnosis of PH. DATA AND METHODS: Patients diagnosed with PH who had undergone PET-CT from literature pertaining were retrospectively analyzed, which were cases of publications from the Cochrane Library, PubMed, Excerpta Medica Database (EMBASE), China National Knowledge Infrastructure (CNKI) and Wanfang databases, from 2008 to June 2022. The other 20 cases of the collection were patients from our hospital from 2008 to June 2022. Patients' symptoms, imaging characteristics of chest CT, PET-CT characteristics, the reason for PET-CT and the complications were analyzed. RESULTS: In this retrospective study, a total of 216 patients were diagnosed with PH and had been examined by PET-CT. 20 of the cases were patients of our hospital from January 2008 to June 2022. The other cases were collected from the literature. The mean diameter of most PH lesions is 1.7 ± 1.0 cm. The mean maximum standardized uptake value (SUVmax) of the PH lesions was 1.2 ± 1.1. Most of their SUVmax were lower than internationally recognized cut-off value (SUVmax = 2.5). PET-CT was superior to CT in the diagnosis of PH but there was a correlation of between CT diagnosis and PET-CT diagnosis for the PH lesions. In order to draw the Receiver operating characteristic (ROC), we selected 29 patients with a clear SUVmax value of their PH lesion, and 29 lung cancer patients with clear SUVmax value in our hospital were collected as a control group. ROC curve analysis showed that the area under curve (AUC) of SUVmax was 0.899, and the optimal diagnostic threshold was SUVmax > 2.65. PET-CT could distinguish PH from malignant lesions with a sensitivity of 89.66% by applying a SUVmax of 2.65 as a cut-off in this study. CONCLUSION: PET-CT might be a useful tool to diagnose PH, which shows a better diagnostic sensitivity than CT. But PET-CT can not be used as a single diagnostic approach, which should be combined with other methods and the patients' history to make the most correct diagnosis.

Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation.

Itaconate has emerged as a novel anti-inflammatory and antioxidative endogenous metabolite, yet its role in allergic airway inflammation (AAI) and the underlying mechanism remains elusive. Here, the itaconate level in the lung was assessed by High Performance Liquid Chromatography (HPLC), and the effects of the Irg1/itaconate pathway on AAI and alveolar macrophage (AM) immune responses were evaluated using an ovalbumin (OVA)-induced AAI model established by wild type (WT) and Irg1-/- mice, while the mechanism of this process was investigated by metabolomics analysis, mitochondrial/cytosolic protein fractionation and transmission electron microscopy in the lung tissues. The results demonstrated that the Irg1 mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while Irg1 deficiency augmented AAI, and this may be attributed to the fact that itaconate suppressed mitochondrial events such as NLRP3 inflammasome activation, oxidative stress and metabolic dysfunction. Furthermore, we identified that the Irg1/itaconate pathway impacted the NLRP3 inflammasome activation and oxidative stress in AMs. Collectively, our findings provide evidence for the first time, supporting the conclusion that in the allergic lung, the itaconate level is markedly increased, which directly regulates AMs' immune responses. We therefore propose that the Irg1/itaconate pathway in AMs is a potential anti-inflammatory and anti-oxidative therapeutic target for AAI.

Willow can be recommended as a strong candidate for the phytoremediation of cadmium and pyrene co-polluted soil under flooding condition.

Soil cadmium (Cd) and pyrene (PYR) pollutions have gained worldwide attention due to their negative effects on the environment. Intermittent flooding in rain-rich areas may affect phytoremediation of Cd and PYR in soil. Therefore, a pot-culture experiment, with and without flooding, was conducted to study the effects of flooding on soil Cd and PYR phytoremediation. Concentrations of Cd, PYR, and nutrients in soils and plants, as well as plant physiological and biochemical responses, were examined. Under both flooding and non-flooding conditions, willow (Salix × aureo-pendula CL 'J1011') demonstrated a better ability to remove soil Cd and PYR. Flooding led to higher Cd accumulation in roots than that in shoots. Conversely, non-flooding resulted in higher Cd accumulation in shoots than that in roots. The maximum concentrations of Cd in shoots were 11.02 and 14.07 mg kg-1 with and without flooding, respectively. The maximum dissipation rates of PYR in soil were 47.35% and 88.61% under flooding and non-flooding conditions, respectively. In addition, flooding significantly increased the photosynthetic pigment, photosynthetic fluorescence, and chlorophyll fluorescence parameters in leaves, compared with non-flooding treatment. Flooding also increased the concentrations of Mg, Mn, P, Fe, and K in roots and shoots. This study outlines an effective insight for the phytoremediation of Cd- and PYR-contaminated soil under flooding condition.

Risk assessment of trace elements accumulation in soil-herbage systems at varied elevation in subalpine grassland of northern Tibet Plateau.

Ecological environment of remote grassland has become a problem in many countries due to mining, tourism, grazing, and other human activities. In this study, a total of 15 pairs of soil-herbage samples were collected in the northeast of the Tibet Plateau to study the relationship between physicochemical properties and content of trace elements in soils at different elevation, and to examine the accumulation and fractionation of heavy metals in soil-herbage systems. In addition, the ecological risk of the subalpine grassland was also assessed. The average concentrations of Hg, As, Cu, Zn, Pb, Cd, Cr, and Mn in soil were higher than their background values of Gansu soil, but the average concentrations of these heavy metals in herbage satisfied Hygienical Standard for Feeds. The speciation analysis of heavy metals in soil indicated that the exchangeable content of heavy metal was very low, except Pb, Cd, and Mn. There was a linear relationship between pH, CaCO3, total phosphorus (TP), organic matter (OM), concentrations of Hg, As, Zn, Pb, Cr, and Mn in soils, dry weight of herbage, and elevation, while there was a quadratic curve trend between Cu, Cd in soils, and elevation. The results of risk assessment showed that there was no obvious ecological risk in the study area.

Paclitaxel-based supramolecular hydrogel loaded with mifepristone for the inhibition of breast cancer metastasis.

Breast cancer is the leading cause of cancer death among women and almost all of the breast cancer-caused mortality is related to metastasis. It has been reported that glucocorticoid facilitates the metastasis of breast cancer in mice, and mifepristone can antagonize the effect of glucocorticoid. Paclitaxel is one of the important drugs in the treatment of breast cancer. Mifepristone combined with paclitaxel could be an effective strategy for inhibiting breast cancer metastasis. However, their inherent defects, in terms of short blood circulation half-life and lack of tumor targeting, not only limit their effectiveness but also cause adverse reactions. Therefore, our aim is to explore a novel protocol against breast cancer metastasis, further optimize its therapeutic efficacy by a nanodelivery system, and explore its mechanism. Herein, a paclitaxel-conjugated and mifepristone-loaded hydrogel (PM-nano) was prepared by self-assembly. Its characterizations were studied. The antimetastatic effect was evaluated in vitro and in vivo and its mechanism was also explored by western blot assay. The resultant PM-nano was developed with favorable water solubility and good biocompatibility. Moreover, PM-nano displayed increased cell uptake properties and stimulated drug release in the tumor micro-acidic environment. The PM-nano was more effective in inhibiting the proliferation and metastasis of breast cancer than other groups in vitro and in vivo. The PM-nano might inhibit metastasis through glucocorticoid receptor/receptor tyrosine kinase-like orphan receptor 1 and MMPs. Taken together, PM-nano showed superior antimetastatic effects against breast cancer and excellent biocompatibility in vitro and in vivo, providing a new option for limiting metastasis.

CpG Oligodeoxynucleotides Attenuate OVA-Induced Allergic Airway Inflammation via Suppressing JNK-Mediated Endoplasmic Reticulum Stress.

PURPOSE: CpG-ODN has been found to attenuate allergic airway inflammation in our previous study. Here, we aimed to further investigate whether CpG-ODN exerts such effect via regulating endoplasmic reticulum (ER) stress and revealed the underlying mechanism. METHODS: Five-week-old C57BL/6 mice were randomly grouped and treated with or without CpG-ODN or/and SP600125. Meantime, RAW264.7 cells were used to investigate the effect of CpG-ODN on OVA-induced ER stress in vitro. The cellularity of bronchoalveolar lavage fluid (BALF) was classified and counted after Wright-Giemsa staining. HE and PAS staining methods were applied to analyze airway inflammation. The protein levels of IL-4, IL-5, IL-13, p-JNK, JNK, CHOP, XBP1, ATF6α and GRP78 in lung tissues were detected by Western blotting. Correspondingly, the ER stress markers were detected by Western blotting and immunofluorescence in RAW264.7 cells. RESULTS: In OVA-induced allergic airway inflammation, CpG-ODN significantly suppressed inflammatory cells infiltration, goblet cell hyperplasia and the protein expression of Th2 cytokines. Moreover, OVA exposure strongly increased the activation of ER stress with higher protein expressions of CHOP, XBP1, ATF6α and GRP78. However, these OVA-induced increase of ER stress markers were markedly suppressed by CpG-ODN treatment. In addition, exposure to OVA significantly increased the phosphorylation of JNK, which was significantly reduced by CpG-ODN treatment. Remarkably, single treatment of SP600125, an antagonist of JNK, functioned similarly as CpG-ODN in mitigating allergic airway inflammation and suppressing OVA-induced activation of ER stress; however, no significant synergistic effect was evidenced by combined treatment of SP600125 and CpG-ODN. Furthermore, in OVA-stimulated RAW264.7 cells, we also found that OVA stimulation increased the expressions of ER stress markers, and CpG-ODN significantly reduced their expression levels via suppressing the phosphorylation of JNK. CONCLUSION: These results indicated that CpG-ODN mitigates allergic airway inflammation via suppressing the activation of JNK-medicated ER stress.

KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion.

BACKGROUND: Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). METHODS: We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. RESULTS: We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed (P < 0.05) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) (P < 0.05, respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control (P < 0.05, respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. CONCLUSION: In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

KIF20B Promotes Cell Proliferation and May Be a Potential Therapeutic Target in Pancreatic Cancer.

KIFs have been reported to play a critical role in a variety of tumors, and KIF20B is a protein in KFIs. In this research, KIF20B was highly expressed in the GEO database and our hospital's data, and high expression of KIF20B suggested poor prognosis. We detect the expression of KIF20B in pancreatic cancer and adjacent normal tissues using immunohistochemistry. Knockdown of KIF20B in pancreatic cancer cell lines, PANC-1 and BxPC-3 cells, inhibited cell proliferation which are detected by colony formation assays, CCK8, and western bolt of Ki-67 and PCNA. Xenograft assay showed a similar result in vivo. KIF20B is a potential therapeutic target in pancreatic cancer.

Multifunctional Hybrid Hydrogel Enhanced Antitumor Therapy through Multiple Destroying DNA Functions by a Triple-Combination Synergistic Therapy.

Brachytherapy, as an effective setting for precise cancer therapy in clinic, can lead to serious DNA damage. However, its therapeutic efficacy is always limited by the DNA self-repair property, tumor hypoxia-associated radiation resistance as well as inhomogeneous distribution of the radioactive material. Herein, a multifunctional hybrid hydrogel (131 I-hydrogel/DOX/GNPs aggregates) is developed by loading gold nanoparticle aggregates (GNPs aggregates) and DOX into a radionuclide iodine-131 (131 I) labelled polymeric hydrogels (131 I-PEG-P(Tyr)8 ) for tumor destruction by completely damaging DNA self-repair functions. This hybrid hydrogel exhibits excellent photothermal/radiolabel stability, biocompatibility, and fluorescence/photothermal /SPECT imaging properties. After local injection, the sustained releasing DOX within tumor greatly inhibits the DNA replication. Meanwhile, GNPs aggregates as a radiosensitizer and photosensitizer show a significant improvement of brachytherapeutic efficacy and cause serious DNA damage. Simultaneously, GNPs aggregates induce mild photothermal therapy under 808 nm laser irradiation, which not only inhibits self-repair of the damaged DNA but also effectively relieves tumor hypoxic condition to enhance the therapeutic effects of brachytherapy, leading to a triple-synergistic destruction of DNA functions. Therefore, this study provides a highly efficient tumor synergistic therapy platform and insight into the synergistic antitumor mechanism in DNA level.

Abscisic acid suppresses the activation of NLRP3 inflammasome and oxidative stress in murine allergic airway inflammation.

Abscisic acid (ABA), a well-known natural phytohormone reportedly exerts anti-inflammatory and anti-oxidative properties in diabetes and colitis. However, the efficacy of ABA against allergic airway inflammation and the underlying mechanism remain unknown. Herein, an OVA-induced murine allergic airway inflammation model was established and treated with ABA in the presence or absence of PPAR-γ antagonist GW9662. The results showed that ABA effectively stunted the development of airway inflammation, and concordantly downregulated OVA-induced activation of NLRP3 inflammasome, suppressed oxidative stress and decreased the expression of mitochondrial fusion/fission markers including Optic Atrophy 1 (OPA1), Mitofusion 2 (Mfn2), dynamin-related protein 1 (DRP1) and Fission 1 (Fis1). Moreover, ABA treatment further increased OVA-induced expression of PPAR-γ, while GW9662 abrogated the inhibitory effect of ABA on allergic airway inflammation as well as on the activation of NLRP3 inflammasome and oxidative stress. Consistently, ABA inhibited the activation of NLRP3 inflammasome, suppressed oxidative stress and mitochondrial fusion/fission in LPS-stimulated Raw264.7 cells via PPAR-γ. Collectively, ABA ameliorates OVA-induced allergic airway inflammation in a PPAR-γ dependent manner, and such effect of ABA may be associated with its inhibitory effect on NLRP3 inflammasome and oxidative stress. Our results suggest the potential of ABA or ABA-rich food in protecting against asthma.