Analysis of treatment-related adverse events and wound complications of surgical resection after neoadjuvant chemoimmunotherapy for non-small cell lung cancer.

Neoadjuvant chemoimmunotherapy is becoming an increasingly important part of the management of lung cancer to facilitate surgical resection. This study aimed to summarize the treatment-related adverse events (TRAEs) and wound complications of neoadjuvant chemoimmunotherapy in non-small cell lung cancer (NSCLC). Eligible studies of neoadjuvant chemoimmunotherapy for NSCLC were identified from PubMed, Embase and Web of Science. The endpoints mainly included TRAEs and wound complications. Stata18 software was used for statistical analysis with p < 0.05 considered statistically significant. Twenty studies including a total of 1072 patients were eligible for this study. Among the patients who received neoadjuvant chemoimmunotherapy, the pooled prevalence of any grade TRAEs was 77% (95% confidence interval [CI] [0.64-0.86]), grade 1-2 TRAEs was 77% (95% CI [0.58-0.89]) and grade ≥3 TRAEs was 26% (95% CI [0.16-0.38]). Surgery-related complications rate was 22% (95% CI [0.14-0.33]). Among the wound complications, the pooled rate of air leakage was 10% (95% CI [0.04-0.23]), pulmonary/wound infection was 8% (95% CI [0.05-0.13]), bronchopleural fistula was 8% (95% CI [0.02-0.27]), bronchopulmonary haemorrhage was 3% (95% CI [0.01-0.05]), pneumonia was 5% (95% CI [0.02-0.10]), pulmonary embolism was 1% (95% CI [0.01-0.03]), pleural effusion was 7% (95% CI [0.03-0.14]) and chylothorax was 4% (95% CI [0.02-0.09]). Overall, neoadjuvant chemoimmunotherapy in NSCLC results a high incidence of grade 1-2 TRAEs but a low risk of increasing the incidence of ≥3 grade TRAEs and wound complications. These results need to be confirmed by more large-scale prospective randomized controlled trials and studies.

Construction and Sensing Amplification of Raspberry-Shaped MOF@MOF.

MOFs@MOFs (metal-organic frameworks, MOFs) possess precise customized functionalities and predesigned structures that enable the implementation of structure and property regulation for specific functions in comparison to traditional single MOFs. However, the synthesis and fluorescence properties of multilayer MOFs@MOFs are still worth improving. Herein, a fluorescent raspberry-shaped MOF@MOF was constructed via optimized seed-mediated synthesis by tuning the reaction time, reaction mode, and reaction concentration, involving the initial synthesis of the UiO-66-NH2 core and then the coating of the UiO-67-bpy shell. The raspberry-shaped UiO-66@67-bpy showed stable fluorescence and desirable sensing selectivity for the Hg2+ ion under the interference of other ions; meanwhile, the raspberry-shaped UiO-66@67-bpy indicated amplified sensing performance than pure UiO-66-NH2, mechanically mixed UiO-66-NH2 + UiO-67-bpy, and UiO-66@UiO-67 counterpart due to the accumulation effect of outer UiO-67-bpy toward Hg2+. Density functional theory (DFT) calculations including adsorption energy calculations and electronic density difference analysis further showed that the enhanced fluorescence quenching was possibly attributed to the outer UiO-67-bpy enrichment promoting the charge transfer between Hg2+ and the ligands of fluorescent UiO-66@67-bpy. The synergistic effect of MOFs@MOFs unlocks more possibilities for the construction of enhanced sensors and other applications.

Decreased Indian hedgehog signaling activates autophagy in endometriosis and adenomyosis.

Indian hedgehog (Ihh) signaling regulates endometrial receptivity and is an indispensable mediator of embryonic implantation. Hedgehog signaling is known to regulate autophagy, and aberrant regulation of autophagy is critically implicated in the pathogenesis of endometriosis and adenomyosis. However, potential dysregulation of Ihh signaling and its role in autophagy modulation in these diseases remain obscure. In this study, we found that components of Ihh signaling were significantly decreased, whereas the autophagy marker protein, LC3BII, was significantly increased in endometrial tissues of women with endometriosis or adenomyosis. Inhibition of Ihh signaling with the small-molecule inhibitor GANT61 or Gli1 silencing in primary endometrial stromal cells increased autophagic activity, as measured by LC3 turnover assay and tandem mCherry-eGFP-LC3B fluorescence microscopy. Furthermore, we observed that GANT61 treatment significantly attenuated hydrogen peroxide-induced cell death, whereas disruption of autophagy with chloroquine diminished this effect. Collectively, these findings reveal that Ihh signaling is suppressed in endometrial tissues of patients with endometriosis or adenomyosis. This abnormal decrease may contribute to endometrial autophagy activation, which may promote aberrant survival of endometrial cells in ectopic sites in these two gynecological diseases.

P2X7 receptor-mediated phenotype switching of pulmonary artery smooth muscle cells in hypoxia.

P2X7R activation contributes to the pathogenesis of pulmonary hypertension. However, the molecular mechanism through which P2X7R participates in pulmonary vascular remodeling is largely unknown. The rats and pulmonary artery smooth muscle cells (PASMCs) were maintained under hypoxia. P2X7R expression was determined by real-time PCR and western blotting. The pathological changes of lung tissue were evaluated via HE staining after treatment with a P2X7R antagonist, A740003. After treatment with A740003 or silencing P2X7R, proliferating cell nuclear antigen (PCNA), phenotype markers and phospho-c-Jun N-terminal kinase (JNK)/JNK expression were tested by western blotting. P2X7R expression in hypoxia group was significantly higher than that in normoxia group in vivo and in vitro. The pathological changes of lung tissue induced by hypoxia were significantly relieved by treatment with a P2X7R antagonist, A740003. Hypoxia stimulated the proliferation and synthetic phenotype of PASMCs, which were aggravated by a P2X7R agonist treatment and alleviated by a P2X7R antagonist or silencing P2X7R mRNA treatment. Silencing P2X7R mRNA significantly decreased the hypoxia-induced upregulation of phospho-JNK/JNK in PASMCs. The phenotype switching of PASMCs in hypoxia was reversed by treatment with JNK inhibitor. The findings indicate that P2X7R may be involved in the hypoxia-induced proliferation and phenotype switching of PASMCs via JNK signaling pathway, which suggests a new therapeutic strategy targeting P2X7R in vascular remodeling of pulmonary arterial hypertension.

The Adaptive Gain Integrating Pixel Detector at the European XFEL.

The Adaptive Gain Integrating Pixel Detector (AGIPD) is an X-ray imager, custom designed for the European X-ray Free-Electron Laser (XFEL). It is a fast, low-noise integrating detector, with an adaptive gain amplifier per pixel. This has an equivalent noise of less than 1 keV when detecting single photons and, when switched into another gain state, a dynamic range of more than 104 photons of 12 keV. In burst mode the system is able to store 352 images while running at up to 6.5 MHz, which is compatible with the 4.5 MHz frame rate at the European XFEL. The AGIPD system was installed and commissioned in August 2017, and successfully used for the first experiments at the Single Particles, Clusters and Biomolecules (SPB) experimental station at the European XFEL since September 2017. This paper describes the principal components and performance parameters of the system.

Excessive corticosterone induces excitotoxicity of hippocampal neurons and sensitivity of potassium channels via insulin-signaling pathway.

Corticosterone (CORT) is a kind of corticosteroid produced by cortex of adrenal glands. Hypothalamic-pituitary-adrenal (HPA) axis hyperfunction leads to excessive CORT, which is associated with depression. Few studies have investigated the role of CORT in voltage-gated ion channels and its upstream signaling pathway in central nervous system. In this study, we investigated the mechanism of excessive CORT resulting in brain impairment on voltage-gated ion channels, and its upstream signaling effectors in hippocampal CA1 neurons. The action potential (AP) and voltage-gated potassium currents were determined by using whole-cell patch-clamp. Insulin and CORT improved the neuronal excitability. Independent effects existed in transient potassium channel (IA) and delay rectifier potassium channel (IK). The inhibition of potassium currents, IA in our experiment, could increase neuronal excitability. CORT led to the excitotoxicity of hippocampal neurons via phosphatidylinositol 3 kinase (PI3K)-mediated insulin-signaling pathway. Therefore, the stimulation of excessive CORT induces excitotoxicity of hippocampal neurons and sensitivity of potassium channels via PI3K-mediated insulin-signaling pathway, which indicates one possible way of depression treatment.

P2X4R promotes airway remodeling by acting on the phenotype switching of bronchial smooth muscle cells in rats.

The P2X4 receptor (P2X4R) contributes to airway inflammation and airway remodeling in mice with allergic asthma. However, the molecular mechanism by which P2X4R affects the airway remodeling in allergic asthma remains largely unknown. We established an allergic asthma model by ovalbumin (OVA) inhalation in BALB/c mice. Compared with the mice in the control group, the expression of proliferating cell nuclear antigen (PCNA) increased and that of alpha-smooth muscle actin (α-SMA) decreased in the OVA-challenged mice. 5-BDBD, a P2X4R antagonist, alleviated the OVA-induced changes. To clarify the role of P2X4R in the phenotype switching of the bronchial smooth muscle, bronchial smooth muscle contractility and p38MAPK expression were investigated. Platelet-derived growth factor-BB (PDGF-BB) was used to activate the proliferation of primary-cultured rat bronchial smooth muscle cells (BSMCs). P2X4R, p38MAPK, and phenotype markers were evaluated using Western blotting or immunofluorescence. PDGF-BB administration increased the P2X4R and phospho-p38MAPK expression in BSMCs, and the increased phospho-p38MAPK expression was downregulated by silencing of the P2X4R mRNA. PDGF-BB stimulated the proliferation and synthetic phenotype of BSMCs, which was aggravated by a P2X4R agonist and alleviated by a P2X4R antagonist or silencing the P2X4R mRNA. The decreased contractile phenotype induced by PDGF-BB was alleviated by a P2X4R antagonist or by silencing the P2X4R mRNA. SB203580, p38MAPK inhibitor, inhibited the PDGF-BB-induced increasing of synthetic phenotype and the proliferation of BSMCs. These findings indicate that P2X4R acts directly on the phenotype switching of BSMCs. Inhibiting P2X4R can promote the contractile differentiation of BSMCs via p38MAPK signaling. Thus, the effect of P2X4R on airway remodeling indicates that this receptor could be a target for future drug candidates.

Hedgehog signaling inhibitor GANT61 induces endoplasmic reticulum stress-mediated protective autophagy in hepatic stellate cells.

Hedgehog (Hh) signaling plays an important role in the viability maintenance of hepatic stellate cells (HSC). HSCs have been identified as the major profibrogenic cells in the liver. The present study revealed that a novel Hh signaling antagonist GANT61 induced apoptosis in the activated human hepatic stellate cell line LX-2 cells, as it dose-dependently caused mitochondrial inner transmembrane potential (ΔΨm) loss and caspase-3 cleavage. Autophagic flux was markedly increased after GANT61 treatment. Moreover, we found that autophagy was a pro-survival factor in GANT61-treated LX-2 cells because autophagic inhibitors 3-Methyladenine (3-MA) or Chloroquine (CQ) significantly aggravated GANT61-induced cytotoxicity. Furthermore, the endoplasmic reticulum (ER)-resident molecular chaperone BiP, a marker of ER stress, was markedly increased after incubation with GANT61. Meanwhile, the PERK-eIF2α-ATF4-CHOP pathway was observed to be activated by GANT61. Salubrinal, a selective inhibitor of ER stress, suppressed GANT61-induced LC3BII expression and enhanced poly (ADP-ribose) polymerase (PARP) cleavage, indicating that ER stress is a trigger of autophagy and suppresses apoptosis in GANT61-treated LX-2 cells. Overall, these results demonstrate that simultaneous inhibition of Hh signaling and autophagy or ER stress could be a better way to reduce activated HSCs.

Detector developments at DESY.

With the increased brilliance of state-of-the-art synchrotron radiation sources and the advent of free-electron lasers (FELs) enabling revolutionary science with EUV to X-ray photons comes an urgent need for suitable photon imaging detectors. Requirements include high frame rates, very large dynamic range, single-photon sensitivity with low probability of false positives and (multi)-megapixels. At DESY, one ongoing development project - in collaboration with RAL/STFC, Elettra Sincrotrone Trieste, Diamond, and Pohang Accelerator Laboratory - is the CMOS-based soft X-ray imager PERCIVAL. PERCIVAL is a monolithic active-pixel sensor back-thinned to access its primary energy range of 250 eV to 1 keV with target efficiencies above 90%. According to preliminary specifications, the roughly 10 cm × 10 cm, 3.5k × 3.7k monolithic sensor will operate at frame rates up to 120 Hz (commensurate with most FELs) and use multiple gains within 27 µm pixels to measure 1 to ∼100000 (500 eV) simultaneously arriving photons. DESY is also leading the development of the AGIPD, a high-speed detector based on hybrid pixel technology intended for use at the European XFEL. This system is being developed in collaboration with PSI, University of Hamburg, and University of Bonn. The AGIPD allows single-pulse imaging at 4.5 MHz frame rate into a 352-frame buffer, with a dynamic range allowing single-photon detection and detection of more than 10000 photons at 12.4 keV in the same image. Modules of 65k pixels each are configured to make up (multi)megapixel cameras. This review describes the AGIPD and the PERCIVAL concepts and systems, including some recent results and a summary of their current status. It also gives a short overview over other FEL-relevant developments where the Photon Science Detector Group at DESY is involved.

Long non-coding RNA PVT1 as a novel biomarker for diagnosis and prognosis of non-small cell lung cancer.

Accumulating evidence has indicated that long non-coding RNA PVT1 is upregulated in various human cancers. However, it remains unclear whether PVT1 is involved in the development and progression of non-small cell lung cancer (NSCLC). The present study was designed to investigate the expression, biological role, and clinical significance of PVT1 in NSCLC. Our results indicated that PVT1 expression was significantly increased in NSCLC tissues and cell lines, and its upregulation was associated with advanced T-stage and tumor-node-metastasis (TNM) stage and regional lymph node metastasis. PVT1 expression levels were robust in differentiating NSCLC tissues from controls. Kaplan-Meier curve and Cox regression analysis showed that high expression of PVT1 was associated with poor overall survival and disease-free survival in NSCLC patients. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays indicated that knockdown of PVT1 remarkably inhibited NSCLC cell proliferation, whereas overexpression of PVT1 significantly promoted cellular proliferation. In addition, PVT1 knockdown increased the number of cells in the G0/G1 phase and reduced the number of cells in the S phase, while overexpression of PVT1 could promote cell cycle progression. Furthermore, our findings also revealed that the messenger RNA (mRNA) and protein expression of P15 and P21 was significantly upregulated in NSCLC cells transfected with PVT1 small interfering RNA (siRNA) and downregulated in cells transfected with pcDNA3.1-PVT1. In conclusion, our study demonstrated that PVT1 might serve as a promising biomarker for diagnosis and prognosis of NSCLC, and it could promote the proliferation of NSCLC cells by downregulating p15 and p21 expression.

MicroRNA-19a regulates lipopolysaccharide-induced endothelial cell apoptosis through modulation of apoptosis signal-regulating kinase 1 expression.

BACKGROUND: MicroRNAs, small non-encoding RNAs that post-transcriptionally modulate expression of their target genes, have been implicated as critical regulatory molecules in endothelial cells. RESULTS: In the present study, we found that overexpression of miR-19a protects endothelial cells from lipopolysaccharide (LPS)-induced apoptosis through the apoptosis signal-regulating kinase 1 (ASK1)/p38 pathway. Quantitative real-time PCR demonstrated that the expression of miR-19a in endothelial cell was markedly down-regulated by LPS stimulation. Furthermore, LPS-induced apoptosis was significantly inhibited by over-expression of miR-19a. Finally, both a luciferase reporter assay and western blot analysis showed that ASK1 is a direct target of miR-19a. CONCLUSIONS: MiR-19a regulates ASK1 expression by targeting specific binding sites in the 3' untranslated region of ASK1 mRNA. Overexpression of miR-19a is an effective method to protect against LPS-induced apoptosis of endothelial cells.

Inhibition of Rac1 activity by controlled release of NSC23766 from chitosan microspheres effectively ameliorates osteoarthritis development in vivo.

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease characterised by cartilage degradation and chondrocyte hypertrophy. A recent study showed that Rac1 promoted expression of MMP13 and chondrocyte hypertrophy within the growth plate. These findings warrant further investigations on the roles of Rac1 in OA development and therapy in animal models. OBJECTIVE: To investigate the role and mechanistic pathway of Rac1 involvement in pathological changes of OA chondrocytes in vitro and OA development in vivo, as well as to develop a strategy of modulating Rac1 activity for OA treatment. MATERIAL AND METHODS: OA and normal cartilage from human or mice were used for immunohistochemical study and Rac1 activity assay. Chondrocytes treated with IL1ß and the untreated control were subjected to the Rac1 activity assay. Chondrocytes transfected with CA-Rac1, DN-Rac1 or GFP were cultured under conditions for inducing calcification. To evaluate the effect of Rac1 in OA development, an OA model was created by anterior cruciate ligament transection in mice. CA-Rac1, DN-Rac1 and GFP lentivirus, or NSC23766, were injected intra-articularly. Joints were subjected to histological analysis. RESULTS: It was found that there is aberrant Rac1 activation in human OA cartilage. Rac1 activity could also be elevated by IL1ß. Additionally, activated Rac1 promoted expression of MMP13, ADAMTS-5 and COLX by chondrocytes, partially through the ß-catenin pathway. Moreover, activation of Rac1 in knee joints by CA-Rac1 lentivirus accelerated OA progression, while inhibition of Rac1 activity by DN-Rac1 lentivirus or Rac1 inhibitor NSC23766 delayed OA development. Therefore, we developed a strategy of controlled release of NSC23766 from chitosan microspheres to OA joints, which effectively protected cartilage from destruction. CONCLUSIONS: These findings demonstrated that Rac1 activity is implicated in OA development. Also, controlled release of Rac1 inhibitor is a promising strategy for OA treatment.

Identification and Characterization of CYP9A40 from the Tobacco Cutworm Moth (Spodoptera litura), a Cytochrome P450 Gene Induced by Plant Allelochemicals and Insecticides.

Cytochrome P450 monooxygenases (P450s) of insects play crucial roles in the metabolism of endogenous and dietary compounds. Tobacco cutworm moth (Spodoptera litura), an important agricultural pest, causes severe yield losses in many crops. In this study, we identified CYP9A40, a novel P450 gene of S. litura, and investigated its expression profile and potential role in detoxification of plant allelochemicals and insecticides. The cDNA contains an open reading frame encoding 529 amino acid residues. CYP9A40 transcripts were found to be accumulated during various development stages of S. litura and were highest in fifth and sixth instar larvae. CYP9A40 was mainly expressed in the midgut and fat body. Larval consumption of xenobiotics, namely plant allelochemicals (quercetin and cinnamic acid) and insecticides (deltamethrin and methoxyfenozide) induced accumulation of CYP9A40 transcripts in the midgut and fat body. Injection of dsCYP9A40 (silencing of CYP9A40 by RNA interference) significantly increased the susceptibility of S. litura larvae to the tested plant allelochemicals and insecticides. These results indicate that CYP9A40 expression in S. litura is related to consumption of xenobiotics and suggest that CYP9A40 is involved in detoxification of these compounds.

Molecular characteristics of Salmonella genomic island 1 in Proteus mirabilis isolates from poultry farms in China.

Six out of the 64 studied Proteus mirabilis isolates from 11 poultry farms in China contained Salmonella genomic island 1 (SGI1). PCR mapping showed that the complete nucleotide sequences of SGI1s ranged from 33.2 to 42.5 kb. Three novel variants, SGI1-W, SGI1-X, and SGI1-Y, have been characterized. Resistance genes lnuF, dfrA25, and qnrB2 were identified in SGI1 for the first time.

Zwitterionic cellulose nanofibers-based hydrogels with high toughness, ionic conductivity, and healable capability in cryogenic environments.

Extreme environmental conditions often lead to irreversible structural failure and functional degradation in hydrogels, limiting their service life and applicability. Achieving high toughness, self-healing, and ionic conductivity in cryogenic environments is vital to broaden their applications. Herein, we present a novel approach to simultaneously enhance the toughness, self-healing, and ionic conductivity of hydrogels, via inducing non-freezable water within the zwitterionic cellulose-based hydrogel skeleton. This approach enables resulting hydrogel to achieve an exceptional toughness of 10.8 MJ m-3, rapid self-healing capability (98.9 % in 30 min), and high ionic conductivity (2.9 S m-1), even when subjected to -40 °C, superior to the state-of-the-art hydrogels. Mechanism analyses reveal that a significant amount of non-freezable water with robust electrostatic interactions is formed within zwitterionic cellulose nanofibers-modified polyurethane molecular networks, imparting superior freezing tolerance and versatility to the hydrogel. Importantly, this strategy harnesses the non-freezable water molecular state of the zwitterionic cellulose nanofibers network, eliminating the need for additional antifreeze and organic solvents. Furthermore, the dynamic Zn coordination within these supramolecular molecule chains enhances interfacial interactions, thereby promoting rapid subzero self-healing and exceptional mechanical strength. Demonstrating its potential, this hydrogel can be used in smart laminated materials, such as aircraft windshields.

Creatine kinase mitochondrial 2 promotes the growth and progression of colorectal cancer via enhancing Warburg effect through lactate dehydrogenase B.

Background: Mitochondrial creatine kinase (MtCK) plays a pivotal role in cellular energy metabolism, exhibiting enhanced expression in various tumors, including colorectal cancer (CRC). Creatine kinase mitochondrial 2 (CKMT2) is a subtype of MtCK; however, its clinical significance, biological functions, and underlying molecular mechanisms in CRC remain elusive. Methods: We employed immunohistochemical staining to discern the expression of CKMT2 in CRC and adjacent nontumor tissues of patients. The correlation between CKMT2 levels and clinical pathological factors was assessed. Additionally, we evaluated the association between CKMT2 and the prognosis of CRC patients using Kaplan-Meier survival curves and Cox regression analysis. Meanwhile, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression levels of CKMT2 in different CRC cell lines. Finally, we explored the biological functions and potential molecular mechanisms of CKMT2 in CRC cells through various techniques, including qRT-PCR, cell culture, cell transfection, western blot, Transwell chamber assays, flow cytometry, and co-immunoprecipitation. Results: We found that CKMT2 was significantly overexpressed in CRC tissues compared with adjacent nontumor tissues. The expression of CKMT2 is correlated with pathological types, tumor size, distant metastasis, and survival in CRC patients. Importantly, CKMT2 emerged as an independent prognostic factor through Cox regression analysis. Experimental downregulation of CKMT2 expression in CRC cell lines inhibited the migration and promoted apoptosis of these cells. Furthermore, we identified a novel role for CKMT2 in promoting aerobic glycolysis in CRC cells through interaction with lactate dehydrogenase B (LDHB). Conclusion: In this study, we found the elevated expression of CKMT2 in CRC, and it was a robust prognostic indicator in CRC patients. CKMT2 regulates glucose metabolism via amplifying the Warburg effect through interaction with LDHB, which promotes the growth and progression of CRC. These insights unveil a novel regulatory mechanism by which CKMT2 influences CRC and provide promising targets for future CRC therapeutic interventions.

Ovatodiolide induces autophagy-mediated cell death through the p62-Keap1-Nrf2 signaling pathway in chronic myeloid leukemia cells.

Ovatodiolide is a macrocyclic diterpenoid compound with various biological activities that displays considerable anticancer potential in different tumor models. However, the underlying mechanism for this antineoplastic activity remains unclear. The aim of the present study was to investigate the anticancer effect and possible molecular mechanism of ovatodiolide in human chronic myeloid leukemia (CML). Ovatodiolide suppressed cell colony formation and induced apoptosis in the K562 and KU812 cells. We also observed that ovatodiolide enhanced the production of reactive oxygen species (ROS), activated Nrf2 signaling, and inhibited mTOR phosphorylation. Autophagic flux was shown to be enhanced after treatment with ovatodiolide in K562 cells. Furthermore, autophagy inhibition alleviated ovatodiolide-induced cell apoptosis, whereas autophagy promotion aggravated apoptosis in CML cells. These results demonstrated that ovatodiolide activates autophagy-mediated cell death in CML cells. Additionally, ovatodiolide transcriptionally activated the expression of p62, and the p62 levels were negatively regulated by autophagy. Moreover, p62-Keap1-Nrf2 signaling was confirmed to be involved in ovatodiolide-induced cell death. Accordingly, LC3B knockdown augmented the ovatodiolide-induced p62 expression, increased the p62-Keap1 interaction, and enhanced the translocation of Nrf2 into the nucleus. In contrast, p62 inhibition abolished the effects that were induced through ovatodiolide treatment. Nrf2 inhibition with ML385 diminished the protective effect of autophagy inhibition in CML cells. Collectively, our results indicate that ovatodiolide induces oxidative stress and provokes autophagy, which effectively decreases the expression of p62 and weakens the protective effect of Nrf2 signaling activation, thus contributing to apoptosis in CML cells.

Azoramide ameliorates cadmium-induced cytotoxicity by inhibiting endoplasmic reticulum stress and suppressing oxidative stress.

Background: Cadmium (Cd) is hazardous to human health because of its cytotoxicity and long biological half-life. Azoramide is a small molecular agent that targets the endoplasmic reticulum (ER) and moderates the unfolded protein response. However, its role in Cd-induced cytotoxicity remains unclear. This study was performed to investigate the protective effect of azoramide against Cd-induced cytotoxicity and elucidate its underlying mechanisms. Methods: Inductively coupled plasma‒mass spectrometry was used to measure Cd concentrations in each tissue of ICR male mice. The human proximal tubule epithelial cell line HK-2 and the human retinal pigment epithelial cell line ARPE-19 were used in the in vitro study. Cell apoptosis was determined by DAPI staining, JC-1 staining, and annexin V/propidium iodide double staining. Intracellular oxidative stress was detected by MitoSOX red staining, western blot, and quantitative real-time PCR. Moreover, ER stress signaling, MAPK cascades, and autophagy signaling were analyzed by western blot. Results: The present data showed that Cd accumulated in various organs of ICR mice, and the concentrations of Cd in the studied organs, from high to low, were as follows: liver > kidney > testis > lung > spleen > eye. Our study demonstrated that azoramide inhibited ER stress by promoting BiP expression and suppressing the PERK-eIF2α-CHOP pathway. Additionally, we also found that azoramide significantly decreased ER stress-associated radical oxidative species production, attenuated p38 MAPK and JNK signaling, and inhibited autophagy, thus suppressing apoptosis in HK-2 and ARPE-19 cells. Conclusion: Our study investigated the effect of azoramide on Cd-induced cytotoxicity and revealed that azoramide may be a therapeutic drug for Cd poisoning.

Bowel Stiffness Assessed by Shear-Wave Ultrasound Elastography Predicts Disease Behavior Progression in Patients With Crohn's Disease.

INTRODUCTION: There is a lack of reliable predictors of disease behavior progression in patients with Crohn's disease (CD). Real-time shear-wave elastography (SWE) is a novel method for evaluating tissue stiffness. However, its value for assessing CD has not yet been investigated. We aimed to explore the value of SWE and other ultrasound parameters at diagnosis in predicting CD behavior progression. METHODS: We retrospectively collected data from patients with CD with the nonstenotic nonpenetrating disease (B1 phenotype based on the Montreal classification). All patients underwent intestinal ultrasound at baseline and were followed up. The end point was defined as disease behavior progression to stricturing (B2) or penetrating (B3) disease. Cox regression analysis was performed for the association between baseline characteristics and subsequent end points. In addition, a multivariate nomogram was established to predict the risk of disease behavior progression quantitatively. RESULTS: A total of 130 patients with CD with B1 phenotype were enrolled. Twenty-seven patients (20.8%) developed B2 or B3 disease, with a median follow-up of 33 months. Multivariate analysis identified that SWE was the only independent predictor of disease behavior progression (hazard ratio 1.08, 95% confidence interval 1.03-1.12, P = 0.001). A reverse of the HR appeared at the cutoff 12.75 kPa. The nomogram incorporating SWE and other clinical characteristics showed a good prediction performance (area under the curve = 0.792). DISCUSSION: Intestinal stiffness assessed using SWE is an independent predictor of disease behavior progression in patients with CD. Patients with CD with SWE >12.75 kPa at diagnosis are prone to progress toward stricturing or penetrating diseases.

Adaptive mechanisms of Campylobacter jejuni to erythromycin treatment.

BACKGROUND: Macrolide is the drug of choice to treat human campylobacteriosis, but Campylobacter resistance to this antibiotic is rising. The mechanisms employed by Campylobacter jejuni to adapt to erythromycin treatment remain unknown and are examined in this study. The transcriptomic response of C. jejuni NCTC 11168 to erythromycin (Ery) treatment was determined by competitive microarray hybridizations. Representative genes identified to be differentially expressed were further characterized by constructing mutants and assessing their involvement in antimicrobial susceptibility, oxidative stress tolerance, and chicken colonization. RESULTS: Following the treatment with an inhibitory dose of Ery, 139 genes were up-regulated and 119 were down-regulated. Many genes associated with flagellar biosynthesis and motility was up-regulated, while many genes involved in tricarboxylic acid cycle, electron transport, and ribonucleotide biosynthesis were down-regulated. Exposure to a sub-inhibitory dose of Ery resulted in differential expression of much fewer genes. Interestingly, two putative drug efflux operons (cj0309c-cj0310c and cj1173-cj1174) were up-regulated. Although mutation of the two operons did not alter the susceptibility of C. jejuni to antimicrobials, it reduced Campylobacter growth under high-level oxygen. Another notable finding is the consistent up-regulation of cj1169c-cj1170c, of which cj1170c encodes a known phosphokinase, an important regulatory protein in C. jejuni. Mutation of the cj1169c-cj1170c rendered C. jejuni less tolerant to atmospheric oxygen and reduced Campylobacter colonization and transmission in chickens. CONCLUSIONS: These findings indicate that Ery treatment elicits a range of changes in C. jejuni transcriptome and affects the expression of genes important for in vitro and in vivo adaptation. Up-regulation of motility and down-regulation of energy metabolism likely facilitate Campylobacter to survive during Ery treatment. These findings provide new insight into Campylobacter adaptive response to antibiotic treatment and may help to understand the mechanisms underlying antibiotic resistance development.