Publications by authors named "Junjie Zhu"

126 Publications

Intestinal Sulfation is Essential to Protect Against Colitis and Colonic Carcinogenesis.

Gastroenterology 2021 Apr 2. Epub 2021 Apr 2.

Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania;; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Background & Aims: Sulfation is a conjugation reaction essential for numerous biochemical and cellular functions in mammals. The 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. The goal of this study is to determine whether and how PAPSS2 plays a role in colitis and colonic carcinogenesis.

Methods: Tissue arrays of human colon cancer specimens, gene expression data, and clinical features of cancer patients were analyzed. Intestinal-specific Papss2 knockout mice (Papss2) were created and subjected to dextran sodium sulfate (DSS)-induced colitis, and colonic carcinogenesis induced by combined treatment of azoxymethane (AOM) and DSS, or AOM alone.

Results: The expression of PAPSS2 is decreased in the colon cancers of mice and humans. The lower expression of PAPSS2 in colon cancer patients is correlated with worse survival. Papss2 mice showed heightened sensitivity to colitis and colon cancer by damaging the intestinal mucosal barrier, increasing intestinal permeability and bacteria infiltration, and worsening the intestinal tumor microenvironment. Mechanistically, the Papss2 mice exhibited reduced intestinal sulfomucin content. Metabolomic analyses revealed the accumulation of bile acids including the farnesoid X receptor (FXR) antagonist bile acid tauro-β-muricholic acid (T-β-MCA), and deficiency in the formation of bile acid-sulfates in the colon of Papss2 mice.

Conclusions: We have uncovered an important role of PAPSS2-mediated sulfation in colitis and colonic carcinogenesis. Intestinal sulfation may represent a potential diagnostic marker, and PAPSS2 may serve as a potential therapeutic target for inflammatory bowel disease and colon cancer.
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http://dx.doi.org/10.1053/j.gastro.2021.03.048DOI Listing
April 2021

bFGF alleviates diabetes-associated endothelial impairment by downregulating inflammation via S-nitrosylation pathway.

Redox Biol 2021 Feb 20;41:101904. Epub 2021 Feb 20.

School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, PR China. Electronic address:

Protein S-nitrosylation is a reversible protein modification implicated in both physiological and pathophysiological regulation of protein function. However, the relationship between dysregulated S-nitrosylation homeostasis and diabetic vascular complications remains incompletely understood. Here, we demonstrate that basic fibroblast growth factor (bFGF) is a key regulatory link between S-nitrosylation homeostasis and inflammation, and alleviated endothelial dysfunction and angiogenic defects in diabetes. Subjecting human umbilical vein endothelial cells (HUVECs) to hyperglycemia and hyperlipidemia significantly decreased endogenous S-nitrosylated proteins, including S-nitrosylation of inhibitor kappa B kinase β (IKKβ) and transcription factor p65 (p65), which was alleviated by bFGF co-treatment. Pretreatment with carboxy-PTIO (c-PTIO), a nitric oxide scavenger, abolished bFGF-mediated S-nitrosylation increase and endothelial protection. Meanwhile, nitrosylation-resistant IKKβ and p65 mutants exacerbated endothelial dysfunction in db/db mice, and in cultured HUVECs subjected to hyperglycemia and hyperlipidemia. Mechanistically, bFGF-mediated increase of S-nitrosylated IKKβ and p65 was attributed to synergistic effects of increased endothelial nitric oxide synthase (eNOS) and thioredoxin (Trx) activity. Taken together, the endothelial protective effect of bFGF under hyperglycemia and hyperlipidemia can be partially attributed to its role in suppressing inflammation via the S-nitrosylation pathway.
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http://dx.doi.org/10.1016/j.redox.2021.101904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972985PMC
February 2021

Visualization of an Accelerated Electrochemical Reaction under an Enhanced Electric Field.

Research (Wash D C) 2021 17;2021:1742919. Epub 2021 Feb 17.

State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.

Locally enhanced electric fields produced by high-curvature structures have been reported to boost the charge transport process and improve the relevant catalytic activity. However, no visual evidence has been achieved to support this new electrochemical mechanism. Here, accelerated electrochemiluminescence (ECL) reactions emitting light are visualized for the first time at the heterogeneous interfaces between microbowls and the supporting electrode surface. The simulation result shows that the electric intensity at the interface with a high curvature is 40-fold higher than that at the planar surface. Consequently, local high electric fields concentrate reactive species to the heterogeneous interfaces and efficiently promote the charge transport reactions, which directly leads to the enhancement of ECL emission surrounding the microbowls. Additionally, the potential to induce visual ECL from a ruthenium complex drops to 0.9 V, which further illustrates the promotion of an electrochemical reaction with the aid of an enhanced electric field. This important visualization of electric field boosted electrochemical reactions helps to establish the proposed electron transfer mechanism and provide an alternative strategy to improve electrocatalytic efficiency.
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http://dx.doi.org/10.34133/2021/1742919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907821PMC
February 2021

The nucleocapsid protein of rice stripe virus in cell nuclei of vector insect regulates viral replication.

Protein Cell 2021 Mar 6. Epub 2021 Mar 6.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.

Rice stripe virus (RSV) transmitted by the small brown planthopper causes severe rice yield losses in Asian countries. Although viral nuclear entry promotes viral replication in host cells, whether this phenomenon occurs in vector cells remains unknown. Therefore, in this study, we systematically evaluated the presence and roles of RSV in the nuclei of vector insect cells. We observed that the nucleocapsid protein (NP) and viral genomic RNAs were partially transported into vector cell nuclei by utilizing the importin α nuclear transport system. When blocking NP nuclear localization, cytoplasmic RSV accumulation significantly increased. In the vector cell nuclei, NP bound the transcription factor YY1 and affected its positive regulation to FAIM. Subsequently, decreased FAIM expression triggered an antiviral caspase-dependent apoptotic reaction. Our results reveal that viral nuclear entry induces completely different immune effects in vector and host cells, providing new insights into the balance between viral load and the immunity pressure in vector insects.
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http://dx.doi.org/10.1007/s13238-021-00822-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936609PMC
March 2021

18F-FDG PET/CT and circulating tumor cells in treatment-naive patients with non-small-cell lung cancer.

Eur J Nucl Med Mol Imaging 2021 Feb 25. Epub 2021 Feb 25.

Department of Nuclear Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Road, Shanghai, 200433, China.

Purpose: This study retrospectively investigated the clinical utility of 2-deoxy-18F-fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) and circulating tumor cells (CTCs) in the diagnosis and prognosis of treatment-naive patients with non-small-cell lung cancer (NSCLC).

Methods: The blood samples of treatment-naive patients with NSCLC were collected for CTCs detection, and the tumor metabolic parameters of F-FDG PET/CT, including maximum standard uptake value (SUVmax), metabolic tumor volume of primary lesion (MTV-P) and combination of primary lesion and metastases (MTV-C), and total lesion glycolysis of primary lesion (TLG-P) and combination of primary lesion and metastases (TLG-C), were analyzed. Age, sex, smoking, serum tumor markers, tumor size, location, TNM stage, and genetic mutations were also reviewed. Moreover, progression-free survival (PFS) and overall survival (OS) of these patients were analyzed.

Results: A total of 309 patients with NSCLC (200 men, 109 women; mean age: 61 ± 9 years) were enrolled in this study, including 217 patients with adenocarcinoma and 92 with squamous cell carcinoma. Of the 309 cases, 11 were misdiagnosed with benign diseases by F-FDG PET/CT. CTCs positivity was detected in 234 cases. The sensitivity of F-FDG PET/CT and CTCs in NSCLC were 96.4% and 75.7%, respectively. SUVmax, MTV-P, TLG-P, MTV-C, TLG-C, tumor size, and serum CYFRA211 levels were significantly higher in CTCs positive group than negative group; and advanced TNM stage, squamous cell carcinoma, and EGFR wild type presented higher CTCs positivity. Multivariate logistic regression analysis revealed that SUVmax was significantly associated with CTCs positivity. Multivariate cox regression analysis showed that TLG-P, TLG-C, and CTCs were independent predictors of PFS in patients with NSCLC, and TLG-C and CTCs were independent predictors of OS.

Conclusions: F-FDG PET/CT was superior to CTCs in the diagnosis of treatment-naive patients with NSCLC. The levels of CTCs in the peripheral blood were associated with tumor glucose metabolism in NSCLC. Metabolic parameters of F-FDG PET/CT and CTCs could separately predict the outcomes of treatment-naive patients with NSCLC.
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http://dx.doi.org/10.1007/s00259-021-05260-zDOI Listing
February 2021

Targeting xenobiotic nuclear receptors PXR and CAR to prevent cobicistat hepatotoxicity.

Toxicol Sci 2021 Feb 25. Epub 2021 Feb 25.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Liver-related diseases including drug-induced liver injury are becoming increasingly prominent in AIDS patients. Cobicistat (COBI) is the backbone of multiple regimens for antiretroviral therapy. The current work investigated the mechanisms of adverse drug-drug interactions associated with COBI that lead to liver damage. For individuals co-infected with HIV and tuberculosis (TB), the World Health Organization recommends the initiation of TB treatment followed by antiretroviral therapy. Rifampicin (RIF), a first line anti-TB drug, is a human specific activator of pregnane X receptor (PXR). Using PXR-humanized mice, we found that RIF-mediated PXR activation potentiates COBI hepatotoxicity. In contrast, rifabutin, a PXR-neutral analog of RIF, has no impact on COBI hepatotoxicity. Because of the crosstalk between PXR and the constitutive androstane receptor (CAR), the role of CAR in COBI hepatotoxicity was also investigated. Similar to PXR, ligand-dependent activation of CAR also potentiates COBI hepatotoxicity. Our further studies illustrated that PXR and CAR modulate COBI hepatotoxicity through the CYP3A4-dependent pathways. In summary, the current work determined PXR and CAR as key modulators of COBI hepatotoxicity. Given the fact that many prescription drugs and herbal supplements can activate PXR and CAR, these two receptors should be considered as targets to prevent COBI hepatotoxicity in the clinic.
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http://dx.doi.org/10.1093/toxsci/kfab023DOI Listing
February 2021

Improving hindlimb locomotor function by Non-invasive AAV-mediated manipulations of propriospinal neurons in mice with complete spinal cord injury.

Nat Commun 2021 02 3;12(1):781. Epub 2021 Feb 3.

F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Departments of Neurology and Ophthalmology, Harvard Medical School, Boston, MA, USA.

After complete spinal cord injuries (SCI), spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. However, it is unknown whether selective manipulation of these circuits can restore locomotor function in the absence of brain-derived inputs. By taking advantage of the compromised blood-spinal cord barrier following SCI, we optimized a set of procedures in which AAV9 vectors administered via the tail vein efficiently transduce neurons in lesion-adjacent spinal segments after a thoracic crush injury in adult mice. With this method, we used chemogenetic actuators to alter the excitability of propriospinal neurons in the thoracic cord of the adult mice with a complete thoracic crush injury. We showed that activating these thoracic neurons enables consistent and significant hindlimb stepping improvement, whereas direct manipulations of the neurons in the lumbar spinal cord led to muscle spasms without meaningful locomotion. Strikingly, manipulating either excitatory or inhibitory propriospinal neurons in the thoracic levels leads to distinct behavioural outcomes, with preferential effects on standing or stepping, two key elements of the locomotor function. These results demonstrate a strategy of engaging thoracic propriospinal neurons to improve hindlimb function and provide insights into optimizing neuromodulation-based strategies for treating SCI.
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http://dx.doi.org/10.1038/s41467-021-20980-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859413PMC
February 2021

Nanoparticle-Mediated Delivery of Inhaled Immunotherapeutics for Treating Lung Metastasis.

Adv Mater 2021 Feb 14;33(7):e2007557. Epub 2021 Jan 14.

Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, 215123, China.

Despite the critical breakthrough achieved by immune checkpoint blockade (ICB), the clinical benefits are usually restricted by inefficient infiltration of immune cells and immune-associated adverse effects. Noninvasive aerosol inhalation, as a definitive procedure for treatment of respiratory diseases, for ICB immunotherapy against lung metastasis, has not been realized to the best knowledge. Herein, an inhaled immunotherapeutic chitosan (CS)-antibody complex is developed for immunotherapy against lung cancer. In this system, CS is used as a carrier to assemble with anti-programmed cell death protein ligand 1 (aPD-L1) to enable efficient transmucosal delivery. Moreover, CS exhibits adjuvant effects to drive potent immune responses via activating the cyclic-di-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Interestingly, repeated inhalation of CS/aPD-L1 complex can effectively activate the immune system by promoting the infiltration of different immune cells especially CD8 T cells around tumor lesions, and finally prolongs the survival of mice to 60 days. Thus, the work presents a unique aerosol inhalation delivery system for ICB antibody, which is promising for immunotherapy against lung metastasis without the concern of systemic toxicity.
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http://dx.doi.org/10.1002/adma.202007557DOI Listing
February 2021

Antifungal sesquiterpenes with post-harvest anthracnose control effect on bananas from the fungus .

Nat Prod Res 2021 Jan 15:1-8. Epub 2021 Jan 15.

Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou, China.

To search for antifungal leads, the metabolites of an insect-derived fungus ZMT01 were investigated, providing five sesquiterpenes (), including new molecules microsphaeropsisins D and E ( and ). The evaluated antifungal activities which are higher than the positive control triadimefon include: and towards (MICs 50, 25 mg L; triadimefon 100 mg L); , , and towards (MICs 25, 12.5, 25, 25; triadimefon 50 mg L), , and towards (MICs 25, 12.5, 25; triadimefon 80 mg L), and towards (MICs 100, 100; triadimefon 150 mg L). The bioassay displayed that the banana anthracnose control effect of (100 mg L) was also higher than that of triadimefon (Inhibition ratios 27.5 ± 2.5%, 55.3 ± 1.4%, 52.1 ± 1.3% for , 22.5 ± 2.1%, 47.2 ± 2.0%, 36.6 ± 2.2% for triadimefon at 4 d, 8 d and 12 d, respectively).
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http://dx.doi.org/10.1080/14786419.2021.1872569DOI Listing
January 2021

Progenitor identification and SARS-CoV-2 infection in human distal lung organoids.

Nature 2020 12 25;588(7839):670-675. Epub 2020 Nov 25.

Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5 basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5 cells in basal organoids revealed a distinct population of ITGA6ITGB4 mitotic cells, whose offspring further segregated into a TNFRSF12A subfraction that comprised about ten per cent of KRT5 basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia.
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http://dx.doi.org/10.1038/s41586-020-3014-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003326PMC
December 2020

Solving post-prandial reduction in performance by adaptive regurgitation in a freshwater fish.

Proc Biol Sci 2020 11 11;287(1938):20202172. Epub 2020 Nov 11.

Department of Collective Behaviour, Max Planck Institute of Animal Behaviour, Konstanz, 78467, Germany.

Foraging animals must balance benefits of food acquisition with costs induced by a post-prandial reduction in performance. Eating to satiation can lead to a reduction in locomotor and escape performance, which increases risk should a threat subsequently arises, but limiting feeding behaviour may be maladaptive if food intake is unnecessarily reduced in the prediction of threats that do not arise. The efficacy of the trade-off between continued and interrupted feeding therefore relies on information about the future risk, which is imperfect. Here, we find that black carp () can balance this trade-off using an strategy; by eating to satiation but regurgitating already ingested food when a threat arises. While degrees of satiation (DS) equal to or greater than 60% reduce elements of escape performance (turning angle, angular velocity, distance moved, linear velocity), at 40% DS or lower, performance in these tasks approaches levels comparable to that at 0% satiation. After experiencing a chasing event, we find that fish are able to regurgitate already ingested food, thereby changing the amount of food in their gastrointestinal tract to consistent levels that maintain high escape performance. Remarkably, regurgitation results in degrees of satiation between 40 and 60% DS, regardless of whether they had previously fed to 40, 60 or 100% DS. Using this response, fish are able to maximize food intake, but regurgitate extra food to maintain escape performance when they encounter a threat. This novel strategy may be effective for continual grazers and species with imperfect information about the level of threat in their environment.
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http://dx.doi.org/10.1098/rspb.2020.2172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735268PMC
November 2020

Microglia-organized scar-free spinal cord repair in neonatal mice.

Nature 2020 11 7;587(7835):613-618. Epub 2020 Oct 7.

F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.

Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons. Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal-but not adult-microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system.
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http://dx.doi.org/10.1038/s41586-020-2795-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704837PMC
November 2020

Cell Type-Specific Roles of CD38 in the Interactions of Isoniazid with NAD in the Liver.

Drug Metab Dispos 2020 12 5;48(12):1372-1379. Epub 2020 Oct 5.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.Z., J.L., H.-C.T., K.L., J.L., W.X., X.M.) and Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (D.M.G.)

NAD is a critical molecule that is involved in multiple cellular functions. CD38 is a multifunctional enzyme with NAD nucleosidase activity. Our previous work revealed the CD38-dependent interactions of isoniazid (INH), an antituberculosis drug, with NAD to form INH-NAD adduct. In the current work, our metabolomic analysis discovered a novel NAD adduct with acetylisoniazid (AcINH), a primary INH metabolite mediated by -acetyltransferase (NAT), and we named it AcINH-NAD. Using Nat1/2(-/-) and Cd38(-/-) mice, we determined that AcINH-NAD formation is dependent on both NAT and CD38. Because NAT is expressed in hepatocytes (HP), whereas CD38 is expressed in Kupffer cells (KC) and hepatic stellate cells (HSC), we explored cell type-specific roles of CD38 in the formation of AcINH-NAD as well as INH-NAD. We found that both INH-NAD and AcINH-NAD were produced in the incubation of INH or AcINH with KC and HSC but not in HP. These data suggest that hepatic nonparenchymal cells, such as KC and HSC, are the major cell types responsible for the CD38-dependent interactions of INH with NAD in the liver. SIGNIFICANCE STATEMENT: The current study identified AcINH-NAD as a novel metabolite of INH in the liver. Our work also revealed the essential roles of nonparenchymal cells, including Kupffer cells and hepatic stellate cells, in the CD38-dependent interactions of NAD with INH, leading to the formation of both INH-NAD and AcINH-NAD in the liver. These data can be used to guide the future studies on the mechanisms of INH and NAD interactions and their contributions to INH-induced liver injury.
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http://dx.doi.org/10.1124/dmd.120.000139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718729PMC
December 2020

CD39: the potential target in small cell lung cancer.

Transl Lung Cancer Res 2020 Aug;9(4):1483-1495

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.

Background: It has been proven that the treatment window of small cell lung cancer (SCLC) is short, so it is vital to find other possible therapeutic targets. CD39 inhibits natural killer (NK) cells and promotes the occurrence and metastasis of tumors. There has been little research about the role of CD39 in SCLC, so we explored the correlation between CD39 and other surface antigens, and its association with survival in SCLC.

Methods: This study included 75 patients with SCLC from Shanghai Pulmonary Hospital. After paraffin embedding and sectioning, immunohistochemistry (IHC) was applied. Then we identify cutoff value for CD39 and other surface antigens based on the analysis of ROC curve in RFS by SPSS. All statistical analyses were based on SPSS and Graphpad Prism8. Chi-square test, Kendall's tau-b correlation analysis, Logistic regression analysis, Kaplan-Meier method, univariate and multivariate Cox regression analysis were conducted. In all analyses, P = 0.05 distinguished whether they had statistical significance.

Results: Of the 75 SCLC patients enrolled in this study, 61.33% positively expressed CD39. A correlation between CD39 and programmed cell death-ligand 1 (PD-L1) (P=0.007), CD3 (P<0.001), CD4 (P<0.001), CD8 (P<0.001), and forkhead box P3 (FOXP3) (P<0.001) on tumor-infiltrating lymphocytes (TILs) was identified by correlation analysis and logistic regression analysis. Based on Kaplan-Meier survival analysis, we found that CD39 affected relapse-free survival (RFS) [negative positive, 95% confidence interval (CI): 0.2765-0.9862, P=0.0390]. SCLC patients with high-expressed CD39 and low-expressed PD-L1 had poor prognosis (P<0.001). Positive expression of CD39 and negative expression of CD3, CD4, CD8, and FOXP3 also indicated shorter RFS (P=0.0409). Univariate and multivariate Cox regression analysis was performed to confirm the factors that influenced RFS.

Conclusions: CD39, programmed cell death-1 (PD-1), and PD-L1 expressed on TILs but not on tumor cells. CD39 has a significant association with PD-L1, CD3, CD4, CD8, and FOXP3 on TILs. The positive expression of CD39 predicts poor prognosis. SCLC patients with low expression of CD39 combined with high expression of PD-L1 or CD3, CD4, CD8, and FOXP3 have a more favorable prognosis.
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http://dx.doi.org/10.21037/tlcr-20-798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481638PMC
August 2020

A "Three-in-One" Multifunctional Probe for Bcl-2/Mcl-1 Profiling and Visualizing in Situ.

Chembiochem 2021 Jan 16;22(2):326-329. Epub 2020 Oct 16.

State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, No. 2 LingGong Road, Dalian, 116023, P. R. China.

Bcl-2 and Mcl-1, the two arms of the anti-apoptotic Bcl-2 family proteins, have been identified as key regulators of apoptosis and effective therapeutic targets of cancer. However, no small-molecular probe is capable of profiling and visualizing both Bcl-2 and Mcl-1 simultaneously in situ. Herein, we report a multifunctional molecular probe (BnN -OPD-Alk) by a "three-in-one" molecular designing strategy, which integrated the Bcl-2/Mcl-1 binding ligand, fluorescent reporter group and photoreactive group azido into the same scaffold. BnN -OPD-Alk exhibited sub-micromolar affinities to Bcl-2/Mcl-1 and bright green self-fluorescence. It was then successfully applied for Bcl-2/Mcl-1 labeling, capturing, enriching, and bioimaging both in vitro and in cells. This strategy could facilitate the precise early diagnosis and effective therapy of dual Bcl-2/Mcl-1-related diseases.
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http://dx.doi.org/10.1002/cbic.202000441DOI Listing
January 2021

Injectable and NIR-Responsive DNA-Inorganic Hybrid Hydrogels with Outstanding Photothermal Therapy.

Adv Mater 2020 Oct 23;32(39):e2004460. Epub 2020 Aug 23.

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 200433, China.

Surgical excision is one of the main treatments for malignant tumors. However, high risk of tumour recurrence is a major challenge. Near-infrared (NIR)-light-induced tumor photothermal therapy has been studied, while its clinical applications are still restricted due to the limited therapeutic effects. To address this, here, a novel NIR-light-responsive and injectable DNA-mediated upconversion and Au nanoparticle hybrid (DNA-UCNP-Au) hydrogel is developed. Due to the confined and concentrated environment induced by the interaction between adjacent DNA strands and UCNP-Au NPs, an ultrastrong photothermal effect is observed. A photothermal efficiency as high as 42.7% is realized in the hydrogel, which is superior to pristine inorganic particles. Upon direct peritumoral injection of the hydrogel and with the treatment of 808 nm laser irradiation, tumors are eradicated and no recurrence is observed. Meanwhile, there are no side effects on normal tissues due to the local treatment. Taking advantage of the high phototherapeutic effect, biocompatibility, and flexible operability in this system, a novel approach for malignant tumor therapy is demonstrated.
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http://dx.doi.org/10.1002/adma.202004460DOI Listing
October 2020

Progenitor identification and SARS-CoV-2 infection in long-term human distal lung organoid cultures.

bioRxiv 2020 Jul 27. Epub 2020 Jul 27.

The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange and is affected by disorders including interstitial lung disease, cancer, and SARS-CoV-2-associated COVID-19 pneumonia. Investigations of these localized pathologies have been hindered by a lack of 3D in vitro human distal lung culture systems. Further, human distal lung stem cell identification has been impaired by quiescence, anatomic divergence from mouse and lack of lineage tracing and clonogenic culture. Here, we developed robust feeder-free, chemically-defined culture of distal human lung progenitors as organoids derived clonally from single adult human alveolar epithelial type II (AT2) or basal cells. AT2 organoids exhibited AT1 transdifferentiation potential, while basal cell organoids progressively developed lumens lined by differentiated club and ciliated cells. Organoids consisting solely of club cells were not observed. Upon single cell RNA-sequencing (scRNA-seq), alveolar organoids were composed of proliferative AT2 cells; however, basal organoid cells contained a distinct mitotic population whose proliferation segregated to a subfraction. Clonogenic organoid growth was markedly enriched within the TNFRSF12A subset of FACS-purified ITGA6 ITGB4 basal cells from human lung or derivative organoids. In vivo, TNFRSF12A cells comprised ~10% of KRT5 basal cells and resided in clusters within terminal bronchioles. To model COVID-19 distal lung disease, we everted the polarity of basal and alveolar organoids to rapidly relocate differentiated club and ciliated cells from the organoid lumen to the exterior surface, thus displaying the SARS-CoV-2 receptor ACE2 on the outwardly-facing apical aspect. Accordingly, basal and AT2 apical-out organoids were infected by SARS-CoV-2, identifying club cells as a novel target population. This long-term, feeder-free organoid culture of human distal lung alveolar and basal stem cells, coupled with single cell analysis, identifies unsuspected basal cell functional heterogeneity and exemplifies progenitor identification within a slowly proliferating human tissue. Further, our studies establish a facile in vitro organoid model for human distal lung infectious diseases including COVID-19-associated pneumonia.
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http://dx.doi.org/10.1101/2020.07.27.212076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386503PMC
July 2020

The role of GPR110 in lung cancer progression.

Ann Transl Med 2020 Jun;8(12):745

Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.

Background: G protein-coupled receptors (GPCRs) are involved in several signaling pathways. However, the roles of many GPCRs in tumor oncogenesis and progression are not fully understood. In our previous study, we concluded that the absence of Gpr110 decelerates the development of liver brosis/cirrhosis into tumorigenesis. In our current study, the role of GPR110 in the oncogenesis and progression of lung cancer was observed.

Methods: After collecting tumor tissues from lung cancer patients, the expression of GPR110 was analyzed by both Western blotting and real-time PCR. Immunofluorescence was used to observe GPR110 expression in human lung cancer cells. A CCK8 kit was used to analyze the proliferation of human lung cancer cells transfected with Gpr110. Changes in cell migration were evaluated with wound healing and Transwell assays. A nude mouse xenograft model was constructed. Lung cancer model was induced in Gpr110 mice with urethane.

Results: GPR110 mRNA and protein expression was significantly higher in lung cancer tissue. GPR110 was barely expressed in H460, A549, H1299, and SPC-A1 cells, but its expression in PC-9 and QG56 cells was significantly higher. Overexpression of GPR110 promoted the proliferation and cell aggregation of H1299 cells and H1299 cell migration was also enhanced. Overexpression of GPR110 in H1299 cells significantly promoted tumor development in the nude mice tumor xenograft model. There was no statistical significance between the Gpr110 and Gpr110 mice despite the lesions in the Gpr110 mice group decreasing at 35 and 40 weeks after the initial injection of urethane.

Conclusions: Our findings indicate that GPR110 promotes the progression of lung cancer through accelerating cell proliferation and migration.
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http://dx.doi.org/10.21037/atm-20-3146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333099PMC
June 2020

Characterization of protein-protein interactions between rice viruses and vector insects.

Insect Sci 2020 Jun 14. Epub 2020 Jun 14.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

Planthoppers are the most notorious rice pests, because they transmit various rice viruses in a persistent-propagative manner. Protein-protein interactions (PPIs) between virus and vector are crucial for virus transmission by vector insects. However, the number of known PPIs for pairs of rice viruses and planthoppers is restricted by low throughput research methods. In this study, we applied DeNovo, a virus-host sequence-based PPI predictor, to predict potential PPIs at a genome-wide scale between three planthoppers and five rice viruses. PPIs were identified at two different confidence thresholds, referred to as low and high modes. The number of PPIs for the five planthopper-virus pairs ranged from 506 to 1985 in the low mode and from 1254 to 4286 in the high mode. After eliminating the "one-too-many" redundant interacting information, the PPIs with unique planthopper proteins were reduced to 343-724 in the low mode and 758-1671 in the high mode. Homologous analysis showed that 11 sets and 31 sets of homologous planthopper proteins were shared by all planthopper-virus interactions in the two modes, indicating that they are potential conserved vector factors essential for transmission of rice viruses. Ten PPIs between small brown planthopper and rice stripe virus (RSV) were verified using glutathione-S-transferase (GST)/His-pull down or co-immunoprecipitation assay. Five of the ten PPIs were proven positive, and three of the five SBPH proteins were confirmed to interact with RSV. The predicted PPIs provide new clues for further studies of the complicated relationship between rice viruses and their vector insects.
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http://dx.doi.org/10.1111/1744-7917.12840DOI Listing
June 2020

Overcoming Obstacles in Pathological Diagnosis of Pulmonary Nodules through Circulating Tumor Cell Enrichment.

Small 2020 06 26;16(25):e2001695. Epub 2020 May 26.

Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University, 507 Zhengmin Road, Shanghai, 200433, China.

With the popularity of low-dose computed tomography (LDCT) in clinical examination of the lung, the prevalence of pulmonary nodules has significantly increased, thus significantly improving the early diagnosis of lung cancer, but also potentially contributing to overtreatment. This study aims to develop a noninvasive method to assist in diagnosing the pulmonary nodules. To do so, 3798 patients are recruited from the Department of Thoracic Surgery at Shanghai Pulmonary Hospital and peripheral blood samples are collected from them before surgery. From these samples, circulating tumor cells (CTC) are isolated using folate receptor (FR) positivity, and then enriched and analyzed in relation to cancer gene expression, stage, and level of invasion. The average CTC concentration of patients with lung disease is 11.97 functional unit (FU) in a 3 mL sample of blood. FR-positive CTC levels correlate with the expression of lung cancer driver genes tumor-node-matastasis (TNM) stage, and pleura invasion. The sensitivity of CTC levels to lung cancer diagnosis is 87.05%. Results from this study demonstrate that the determination of FR-positive CTC concentration is a convenient and time-saving strategy to improve the pathological diagnosis of pulmonary nodules.
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http://dx.doi.org/10.1002/smll.202001695DOI Listing
June 2020

ABCG2 Deficiency Does Not Alter Dolutegravir Metabolism and Pharmacokinetics.

J Pharmacol Exp Ther 2020 07 17;374(1):38-43. Epub 2020 Apr 17.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy (J.Z., X.T., A.I.S., X.M.) and Division of Infectious Disease, Department of Medicine (D.K.M.), University of Pittsburgh, Pittsburgh, Pennsylvania

Dolutegravir (DTG) is a potent integrase inhibitor of human immunodeficiency virus. Because DTG is a substrate of the efflux transporter ABCG2 and ABCG2 is highly polymorphic, we asked whether dose adjustment of DTG is needed for ABCG2-deficient individuals. Using Abcg2-null mice, the current work investigated the impact of ABCG2 deficiency on DTG metabolism and pharmacokinetics. Compared with wild-type mice, no statistically significant difference was found in the systemic and tissue-specific (liver, kidney, and brain) pharmacokinetics of DTG in Abcg2-null mice. In addition, ABCG2 deficiency had no statistically significant impact on the production and excretion of DTG metabolites. In summary, this study demonstrated that deficiency of ABCG2 does not alter DTG metabolism and pharmacokinetics, suggesting that dose adjustment of DTG is not needed for individuals with ABCG2 deficiency. SIGNIFICANCE STATEMENT: The current work demonstrated that deficiency of ATP-binding cassette subfamily G member 2 (ABCG2) does not alter Dolutegravir (DTG) metabolism and pharmacokinetics, suggesting that dose adjustment of DTG is not needed for individuals with ABCG2 deficiency.
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http://dx.doi.org/10.1124/jpet.119.264424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292963PMC
July 2020

Inhibition of the endoplasmic reticulum (ER) stress-associated IRE-1/XBP-1 pathway alleviates acute lung injury via modulation of macrophage activation.

J Thorac Dis 2020 Mar;12(3):284-295

Department of Thoracic Surgery, Shanghai Pulmonary Hospital affiliated to Tongji University, Shanghai 200433, China.

Background: Both endoplasmic reticulum (ER) stress and macrophage diversity contribute to inflammatory processes in lung injury. However, the interaction between ER stress and macrophage M1/M2 imbalance in lung inflammation remains unclear. The present study, thus, aimed to evaluate the role of ER stress-mediated macrophage phenotype changes in lipopolysaccharide (LPS)-induced acute lung injury (ALI).

Methods: Lung inflammation and injury were examined in a murine model of LPS-induced ALI with or without ER stress inhibitors. Alveolar macrophage (AM) polarization was determined by flow cytometry. Bone marrow-derived macrophages (BMDMs) were treated with either an ER stress inducer, inhibitor, or an IRE-1 endonuclease inhibitor before being polarized to an M1 and M2 phenotype. The macrophage polarization status was examined via RT-PCR and flow cytometry.

Results: Our results indicated that ER stress and IRE-1/XBP-1 signaling are activated in LPS-induced ALI. Furthermore, we observed that AM polarizes to an inflammatory phenotype upon exposure to LPS in the induction phase and an anti-inflammatory phenotype in the resolution phase of lung inflammation. Inhibition of ER stress attenuated the pathophysiological features of LPS-induced lung inflammation/injury, as evidenced by a decrease in bronchoalveolar lavage (BAL) protein levels, the number of inflammatory cells, and the expression level of inflammatory mediators. In addition, the ER stress inducer promoted M1 polarization and the switch from M2 to M1 in BMDMs, whereas inhibition of ER stress and XBP-1 splicing suppressed M1 but did not promote M2, both and

Conclusions: Our results demonstrated that inhibition of the ER stress-associated IRE-1/XBP-1 signaling pathway suppresses M1 polarization and ameliorates LPS-induced lung injury. This indicates that the interaction between ER stress and macrophage polarization might be a novel therapeutic target for endotoxin-induced lung inflammatory disorders.
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http://dx.doi.org/10.21037/jtd.2020.01.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139036PMC
March 2020

Specific gut microbiome signature predicts the early-stage lung cancer.

Gut Microbes 2020 07 2;11(4):1030-1042. Epub 2020 Apr 2.

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai, China.

Alterations of gut microbiota have been implicated in multiple diseases including cancer. However, the gut microbiota spectrum in lung cancer remains largely unknown. Here we profiled the gut microbiota composition in a discovery cohort containing 42 early-stage lung cancer patients and 65 healthy individuals through the 16S ribosomal RNA (rRNA) gene sequencing analysis. We found that lung cancer patients displayed a significant shift of microbiota composition in contrast to the healthy populations. To identify the optimal microbiota signature for noninvasive diagnosis purpose, we took advantage of Support-Vector Machine (SVM) and found that the predictive model with 13 operational taxonomic unit (OTU)-based biomarkers achieved a high accuracy in lung cancer prediction (area under curve, AUC = 97.6%). This signature performed reasonably well in the validation cohort (AUC = 76.4%), which contained 34 lung cancer patients and 40 healthy individuals. To facilitate potential clinical practice, we further constructed a 'patient discrimination index' (PDI), which largely retained the prediction efficiency in both the discovery cohort (AUC = 92.4%) and the validation cohort (AUC = 67.7%). Together, our study uncovered the microbiota spectrum of lung cancer patients and established the specific gut microbial signature for the potential prediction of the early-stage lung cancer.
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http://dx.doi.org/10.1080/19490976.2020.1737487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524275PMC
July 2020

Impaired Bile Secretion Promotes Hepatobiliary Injury in Sickle Cell Disease.

Hepatology 2020 12 13;72(6):2165-2181. Epub 2020 Nov 13.

Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Background And Aims: Hepatic crisis is an emergent complication affecting patients with sickle cell disease (SCD); however, the molecular mechanism of sickle cell hepatobiliary injury remains poorly understood. Using the knock-in humanized mouse model of SCD and SCD patient blood, we sought to mechanistically characterize SCD-associated hepato-pathophysiology applying our recently developed quantitative liver intravital imaging, RNA sequence analysis, and biochemical approaches.

Approach And Results: SCD mice manifested sinusoidal ischemia, progressive hepatomegaly, liver injury, hyperbilirubinemia, and increased ductular reaction under basal conditions. Nuclear factor kappa B (NF-κB) activation in the liver of SCD mice inhibited farnesoid X receptor (FXR) signaling and its downstream targets, leading to loss of canalicular bile transport and altered bile acid pool. Intravital imaging revealed impaired bile secretion into the bile canaliculi, which was secondary to loss of canalicular bile transport and bile acid metabolism, leading to intrahepatic bile accumulation in SCD mouse liver. Blocking NF-κB activation rescued FXR signaling and partially ameliorated liver injury and sinusoidal ischemia in SCD mice.

Conclusions: These findings identify that NF-κB/FXR-dependent impaired bile secretion promotes intrahepatic bile accumulation, which contributes to hepatobiliary injury of SCD. Improved understanding of these processes could potentially benefit the development of therapies to treat sickle cell hepatic crisis.
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http://dx.doi.org/10.1002/hep.31239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923682PMC
December 2020

Structure-based design, synthesis, and evaluation of Bcl-2/Mcl-1 dual inhibitors.

Arch Pharm (Weinheim) 2020 May 16;353(5):e2000005. Epub 2020 Mar 16.

State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.

Based on our previously reported Bcl-2/Mcl-1 dual inhibitor 4-thiomorpholinyl-2-cyano-3-amidinophenalenone (A1) that simultaneously occupies the p2 and p4 hydrophobic pockets of Bcl-2 and Mcl-1, we optimized molecules with different bond angles of the groups extending to the p4 pocket and bulky hydrophobic groups to explore p2. Research on structure-activity relationship resulted in a new derivative B4 that is capable of occupying both the p2 and p4 more deeply and completely than A1, with K values determined by fluorescence polarization assay (FPAs) improving to 0.31 μM for Bcl-2 and 0.16 μM for Mcl-1. Furthermore, B4 exhibited selective lethality on cancer cells over normal cells. It showed stronger apoptosis induction than (-)-gossypol on a Bcl-2/Mcl-1-dependent cancer cell line and killed an Mcl-1-dependent cell line which is resistant to ABT-199 treatment.
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http://dx.doi.org/10.1002/ardp.202000005DOI Listing
May 2020

Clinicopathological and Prognostic Significance of Rearrangement in Patients with Surgically Resected Lung Adenocarcinoma: A Propensity Score Matching Study.

Cancer Manag Res 2020 24;12:589-598. Epub 2020 Jan 24.

Department of Radiology, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People's Republic of China.

Objective: The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase () fusion gene is a key oncogenic driver in non-small cell lung cancer (NSCLC). This study analyzed the clinicopathological characteristics and prognostic significance of fusion gene in patients with surgically resected adenocarcinoma.

Methods: The clinicopathological characteristics of 1056 consecutive patients with surgically resected stage I-IIIA adenocarcinoma were collected from February 2014 to October 2014, and rearrangement was detected using real-time polymerase chain reaction (RT-PCR) technology. To compare the imaging and pathological features, a propensity score matching (PSM) method was performed. The follow-up information was collected to evaluate the long-term outcomes of patients with rearrangement.

Results: The prevalence of rearrangement was 6.6% in 1056 consecutive patients. A total of 70 positive and 210 negative patients were identified after PSM. Imaging and pathological analyses showed that rearrangement was significantly associated with less ground-glass opacity (GGO) (adjusted OR=1.38, 95% CI=1.03-1.85, =0.029) and higher prevalence of non-invasive mucinous adenocarcinoma mucin-laden adenocarcinomas (non-IMA MLA, adjusted OR=6.79, 95% CI=2.69-17.17, <0.001). rearrangement was found to be an unfavorable prognostic factor for disease-free survival (DFS) in female patients (HR=2.26, 95% CI=1.13-4.53, =0.021).

Conclusion: Our results suggest that adenocarcinomas harboring fusion gene exhibit specific radiological and pathological characteristics compared with negative adenocarcinomas. In female patients, rearrangement was associated with shorter DFS.
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http://dx.doi.org/10.2147/CMAR.S229217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986412PMC
January 2020

Acetaminophen-Induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-Dependent Manner in Mouse Liver.

Drug Metab Dispos 2020 05 24;48(5):326-336. Epub 2020 Feb 24.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (Y.B., P.W., X.S., J.E.M., X.Z.); Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China (P.W., L.Z.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.Z., X.M.); and Departments of Pharmaceutical Sciences (J.X.) and Clinical Pharmacy (J.S., H.-J.Z.), College of Pharmacy, University of Michigan, Ann Arbor, Michigan

Drug-induced liver injury (DILI) is a global medical problem. The risk of DILI is often related to expression and activities of drug-metabolizing enzymes, especially cytochrome P450s (P450s). However, changes on expression and activities of P450s after DILI have not been determined. The aim of this study is to fill this knowledge gap. Acetaminophen (APAP) was used as a model drug to induce DILI in C57BL/6J mice at different ages of days 10 (infant), 22 (child), and 60 (adult). DILI was assessed by levels of alanine aminotransferase and aspartate aminotransferase in plasma with a confirmation by H&E staining on liver tissue sections. The expression of selected P450s at mRNA and protein levels was measured by real-time polymerase chain reaction and liquid chromatography-tandem mass spectrometry, respectively. The activities of these P450s were determined by the formation of metabolites from probe drugs for each P450 using ultraperformance liquid chromatography-quadrupole time of flight mass spectrometry. DILI was induced at mild to severe levels in a dose-dependent manner in 200, 300, and 400 mg/kg APAP-treated groups at child and adult ages, but not at the infant age. Significantly decreased expression at mRNA and protein levels as well as enzymatic activities of CYP2E1, 3A11, 1A2, and 2C29 were found at child and adult ages. Adult male mice were more susceptible to APAP-induced liver injury than female mice with more decreased expression of P450s. These results suggest that altered levels of P450s in livers severely injured by drugs may affect the therapeutic efficacy of drugs, which are metabolized by P450s, more particularly for males. SIGNIFICANCE STATEMENT: The current study in an animal model demonstrates that acetaminophen-induced liver injury results in decreased expression and enzyme activities of several examined drug-metabolizing cytochrome P450s (P450s). The extent of such decreases is correlated to the degree of liver injury severity. The generated data may be translated to human health for patients who have drug-induced liver injury with decreased capability to metabolize drugs by certain P450s.
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http://dx.doi.org/10.1124/dmd.119.089557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153563PMC
May 2020

LATS suppresses mTORC1 activity to directly coordinate Hippo and mTORC1 pathways in growth control.

Nat Cell Biol 2020 02 3;22(2):246-256. Epub 2020 Feb 3.

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

The Hippo and mammalian target of rapamycin complex 1 (mTORC1) pathways are the two predominant growth-control pathways that dictate proper organ development. We therefore explored potential crosstalk between these two functionally relevant pathways to coordinate their growth-control functions. We found that the LATS1 and LATS2 kinases, the core components of the Hippo pathway, phosphorylate S606 of Raptor, an essential component of mTORC1, to attenuate mTORC1 activation by impairing the interaction of Raptor with Rheb. The phosphomimetic Raptor-S606D knock-in mutant led to a reduction in cell size and proliferation. Compared with Raptor mice, Raptor knock-in mice exhibited smaller livers and hearts, and a significant inhibition of elevation in mTORC1 signalling induced by Nf2 or Lats1 and Lats2 loss. Thus, our study reveals a direct link between the Hippo and mTORC1 pathways to fine-tune organ growth.
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http://dx.doi.org/10.1038/s41556-020-0463-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076906PMC
February 2020

Impact of obese levels on the hepatic expression of nuclear receptors and drug-metabolizing enzymes in adult and offspring mice.

Acta Pharm Sin B 2020 Jan 28;10(1):171-185. Epub 2019 Nov 28.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.

The prevalence of obesity-associated conditions raises new challenges in clinical medication. Although altered expression of drug-metabolizing enzymes (DMEs) has been shown in obesity, the impacts of obese levels (overweight, obesity, and severe obesity) on the expression of DMEs have not been elucidated. Especially, limited information is available on whether parental obese levels affect ontogenic expression of DMEs in children. Here, a high-fat diet (HFD) and three feeding durations were used to mimic different obese levels in C57BL/6 mice. The hepatic expression of five nuclear receptors (NRs) and nine DMEs was examined. In general, a trend of induced expression of NRs and DMEs (except for and ) was observed in HFD groups compared to low-fat diet (LFD) groups. Differential effects of HFD on the hepatic expression of DMEs were found in adult mice at different obese levels. Family-based dietary style of an HFD altered the ontogenic expression of DMEs in the offspring older than 15 days. Furthermore, obese levels of parental mice affected the hepatic expression of DMEs in offspring. Overall, the results indicate that obese levels affected expression of the DMEs in adult individuals and that of their children. Drug dosage might need to be optimized based on the obese levels.
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http://dx.doi.org/10.1016/j.apsb.2019.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976990PMC
January 2020

Prognostic Factors and Treatment Options for Patients with High-Grade Chondrosarcoma.

Med Sci Monit 2019 Nov 25;25:8952-8967. Epub 2019 Nov 25.

Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China (mainland).

BACKGROUND The goal of this study was to determine the prognostic factors exclusive for high-grade chondrosarcoma and whether adjuvant radiotherapy could achieve better overall survival (OS) or cancer-specific survival (CSS) for patients with high-grade chondrosarcoma. MATERIAL AND METHODS Surveillance, Epidemiology, and End Results (SEER) cancer registry database was utilized to extract the chondrosarcoma cases diagnosed between 1973 and 2014. Among these cases, the histological grades of poorly differentiated (grade 3) and undifferentiated (grade 4) were categorized as high-grade and included in this study. Chondrosarcoma OS and CSS were the primary outcomes in the present study. The log-rank test was performed for univariate analysis, and the Cox regression model was conducted for multivariate analysis. RESULTS A total of 743 patients with high-grade chondrosarcoma were identified in this study (430 cases were poorly differentiated tumors, and 313 cases were undifferentiated tumors). Age at diagnosis, pathological grade, histo-type, SEER stage, tumor size and surgical resection were identified as independent predictors in both OS and CSS analysis of high-grade chondrosarcoma. When stratified by histological grade, surgical resection remained the effective treatment. Strikingly, radiotherapy was determined as an independent protective factor in both OS and CSS analysis of undifferentiated (grade 4) dedifferentiated chondrosarcoma, and adjuvant radiotherapy combined surgical resection could improve both the OS and CSS of patients with undifferentiated myxoid and dedifferentiated chondrosarcoma compared with other treatment regimens. CONCLUSIONS Our study first demonstrated that adjuvant radiotherapy combined surgery could improve the survival of patients with undifferentiated myxoid and dedifferentiated chondrosarcoma. These results encourage the application of adjuvant radiotherapy for patients with high-grade chondrosarcoma and maximize the patients' outcome.
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http://dx.doi.org/10.12659/MSM.917959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894367PMC
November 2019