Publications by authors named "Shanshan Deng"

43 Publications

Tanshinone IIA Protects Against Cerebral Ischemia Reperfusion Injury by Regulating Microglial Activation and Polarization NF-κB Pathway.

Front Pharmacol 2021 19;12:641848. Epub 2021 Apr 19.

Department of Pharmacy, Punan Hospital, Pudong New District, Shanghai, China.

Tanshinone IIA, a fat-soluble diterpenoid isolated from Salvia miltiorrhiza Bunge, has been shown to attenuate the cerebral ischemic injury. The aim of this study was to examine the effects on neuroprotection and microglia activation of Tanshinone IIA. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO). We found that Tanshinone IIA significantly reduced infarction volume, alleviated neuronal injuries, reduced the release of TNF-α, IL-1β, and IL-6, increased SOD activity, and decrease the content of MDA in MCAO rats. Hematoxylin and eosin staining, Nissl staining, TUNEL staining and immunofluorescence staining showed that Tanshinone IIA improved the distribution and morphology of neurons in brain tissues and reduced apoptosis. In addition, Co-immunofluorescence staining of rat brain tissues and the mRNA expression levels of CD11b, CD32, iNOS, and Arg-1, CD206, IL-10 in BV2 cells indicated that Tanshinone IIA can downregulate M1 microglia and upregulate M2 microglia in MCAO rats. Further, BV2 microglial cells were subjected to oxygen-glucose deprivation, the protein expression levels were detected by western blot. Tanshinone IIA inhibited the expression levels of NF-κB signaling pathway related proteins. Taken together, this study suggested that Tanshinone IIA modulated microglial M1/M2 polarization the NF-κB signaling pathway to confer anti-neuroinflammatory effects.
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http://dx.doi.org/10.3389/fphar.2021.641848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090935PMC
April 2021

Discovery of a Highly Selective and Potent TRPC3 Inhibitor with High Metabolic Stability and Low Toxicity.

ACS Med Chem Lett 2021 Apr 5;12(4):572-578. Epub 2021 Mar 5.

Department of Pharmaceutical Sciences, College of Pharmacy, the University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.

The overactivation of transient receptor potential canonical 3 (TRPC3) is associated with neurodegenerative diseases and hypertension. Pyrazole 3 (Pyr3) is reported as the most selective TRPC3 inhibitor, but it has two inherent structural limitations: (1) the labile ester moiety leads to its rapid hydrolysis to the inactive Pyr8 , and (2) the alkylating trichloroacrylic amide moiety is known to be toxic. To circumvent these limitations, we designed a series of conformationally restricted Pyr3 analogues and reported that compound maintains high potency and selectivity for human TRPC3 over its closely related TRP channels. It has significantly improved metabolic stability compared with Pyr3 and has a good safety profile. Preliminary evaluation of demonstrated its ability to rescue Aβ-induced neuron damage with similar potency to that of Pyr3 . Collectively, these results suggest that represents a promising scaffold to potentially ameliorate the symptoms associated with TRPC3-mediated neurological and cardiovascular disorders.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040052PMC
April 2021

GALNT2 promotes cell proliferation, migration, and invasion by activating the Notch/Hes1-PTEN-PI3K/Akt signaling pathway in lung adenocarcinoma.

Life Sci 2021 Jul 27;276:119439. Epub 2021 Mar 27.

Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. Electronic address:

Aims: Our study aimed to investigate the function of GALNT2 in lung adenocarcinoma (LUAD).

Main Methods: We used network tools and tissue microarray immunohistochemistry to measure the expression levels of GALNT2 in LUAD. Kaplan-Meier curves and Cox regression methods were used in survival analysis. We detected the role of GALNT2 in cell lines by Cell Counting Kit-8, colony formation, transwell, and wound healing assays. We performed Western blotting to evaluate downstream protein levels.

Key Findings: GALNT2 was highly expressed in LUAD samples and indicated a poor prognosis. Knockdown of GALNT2 suppressed cell line proliferation, migration, and invasion abilities, while overexpression of GALNT2 enhanced those phenotypes. Moreover, GALNT2 activated Notch/Hes1-PTEN-PI3K/Akt signaling axis.

Significance: Our data confirmed the cancer-promoting effect of GALNT2, and might provide a new approach for LUAD therapy.
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http://dx.doi.org/10.1016/j.lfs.2021.119439DOI Listing
July 2021

Is there a correlation between miR-301a expression and neoadjuvant chemotherapy efficacy in breast cancer tissue?

Biochem Biophys Rep 2021 Jul 8;26:100947. Epub 2021 Feb 8.

Thoracic Oncology Department, Zunyi Medical University, NO.2 Affiliated Hospital, Zunyi, Guizhou, 563006, PR China.

Neoadjuvant chemotherapy (NAC) is the standard therapeutic regimen for locally advanced breast cancer. However, clinical physical examination and imaging results fail to accurately assess the treatment response, and postoperative pathological examination has a time lag in response to therapeutic effect which is not conducive to the timely adjustment of treatment strategies. A previous study has shown that miR-301a was associated with invasion and metastasis in breast cancer, and was found to be involved in endocrine therapy resistance; however, evidence regarding the correlation between miR-301a expression and NAC efficacy remains scarce. In this study, 101 patients with locally advanced breast cancer were included. All patients received anthracycline based chemotherapy. The expression level of miR-301a in pretreatment core needle biopsy tissues was determined by real-time polymerase chain reaction analysis. Relevant clinicopathological data were collected, and the correlation between miR-301a expression and NAC efficacy was assessed. Based on our data, miR-301a cannot be used to identify whether breast cancer benefits from NAC, and no correlation was observed between miR-301a expression and clinicopathological characteristics. In conclusion, miR-301a may not be a potential prognostic biomarker of NAC efficacy in breast cancer.
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http://dx.doi.org/10.1016/j.bbrep.2021.100947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878978PMC
July 2021

CVB3 VP1 interacts with MAT1 to inhibit cell proliferation by interfering with Cdk-activating kinase complex activity in CVB3-induced acute pancreatitis.

PLoS Pathog 2021 Feb 8;17(2):e1008992. Epub 2021 Feb 8.

The First Affiliated Hospital of Nanchang University, Nanchang, China.

Coxsackievirus B3 (CVB3) belongs to the genus Enterovirus of the family Picornaviridae and can cause acute acinar pancreatitis in adults. However, the molecular mechanisms of pathogenesis underlying CVB3-induced acute pancreatitis have remained unclear. In this study, we discovered that CVB3 capsid protein VP1 inhibited pancreatic cell proliferation and exerted strong cytopathic effects on HPAC cells. Through yeast two-hybrid, co-immunoprecipitation, and confocal microscopy, we show that Menage a trois 1 (MAT1), a subunit of the Cdk-Activating Kinase (CAK) complex involved in cell proliferation and transcription, is a novel interaction protein with CVB3 VP1. Moreover, CVB3 VP1 inhibited MAT1 accumulation and localization, thus interfering with its interaction with CDK7. Furthermore, CVB3 VP1 could suppress CAK complex enzymic phosphorylation activity towards RNA Pol II and CDK4/6, direct substrates of CAK. VP1 also suppresses phosphorylation of retinoblastoma protein (pRb), an indirect CAK substrate, especially at phospho-pRb Ser780 and phospho-pRb Ser807/811 residues, which are associated with cell proliferation. Finally, we present evidence using deletion mutants that the C-terminal domain (VP1-D8, 768-859aa) is the minimal VP1 region required for its interaction with MAT1, and furthermore, VP1-D8 alone was sufficient to arrest cells in G1/S phase as observed during CVB3 infection. Taken together, we demonstrate that CVB3 VP1 can inhibit CAK complex assembly and activity through direct interaction with MAT1, to block MAT1-mediated CAK-CDK4/6-Rb signaling, and ultimately suppress cell proliferation in pancreatic cells. These findings substantially extend our basic understanding of CVB3-mediated pancreatitis, providing strong candidates for strategic therapeutic targeting.
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http://dx.doi.org/10.1371/journal.ppat.1008992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895353PMC
February 2021

Role of hydrogenated moiety in redox treatability of 6:2 fluorotelomer sulfonic acid in chrome mist suppressant solution.

J Hazard Mater 2021 Apr 18;408:124875. Epub 2020 Dec 18.

State Key Joint Laboratory of Environment Simulation and Pollution Control (SKJLESPC), Beijing Key Laboratory for Emerging Organic Contaminants Control (BKLEOC), School of Environment, POPs Research Center, Tsinghua University, Beijing 100084, China.

6:2 Fluorotelomer sulfonic acid (6:2 FTS) is used as alternative to perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) for different purposes such as chrome mist suppressant (CMS) and active ingredient in fire-fighting foams. In this study, degradability of 6:2 FTS under ultraviolet/persulfate (UV/PS) and ultraviolet/sulfite (UV/SF), which are typical technologies for advanced oxidation and reduction, were investigated respectively. Due to the hydrogenated moiety, 6:2 FTS was decomposed completely by UV/PS within 10 min, forming a mixture of short-chain perfluoroalkyl carboxylic acids with variable chain length (2-7 carbon atoms). Such oxidation products account for > 50% organofluorine of 6:2 FTS unmineralized portion. 6:2 FTS degradability under reductive UV/SF system was dramatically slowed down by the hydrogenated moiety, which lowered electron affinity and, consequently, reactivity with aqueous electron (e‾) produced by UV/SF. Fluorine mass balance showed that degradation intermediates were almost negligible: most of decomposed 6:2 FTS fluorine was converted to fluoride. A real 6:2 FTS-based CMS solution prepared from a commercial product was also tested. Both types of treatment were effective and in good agreement with the trends observed for tests with sole 6:2 FTS. Moreover, experimental results highlighted a remarkable amount of identifiable (like 4:2 FTS, 8:2 FTS and other per-/polyfluoroalkyl substances) and unidentifiable components in the CMS mixture. Indeed, fluoride concentration under UV/SF (73.8 mg/L) and UV/PS (44.9 mg/L) treatment were both higher than the estimated total concentration (<23 mg/L, according to 6:2 FTS concentration). Results strongly suggest that an oxidation pretreatment followed by reduction might be a better way to degrade and defluorinate 6:2 FTS and other precursors with non-fluorinated moieties, rather than employing single reduction or oxidation technology.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124875DOI Listing
April 2021

ADFP promotes cell proliferation in lung adenocarcinoma via Akt phosphorylation.

J Cell Mol Med 2021 Jan 29;25(2):827-839. Epub 2020 Nov 29.

Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Previously, we identified differentially expressed proteins, including ADFP, between lung adenocarcinoma (LAC) tissue and paired normal bronchioloalveolar epithelium. In this study, we investigated the role of ADFP in LAC. ADFP levels in the serum of patients with lung cancer and benign diseases were measured by enzyme-linked immunosorbent assays (ELISA). shRNA was used to knock-down or overexpress ADFP in A549 and NCI-H1299 cells. The biological function of ADFP and its underlying mechanisms was evaluated in vivo and in vitro. ADFP was highly expressed in the serum of lung cancer patients, especially those with LAC. ADFP promoted cell proliferation and up-regulated the p-Akt/Akt ratio in A549 and NCI-H1299 cells in vitro. Furthermore, in nude mice, ADFP promoted tumour formation with high levels of p-Akt/Akt, Ki67 and proliferating cell nuclear antigen (PCNA). Similar to the effect of ADFP knock-down, MK-2206 (a phosphorylation inhibitor of Akt) reduced A549 and NCI-H1299 cell proliferation. In ADFP-overexpressing A549 and NCI-H1299 cells, proliferation was suppressed by MK-2206 and returned to the control level. ADFP did not regulate invasion, migration or adhesion in LAC cells. Together, these results suggest that ADFP promotes LAC cell proliferation in vitro and in vivo by increasing Akt phosphorylation level.
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http://dx.doi.org/10.1111/jcmm.16136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812254PMC
January 2021

Occurrence and variations of pharmaceuticals and personal-care products in rural water bodies: A case study of the Taige Canal (2018-2019).

Sci Total Environ 2021 Mar 17;762:143138. Epub 2020 Oct 17.

State Key Joint Laboratory of Environment Simulation and Pollution Control (SKLESPC), Beijing Key Laboratory for Emerging Organic Contaminants Control (BKLEOC), Beijing Laboratory for Environmental Frontier Technologies (BLEFT), School of Environment, Tsinghua University, Beijing 100084, China.

A systematic monitoring campaign of pharmaceuticals and personal-care products (PPCPs) was performed in the Taige Canal basin, which is located in a rural area of the Yangtze River Delta. A total of 55 out of 61 monitored PPCPs were detected, with concentrations up to 647 ng/L. The maximum concentrations of 75% of monitored antibiotics and 80% of non-antibiotics were above the median values of previously reported maximum concentrations in China, indicating that the basin is heavily contaminated. It is estimated that the PPCP mass flow of the Taige Canal (0.06-0.58 kg/day) entering into Lake Taihu is similar to that of the influent of a wastewater treatment plant. Analysis of the seasonal variation shows that, during the wet season, the average total concentration of sulfonamides was 8 and 11 times that of the normal season and dry season, respectively. The concentration of sulfachlorpyridazine accounted for 40.37% of total antibiotics, suggesting heavy pollution from the animal-breeding industry in this area. The PPCP mass flow rates observed in 2019 were lower than those of 2018 in the same season, and this interannual variation is mainly attributable to water pollution controls in the watershed. Combined analysis of ordination and clustering indicates that the distribution of PPCPs in the Taige Canal is affected by the confluence with Yong'an River and human activities such as water pollution control. Water-sediment distribution analysis demonstrates that the sediment-water distribution coefficients of quinolone and macrolide were higher than those of sulfonamide, lincosamide and chloramphenicol.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143138DOI Listing
March 2021

Applicability of the adjusted graded prognostic assessment for lung cancer with brain metastases using molecular markers (Lung-molGPA) in a Chinese cohort: A retrospective study of multiple institutions.

Cancer Med 2020 12 7;9(23):8772-8781. Epub 2020 Oct 7.

Department of Thoracic Oncology, Cancer Centre, Sichuan University West China Hospital, Chengdu, Sichuan, P.R. China.

Background: In this era of precision medicine, prognostic heterogeneity is an important feature of patients with non-small cell lung cancer (NSCLC) with brain metastases (BM). This multi-institutional study is aimed to verify the applicability of the adjusted Lung-molGPA model for NSCLC with BM in a Chinese cohort.

Methods: This retrospective study included 1903 patients at three hospitals in Southwest China. The performance of the Lung-molGPA model was compared with that of the adjusted DS-GPA model in terms of estimating the survival of NSCLC with BM.

Results: The median OS of this patient cohort was 27.0 months, and the adenocarcinoma survived longer than the non-adenocarcinoma (28.0 months vs 18.7 months, p < 0.001). The adjusted Lung-molGPA model was more accurate in predicting survival of adenocarcinoma patients than the adjusted DS-GPA model (C-index: 0.615 vs 0.571), and it was not suitable for predicting survival of non-adenocarcinoma patients (p = 0.286, 1.5-2.0 vs 2.5-3.0; p = 0.410, 2.5-3.0 vs 3.5-4.0).

Conclusions: The adjusted Lung-molGPA model is better than the DS-GPA model in predicting the prognosis of adenocarcinoma patients. However, it failed to estimate the prognosis for non-adenocarcinoma patients.
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http://dx.doi.org/10.1002/cam4.3485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724493PMC
December 2020

Nanoformulation design and therapeutic potential of a novel tubulin inhibitor in pancreatic cancer.

J Control Release 2021 Jan 30;329:585-597. Epub 2020 Sep 30.

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address:

Successful treatment of pancreatic cancer remains a challenge due to desmoplasia, development of chemoresistance, and systemic toxicity. Herein, we synthesized (6-(3-hydroxy-4-methoxylphenyl)pyridin-2-yl) (3,4,5-trimethoxyphenyl)methanone (CH-3-8), a novel microtubule polymerization inhibitor with little susceptible to transporter-mediated chemoresistance. CH-3-8 binding to the colchicine-binding site in tubulin protein was confirmed by tubulin polymerization assay and molecular modeling. CH-3-8 disrupted microtubule dynamics at the nanomolar concentration in MIA PaCa-2 and PANC-1 pancreatic cancer cell lines. CH-3-8 significantly inhibited the proliferation of these cells, induced G2/M cell cycle arrest, and led to apoptosis. CH-3-8 is hydrophobic with an aqueous solubility of 0.97 ± 0.16 μg/mL at pH 7.4. We further conjugated it with dodecanol through diglycolate linker to increase hydrophobicity and thus loading in lipid-based delivery systems. Hence, we encapsulated CH-3-8 lipid conjugate (LDC) into methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol) (mPEG-b-PCC-g-DC) polymeric nanoparticles (NPs) by solvent evaporation, resulting in a mean particle size of 125.6 ± 2.3 nm and drug loading of 10 ± 1.0% (w/w) while the same polymer could only load 1.6 ± 0.4 (w/w) CH-3-8 using the same method. Systemic administration of 6 doses of CH-3-8 and LDC loaded NPs at the dose of 20 mg/kg into orthotopic pancreatic tumor-bearing NSG mice every alternate day resulted in significant tumor regression. Systemic toxicity was negligible, as evidenced by histological evaluations. In conclusion, CH-3-8 LDC loaded NPs have the potential to improve outcomes of pancreatic cancer by overcoming transporter-mediated chemoresistance and reducing systemic toxicity.
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http://dx.doi.org/10.1016/j.jconrel.2020.09.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904572PMC
January 2021

Orally available tubulin inhibitor VERU-111 enhances antitumor efficacy in paclitaxel-resistant lung cancer.

Cancer Lett 2020 12 11;495:76-88. Epub 2020 Sep 11.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. Electronic address:

Lung cancer is the most common cause of cancer associated mortality. Chemotherapeutic agents, such as paclitaxel, are important treatment options but drug resistance often develops upon prolonged use. We report here the preclinical evaluation of a new orally available tubulin inhibitor, VERU-111, which can overcome several ABC-transporters mediated multi-drug resistance associated with taxane treatment. In vitro, VERU-111 prevents cell proliferation, invasion, migration and colony formation in both paclitaxel-sensitive and paclitaxel-resistant A549 lung cancer cells. VERU-111 effectively inhibits tubulin polymerization, arrests cells in G2/M phase, and induces cancer cell apoptosis. Further evaluation of various apoptotic proteins revealed that treatment of VERU-111 increases the expression of cleaved-PARP, cleaved-caspase-3 and p-histone H3 proteins. In vivo, orally administered VERU-111 in a paclitaxel-sensitive A549 xenograft model strongly inhibits tumor growth in a dose-dependent manner and is equally potent with paclitaxel. When tested in a highly paclitaxel-resistant A549/TxR tumor model, VERU-111 is as effective as the parental A549 model in significantly reducing the tumor volume, whereas paclitaxel is essentially ineffective. Collectively, this study showed that VERU-111 is a promising new generation of anti-tubulin agent for the treatment of taxane-resistant lung cancer.
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http://dx.doi.org/10.1016/j.canlet.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669640PMC
December 2020

Molecular modelling guided design, synthesis and QSAR analysis of new small molecule non-lipid autotaxin inhibitors.

Bioorg Chem 2020 10 26;103:104188. Epub 2020 Aug 26.

Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address:

The lysophospholipase D autotaxin (ATX) generates lysophosphatidic acid (LPA) that activates six cognate G-protein coupled receptors (GPCR) in cancerous cells, promoting their motility and invasion. Four novel compounds were generated aided by molecular docking guided design and synthesis techniques to obtain new dual inhibitors of ATX and the lysophosphatidic acid receptor subtype 1 (LPAR1). Biological evaluation of these compounds revealed two compounds, 10 and 11, as new ATX enzyme inhibitors with potencies in the range of 218-220 nM and water solubility (>100 µg/mL), but with no LPAR1 inhibitory activity. A QSAR model was generated that included four newly designed compounds and twenty-one additional compounds that we have reported previously. The QSAR model provided excellent predictability of the pharmacological activity and potency among structurally related drug candidates. This model will be highly useful in guiding the synthesis of new ATX inhibitors in the future.
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http://dx.doi.org/10.1016/j.bioorg.2020.104188DOI Listing
October 2020

Augmented Lipocalin-2 Is Associated with Chronic Obstructive Pulmonary Disease and Counteracts Lung Adenocarcinoma Development.

Am J Respir Crit Care Med 2021 01;203(1):90-101

Department of Epidemiology.

Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator (lipocalin-2) was increased in normal airways from mice with knockout of the airway lineage gene () and that are prone to developing inflammation and LUAD. Yet, the role of LCN2 in lung inflammation and LUAD is poorly understood. Delineate the role of induction in LUAD pathogenesis. Normal airway brushings, uninvolved lung tissues, and tumors from mice before and after tobacco carcinogen exposure were analyzed by RNA sequencing. mRNA was analyzed in public and in-house data sets of LUAD, lung squamous cancer (LUSC), chronic obstructive pulmonary disease (COPD), and LUAD/LUSC with COPD. LCN2 protein was immunohistochemically analyzed in a tissue microarray of 510 tumors. Temporal lung tumor development, gene expression programs, and host immune responses were compared between and / littermates. was progressively elevated during LUAD development and positively correlated with proinflammatory cytokines and inflammation gene sets. was distinctively elevated in human LUADs, but not in LUSCs, relative to normal lungs and was associated with COPD among smokers and patients with LUAD. Relative to mice, / littermates exhibited significantly increased lung tumor development concomitant with reduced T-cell abundance (CD4) and richness, attenuated antitumor immune gene programs, and increased immune cell expression of protumor inflammatory cytokines. Augmented LCN2 expression is a molecular feature of COPD-associated LUAD and counteracts LUAD development by maintaining antitumor immunity.
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http://dx.doi.org/10.1164/rccm.202004-1079OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781147PMC
January 2021

Interplay between estrogen and Stat3/NF-κB-driven immunomodulation in lung cancer.

Carcinogenesis 2020 11;41(11):1529-1542

Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

K-ras mutant lung adenocarcinoma (LUAD) is the most common type of lung cancer, displays abysmal prognosis and is tightly linked to tumor-promoting inflammation, which is increasingly recognized as a target for therapeutic intervention. We have recently shown a gender-specific role for epithelial Stat3 signaling in the pathogenesis of K-ras mutant LUAD. The absence of epithelial Stat3 in male K-ras mutant mice (LR/Stat3Δ/Δ mice) promoted tumorigenesis and induced a nuclear factor-kappaB (NF-κB)-driven pro-tumor immune response while reducing tumorigenesis and enhancing anti-tumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-κB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Δ/Δ females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-κB-driven immunosuppressive response, and reduced anti-tumor cytotoxicity, whereas estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-κB-driven immunosuppression and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-κB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Δ/Δ males, but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-κB-driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD.
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http://dx.doi.org/10.1093/carcin/bgaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896112PMC
November 2020

Mechanochemical degradation of perfluorohexane sulfonate: Synergistic effect of ferrate(VI) and zero-valent iron.

Environ Pollut 2020 Sep 19;264:114789. Epub 2020 May 19.

State Key Joint Laboratory of Environmental Simulation and Pollution Control (SKLESPC), Beijing Key Laboratory for Emerging Organic Contaminants Control (BKLEOC), School of Environment, Tsinghua University, Beijing, 100084, China.

Perfluorohexane sulfonate (PFHxS) has been newly recommended to be added into the Stockholm Convention on persistent organic pollutants (POPs). As one of the major perfluoroalkyl pollutants, its long half-time in human serum and neurotoxicity are cause for significant concern. Although mechanochemical degradation has been evaluated as a promising ecofriendly technology to treat pollutants, the extraordinary stability of poly- and perfluoroalkyl substances (PFASs) raises harsh requirements for co-milling reagents. In the present study, zero-valent iron (ZVI) and ferrate(VI) were for the first time used as the co-milling reagents to degrade PFHxS. When ZVI and ferrate(VI) were used alone, both the degradation and defluorination efficiencies were low. However, after milling at the optimum ratio (ferrate(VI):ZVI = 1:2) for 4 h, the synergistic effect of ZVI and ferrate(VI) resulted in almost complete degradation (100%) and defluorination (95%). Two points can account for this excellent performance: (1) the mechanochemical energy input in the system initiates and prominently promotes related reactions; and (2) the active species generated from the reactions among ZVI, ferrate(VI) and other high-valent iron species will accelerate the process of electron transfer. The sulfonate group comprises the favorable attack sites, as corroborated by both the identified intermediates and quantum chemical calculations. The homolysis of the C-S bond is not only the triggering step, but also the rate-limiting step. In summary, the present work confirms the feasibility and underlying mechanism of the ZVI-ferrate(VI) co-milling system to defluorinate PFHxS, which might be a promising technology to treat PFASs in solid wastes.
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http://dx.doi.org/10.1016/j.envpol.2020.114789DOI Listing
September 2020

Understanding the Complexity of the Tumor Microenvironment in K-ras Mutant Lung Cancer: Finding an Alternative Path to Prevention and Treatment.

Front Oncol 2019 22;9:1556. Epub 2020 Jan 22.

Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Kirsten rat sarcoma viral oncogene (K-ras) is a well-documented, frequently mutated gene in lung cancer. Since K-ras regulates numerous signaling pathways related to cell survival and proliferation, mutations in this gene are powerful drivers of tumorigenesis and confer prodigious survival advantages to developing tumors. These malignant cells dramatically alter their local tissue environment and in the process recruit a powerful ally: inflammation. Inflammation in the context of the tumor microenvironment can be described as either antitumor or protumor (i.e., aiding or restricting tumor progression, respectively). Many current treatments, like immune checkpoint blockade, seek to augment antitumor inflammation by alleviating inhibitory signaling in cytotoxic T cells; however, a burgeoning area of research is now focusing on ways to modulate and mitigate protumor inflammation. Here, we summarize the interplay of tumor-promoting inflammation and K-ras mutant lung cancer pathogenesis by exploring the cytokines, signaling pathways, and immune cells that mediate this process.
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http://dx.doi.org/10.3389/fonc.2019.01556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987304PMC
January 2020

Strand displacement DNA synthesis by DNA polymerase gp90 exo of Pseudomonas aeruginosa phage 1.

Biochimie 2020 Mar 3;170:73-87. Epub 2020 Jan 3.

Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health & West China Fourth Hospital, Sichuan University, Chengdu, 610041, China. Electronic address:

Strand displacement DNA synthesis is essential for DNA replication. Gp90, the sole DNA polymerase of Pseudomonas aeruginosa phage 1, can bypass multiply DNA lesions. However, whether it can perform strand displacement synthesis is still unknown. In this work, we found that gp90 exo could perform strand displacement synthesis, albeit its activity and processivity were lower than those of primer extension. Gp90 exo itself could not unwind Y-shaped or fork DNA. Tail and gap at DNA fork were necessary for efficient synthesis. High GC content obviously inhibited strand displacement synthesis. Consecutive GC sequence at the entrance of fork showed more inhibition effect on DNA synthesis than that in the downstream DNA fork. The fraction of productive polymerase and DNA complex (A values) was higher for fork than gap; while their average extension rates (k values) were similar. However, both A and k values were lower than those for the primer/template (P/T) substrate. The binding of gp90 exo to fork was tighter than P/T or gap in the absence of dATP. In the presence of dATP to form ternary complex, the binding affinity of gp90 exo to P/T or gap was increased compared with that in the binary complex. Abasic site, 8-oxoG, and O-MeG inhibited and even blocked strand displacement synthesis. This work shows that gp90 exo could perform strand displacement DNA synthesis at DNA fork, discovering the presence of new functions of PaP1 DNA polymerase in DNA replication and propagation of PaP1.
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http://dx.doi.org/10.1016/j.biochi.2019.12.013DOI Listing
March 2020

Structure-Activity Relationship Study of Novel 6-Aryl-2-benzoyl-pyridines as Tubulin Polymerization Inhibitors with Potent Antiproliferative Properties.

J Med Chem 2020 01 7;63(2):827-846. Epub 2020 Jan 7.

Department of Pharmaceutical Sciences, College of Pharmacy , University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States.

We recently reported the crystal structure of tubulin in complex with a colchicine binding site inhibitor (CBSI), ABI-231, having 2-aryl-4-benzoyl-imidazole (ABI). Based on this and additional crystal structures, here we report the structure-activity relationship study of a novel series of pyridine analogues of ABI-231, with compound being the most potent one (average IC ∼ 1.8 nM) against a panel of cancer cell lines. We determined the crystal structures of another potent CBSI ABI-274 and in complex with tubulin and confirmed their direct binding at the colchicine site. inhibited tubulin polymerization, strongly suppressed A375 melanoma tumor growth, induced tumor necrosis, disrupted tumor angiogenesis, and led to tumor cell apoptosis in vivo. Collectively, these studies suggest that represents a promising new generation of tubulin inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01815DOI Listing
January 2020

An Orally Available Tubulin Inhibitor, VERU-111, Suppresses Triple-Negative Breast Cancer Tumor Growth and Metastasis and Bypasses Taxane Resistance.

Mol Cancer Ther 2020 02 23;19(2):348-363. Epub 2019 Oct 23.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee.

Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancer cases in the United States. TNBC has poorer overall prognosis relative to other molecular subtypes due to rapid onset of drug resistance to conventional chemotherapies and increased risk of visceral metastases. Taxanes like paclitaxel are standard chemotherapies that stabilize microtubules, but their clinical efficacy is often limited by drug resistance and neurotoxicities. We evaluated the preclinical efficacy of a novel, potent, and orally bioavailable tubulin inhibitor, VERU-111, in TNBC models. VERU-111 showed potent cytotoxicity against TNBC cell lines, inducing apoptosis and cell-cycle arrest in a concentration-dependent manner. VERU-111 also efficiently inhibited colony formation, cell migration, and invasion. Orally administered VERU-111 inhibited MDA-MB-231 xenograft growth in a dose-dependent manner, with similar efficacies to paclitaxel, but without acute toxicity. VERU-111 significantly reduced metastases originating from the mammary fat pad into lung, liver, and kidney metastasis in an experimental metastasis model. Moreover, VERU-111, but not paclitaxel, suppressed growth of luciferase-labeled, taxane-resistant, patient-derived metastatic TNBC tumors. In this model, VERU-111 repressed growth of preestablished axillary lymph node metastases and lung, bone, and liver metastases at study endpoint, whereas paclitaxel enhanced liver metastases relative to vehicle controls. Collectively, these studies strongly suggest that VERU-111 is not only a potent inhibitor of aggressive TNBC phenotypes, but it is also efficacious in a taxane-resistant model of metastatic TNBC. Thus, VERU-111 is a promising new generation of tubulin inhibitor for the treatment of TNBC and may be effective in patients who progress on taxanes.Results presented in this study demonstrate the efficacy of VERU-111 and provide strong rationale for future development of VERU-111 as an effective treatment for metastatic breast cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007836PMC
February 2020

The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy.

Expert Opin Drug Discov 2019 07 9;14(7):667-682. Epub 2019 May 9.

a Department of Pharmaceutical Sciences, College of Pharmacy , University of Tennessee Health Science Center , Memphis , TN , USA.

: Hypoxia is one of the intrinsic features of solid tumors, and it is always associated with aggressive phenotypes, including resistance to radiation and chemotherapy, metastasis, and poor patient prognosis. Hypoxia manifests these unfavorable effects through activation of a family of transcription factors, Hypoxia-inducible factors (HIFs) play a pivotal role in the adaptation of tumor cells to hypoxic and nutrient-deprived conditions by upregulating the transcription of several pro-oncogenic genes. Several advanced human cancers share HIFs activation as a final common pathway. : This review highlights the role and regulation of the HIF-1/2 in cancers and alludes on the biological complexity and redundancy of HIF-1/2 regulation. Moreover, this review summarizes recent insights into the therapeutic approaches targeting the HIF-1/2 pathway. : More studies are needed to unravel the extensive complexity of HIFs regulation and to develop more precise anticancer treatments. Inclusion of HIF-1/2 inhibitors to the current chemotherapy regimens has been proven advantageous in numerous reported preclinical studies. The combination therapy ideally should be personalized based on the type of mutations involved in the specific cancers, and it might be better to include two drugs that inhibit HIF-1/2 activity by synergistic molecular mechanisms.
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http://dx.doi.org/10.1080/17460441.2019.1613370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559821PMC
July 2019

Nuclear localization of Newcastle disease virus matrix protein promotes virus replication by affecting viral RNA synthesis and transcription and inhibiting host cell transcription.

Vet Res 2019 Mar 20;50(1):22. Epub 2019 Mar 20.

Key Laboratory of Animal Genetics, Breeding and Reproduction in The Plateau Mountainous Region, Ministry of Education, Guizhou University, Guiyang, China.

Nuclear localization of paramyxovirus proteins is crucial for virus life cycle, including the regulation of viral replication and the evasion of host immunity. We previously showed that a recombinant Newcastle disease virus (NDV) with nuclear localization signal mutation in the matrix (M) protein results in a pathotype change and attenuates viral pathogenicity in chickens. However, little is known about the nuclear localization functions of NDV M protein. In this study, the potential functions of the M protein in the nucleus were investigated. We first demonstrate that nuclear localization of the M protein could not only promote the cytopathogenicity of NDV but also increase viral RNA synthesis and transcription efficiency in DF-1 cells. Using microarray analysis, we found that nuclear localization of the M protein might inhibit host cell transcription, represented by numerous up-regulating genes associated with transcriptional repressor activity and down-regulating genes associated with transcriptional activator activity. The role of representative up-regulated gene prospero homeobox 1 (PROX1) and down-regulated gene aryl hydrocarbon receptor (AHR) in the replication of NDV was then evaluated. The results show that siRNA-mediated knockdown of PROX1 or AHR significantly reduced or increased the viral RNA synthesis and viral replication, respectively, demonstrating the important roles of the expression changes of these genes in NDV replication. Together, our findings demonstrate for the first time that nuclear localization of NDV M protein promotes virus replication by affecting viral RNA synthesis and transcription and inhibiting host cell transcription, improving our understanding of the molecular mechanism of NDV replication and pathogenesis.
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http://dx.doi.org/10.1186/s13567-019-0640-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425612PMC
March 2019

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy.

Med Res Rev 2019 07 11;39(4):1398-1426. Epub 2019 Feb 11.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee.

Microtubule (MT)-targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT-targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.
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http://dx.doi.org/10.1002/med.21568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857175PMC
July 2019

Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer.

Nat Commun 2018 11 2;9(1):4589. Epub 2018 Nov 2.

Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA.

Lung adenocarcinomas (LUADs) with mutations in the K-ras oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of K-ras mutant LUAD are poorly understood. Here, we develop a lung epithelial specific K-ras mutant/Stat3 conditional knockout (LR/Stat3) mouse model. Epithelial Stat3 deletion results in intriguing sex-associated discrepancies; K-ras mutant tumors are decreased in female LR/Stat3 mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following Stat3 deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/Stat3 mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments K-ras mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial Stat3 signaling in K-ras mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.
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http://dx.doi.org/10.1038/s41467-018-07042-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214980PMC
November 2018

Degradation of PFOA Substitute: GenX (HFPO-DA Ammonium Salt): Oxidation with UV/Persulfate or Reduction with UV/Sulfite?

Environ Sci Technol 2018 10 27;52(20):11728-11734. Epub 2018 Sep 27.

State Key Joint Laboratory of Environment Simulation and Pollution Control (SKJLESPC), Beijing Key Laboratory for Emerging Organic Contaminants Control (BKLEOC), School of Environment, POPs Research Center , Tsinghua University , Beijing 100084 , China.

Hexafluoropropylene oxide dimer acid (HFPO-DA, ammonium salt with trade name: GenX) has been recently detected in river water worldwide. There are significant concerns about its persistence, and potential adverse effects to the biota. In this study, the degradability of GenX by typical advanced redox technologies (UV/persulfate and UV/sulfate) is investigated. Results demonstrate that <5% GenX is oxidized after 3 h in UV/persulfate system, which is much lower than ∼27% for PFOA. In comparison, GenX can be readily degraded and defluorinated by hydrated electron (e) generated by UV/sulfite system. Specifically, GenX is not detectable after 2 h, and >90% of fluoride ion is recovered 6 h later. This is attributed to the accumulation and subsequent degradation of CFCFCOOH and CFCOOH, which are stable intermediates of GenX degradation. Mechanistic investigations suggest that the etheric bond in the molecule is a favorable attack point for the e. Such finding is corroborated by quantum chemical calculations. The side CF- at the α-carbon probably acts as an effective barrier that prevents GenX from being cleaved by SO• or OH• at its most sensible point (i.e. the carboxyl group). This study illustrates that reduction by UV/sulfite might be a promising technology to remove GenX from contaminated water.
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http://dx.doi.org/10.1021/acs.est.8b02172DOI Listing
October 2018

Mechanochemical formation of chlorinated phenoxy radicals and their roles in the remediation of hexachlorobenzene contaminated soil.

J Hazard Mater 2018 06 26;352:172-181. Epub 2018 Mar 26.

Institute of Nuclear and New Energy Technology, Tsinghua University, Haidian District, Beijing 100084, China.

Mechanochemical degradation (MCD) is a promising eco-friendly method to dispose persistent organic pollutants (POPs). Mechanically induced free-radical attack was thought to be one of the key elements in initiating and accelerating the dechlorination and degradation of POPs. In this study, mechanochemical formation of free-radicals and their roles in the remediation of hexachlorobenzene (HCB) contaminated soil were explored using both of experimental analysis and quantum chemical calculations. It was found that chlorinated phenoxy radicals(CB-O) can be produced in the milling process and they played a vital role in the dechlorination of HCB, based on the results of electron spin-resonance (ESR) and X-ray photoelectron spectra (XPS). Two transition states of mechanochemical reaction along the formation of pentachlorinated phenoxy radical (PeCB-O) were located, with the energy barriers of 39.4 and 3.4 kJ/mol. The localized orbital locator (LOL), Mayer bond order and topological analysis were also implemented to depict the process in detail. Free-radical attack dominated dechlorination pathway of HCB in the MCD process was also verified by the Fukui function analysis. The study on the mechanically-induced generation of free-radicals and their associated modes of action on the degradation of HCB will provide a deep insight into mechanochemical remediation mechanism of POPs contaminated soil.
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http://dx.doi.org/10.1016/j.jhazmat.2018.03.045DOI Listing
June 2018

Importin α5 negatively regulates importin β1-mediated nuclear import of Newcastle disease virus matrix protein and viral replication and pathogenicity in chicken fibroblasts.

Virulence 2018 12;9(1):783-803

c Key Laboratory of Animal Infectious Diseases of Ministry of Agriculture , Yangzhou University , Yangzhou , China.

The matrix (M) protein of Newcastle disease virus (NDV) is demonstrated to localize in the nucleus via intrinsic nuclear localization signal (NLS), but cellular proteins involved in the nuclear import of NDV M protein and the role of M's nuclear localization in the replication and pathogenicity of NDV remain unclear. In this study, importin β1 was screened to interact with NDV M protein by yeast two-hybrid screening. This interaction was subsequently confirmed by co-immunoprecipitation and pull-down assays. In vitro binding studies indicated that the NLS region of M protein and the amino acids 336-433 of importin β1 that belonged to the RanGTP binding region were important for binding. Importantly, a recombinant virus with M/NLS mutation resulted in a pathotype change of NDV and attenuated viral replication and pathogenicity in chicken fibroblasts and SPF chickens. In agreement with the binding data, nuclear import of NDV M protein in digitonin-permeabilized HeLa cells required both importin β1 and RanGTP. Interestingly, importin α5 was verified to interact with M protein through binding importin β1. However, importin β1 or importin α5 depletion by siRNA resulted in different results, which showed the obviously cytoplasmic or nuclear accumulation of M protein and the remarkably decreased or increased replication ability and pathogenicity of NDV in chicken fibroblasts, respectively. Our findings therefore demonstrate for the first time the nuclear import mechanism of NDV M protein and the negative regulation role of importin α5 in importin β1-mediated nuclear import of M protein and the replication and pathogenicity of a paramyxovirus.
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http://dx.doi.org/10.1080/21505594.2018.1449507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955436PMC
December 2018

Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site: Structural Basis and Antitumor Efficacy.

J Med Chem 2018 02 12;61(4):1704-1718. Epub 2018 Feb 12.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States.

We report the design, synthesis, and biological evaluation of heterocyclic-fused pyrimidines as tubulin polymerization inhibitors targeting the colchicine binding site with significantly improved therapeutic index. Additionally, for the first time, we report high-resolution X-ray crystal structures for the best compounds in this scaffold, 4a, 4b, 6a, and 8b. These structures not only confirm their direct binding to the colchicine site in tubulin and reveal their detailed molecular interactions but also contrast the previously published proposed binding mode. Compounds 4a and 6a significantly inhibited tumor growth in an A375 melanoma xenograft model and were accompanied by elevated levels of apoptosis and disruption of tumor vasculature. Finally, we demonstrated that compound 4a significantly overcame clinically relevant multidrug resistance in a paclitaxel resistant PC-3/TxR prostate cancer xenograft model. Collectively, these studies provide preclinical and structural proof of concept to support the continued development of this scaffold as a new generation of tubulin inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912893PMC
February 2018

Repression of intestinal transporters and FXR-FGF15 signaling explains bile acids dysregulation in experimental colitis-associated colon cancer.

Oncotarget 2017 Sep 28;8(38):63665-63679. Epub 2017 Jun 28.

State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.

Bile acids (BAs) are important endogenous signaling molecules that play vital roles in the pathological development of various diseases including colitis-associated cancer (CAC). BAs were previously found dysregulated under conditions of CAC; however, the exact patterns and underlying molecular mechanisms remain largely elusive. Based on the development of a method for comprehensive analysis of BAs, this study aims to elucidate the dysregulation patterns and involved mechanisms in a typical CAC model induced by azoxymethane (AOM)/dextran sodium sulfate (DSS). CAC mice showed decreased BAs transformation in gut and glucuronidation in colon, leading to accumulation of primary BAs but reduction of secondary BAs in colon. CAC mice were characterized by an accumulation of BAs in various compartments except ileum, which is in line with repressed ileal FXR-FGF15 feedback signaling and the increased expression of hepatic CYP7A1. The compromised ileal FXR-FGF15 signaling was caused in part by the reduced absorption of FXR ligands including free and tauro-conjungated BAs due to the downregulation of various transporters of BAs in the ileum of CAC mice.
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http://dx.doi.org/10.18632/oncotarget.18885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609951PMC
September 2017

Dissemination of macrolides, fusidic acid and mupirocin resistance among clinical isolates.

Oncotarget 2017 Aug 22;8(35):58086-58097. Epub 2017 Jul 22.

Non-Coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu 610500, China.

As an increasingly common cause of skin infections worldwide, the prevalence of antibiotic-resistant () across China has not been well documented. This literature aims to study the resistance profile to commonly used antibiotics, including macrolides, fusidic acid (FA) and mupirocin, and its relationship to the genetic typing in 34 strains, including 6 methicillin-resistant (MRSA), isolated from a Chinese hospital. The MIC results showed 27 (79.4%), 1 (2.9%) and 6 (17.6%) isolates were resistant to macrolides, FA and mupirocin, respectively. Among 27 macrolide-resistant isolates, 5 (18.5%) were also resistant to mupirocin and 1 (3.7%) to FA. A total of 13 available resistant genes were analyzed in 28 antibiotic-resistant strains using polymerase chain reaction (PCR). The positive rates of macrolide-resistant , , , and low level mupirocin-resistant mutations were 11.1%, 25.9%, 51.9%, 7.4% and 100%, respectively. Other determinants for FA- and high level mupirocin-resistance were not found. The results of multilocus sequence typing (MLST) and pulsed field gel electrophoresis (PFGE) revealed 13 sequence types (STs) and 18 clusters in 23 resistant gene positive isolates. Among these STs, ST5 was most prevalent, accounting for 18.2%. Notably, various clusters were found with similar resistance phenotype and genotype, exhibiting a weak genetic relatedness and high genetic heterogeneities. In conclusion, macrolides, especially erythromycin, are not appropriate to treat skin infections caused by , and more effective measures are required to reduce the dissemination of macrolides, FA and mupirocin resistance of the pathogen.
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http://dx.doi.org/10.18632/oncotarget.19491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601635PMC
August 2017

Characterization of a blaNDM‑1‑harboring plasmid from a Salmonella enterica clinical isolate in China.

Mol Med Rep 2017 Aug 8;16(2):1087-1092. Epub 2017 Jun 8.

Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.

The plasmid-mediated transmission of antibiotic resistance genes has been reported to be involved in the development of antibiotic resistance in bacteria, and poses a serious threat for the success of bacterial infection treatment and human health worldwide. The present study used a 454 GS‑FLX pyrosequencing system to determine the ~140 kb nucleotide sequence of plasmid pHS36‑NDM, which was identified in a Salmonella Stanley isolate from the stool sample of an 11‑month‑old girl at Lishui Central Hospital, China, and which contains a New Delhi metallo‑β‑lactamase‑1 (NDM‑1) carbapenem resistance gene (blaNDM‑1). The 181 open reading frames encode proteins with functions including replication, stable inheritance, antibiotic resistance and mobile genetic elements. Both horizontal transfer and passage stability‑related genes were identified in pHS36‑NDM, including a conserved type 4 secretion system and stbA (stable plasmid inheritance protein A). Two multidrug resistance gene islands were identified: The ISEcp1‑blaCMY transposition unit which contains a CMY‑6 β‑lactamase gene (blaCMY‑6) and a quaternary ammonium compound resistance gene (sugE); and the intI1‑ISCR27 accessory region, which contained a trimethoprim resistance gene (dfrA12), two aminoglycoside resistance genes (aadA2 and rmtC), a truncated quaternary ammonium compound resistance gene (qacE∆1), a sulfonamide resistance gene (sul1), the blaNDM‑1 carbapenemase and a bleomycin resistance gene (bleMBL). pHS36‑NDM shared high homology with other blaNDM‑1‑containing plasmids reported in Sweden, Italy and Japan. However, no previous international travel history was documented for the patient and her family, even to neighboring cities. Furthermore, pHS36‑NDM is of a different incompatibility group to other published blaNDM‑1‑carrying plasmids reported in China, with low homology in the surrounding structure of blaNDM‑1. The present study will facilitate the understanding of the underlying resistance and dispersal mechanism of pHS36‑NDM, and will deepen our recognition of the ongoing spread of the blaNDM‑1‑containing plasmids.
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http://dx.doi.org/10.3892/mmr.2017.6733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562004PMC
August 2017