Publications by authors named "Hong-Yu Li"

198 Publications

Variation in Parasitoid Virulence of during the Targeting of Two Host Beetles.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

In host-parasitoid interactions, antagonistic relationship drives parasitoids to vary in virulence in facing different hosts, which makes these systems excellent models for stress-induced evolutionary studies. Venom compositions varied between two strains of , Tb-Bl and Tb-On. Tb-Bl targets pupae as hosts, and Tb-On is a sub-population of Tb-Bl, which has been experimentally adapted to a new host, . Aiming to examine variation in parasitoid virulence of the two strains toward two hosts, we used reciprocal injection experiments to compare effect of venom/ovarian fluids from the two strains on cytotoxicity, inhibition of immunity and fat body lysis of the two hosts. We found that Tb-Onvenom was more virulent towards plasmatocyte spreading, granulocyte function and phenoloxidase activity than Tb-Blvenom. Tb-Blovary was able to suppress encapsulation and phagocytosis in both hosts; however, Tb-Onovary inhibition targeted only . Our data suggest that the venom undergoes rapid evolution when facing different hosts, and that the wasp has good evolutionary plasticity.
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http://dx.doi.org/10.3390/ijms22073581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036858PMC
March 2021

[Identification of Chinese medicine sea snake based on cytochrome B (Cytb)].

Zhongguo Zhong Yao Za Zhi 2021 Mar;46(5):1102-1116

Guangxi University of Chinese Medicine Nanning 530200,China.

The identification of species primordium has been one of the hot issues in the identification of traditional Chinese medicine. Sea snake is one of the most valuable Chinese medicinal materials in China. In order to understand the origin and varieties of sea snake in the market, we studied the molecular identification of 46 sea snakes by cytochrome B(Cytb). After comparison and manual correction, the sequence length was 582 bp, and the content of A+T(58.9%) was higher than that of G+C(41.1%). There exist 197 variable sites and 179 parsimony-informative sites of the sequence. There are 44 kinds of sequence alignment with consistency equal to 100%, and 2 kinds equal to 96%. A total of 408 Cytb effective sequences were downloaded from GenBank database, with a total of 68 species. Phylogenetic tree of a total of 454 sea snake sequences with the samples in this study were constructed by neighbor-joining trees and Bayesian inference method, respectively, which can identify 42 samples of medicinal materials, while 4 samples can not be identified because of their low node support. The results showed that the species of the sea snake medicine were at least from 2 genera and 5 species, namely, Aipysurus eydouxii, Hydrophis curtus, H. caerulescen, H. curtus, H. ornatus and H. spiralis. This study suggested that the original species of commercial sea snake are very complex and can provide insight into the identification of sea snakes.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20201221.101DOI Listing
March 2021

Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response.

NAR Cancer 2021 Mar 22;3(1):zcab010. Epub 2021 Mar 22.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.

The RNA methyltransferase TRDMT1 has recently emerged as a key regulator of homologous recombination (HR) in the transcribed regions of the genome, but how it is regulated and its relevance in cancer remain unknown. Here, we identified that TRDMT1 is poly-ubiquitinated at K251 by the E3 ligase TRIM28, removing TRDMT1 from DNA damage sites and allowing completion of HR. Interestingly, K251 is adjacent to G155 in the 3D structure, and the G155V mutation leads to hyper ubiquitination of TRDMT1, reduced TRDMT1 levels and impaired HR. Accordingly, a TRDMT1 G155V mutation in an ovarian cancer super responder to platinum treatment. Cells expressing TRDMT1-G155V are sensitive to cisplatin and . In contrast, high expression of TRDMT1 in patients with ovarian cancer correlates with platinum resistance. A potent TRDMT1 inhibitor resensitizes TRDMT1-high tumor cells to cisplatin. These results suggest that TRDMT1 is a promising therapeutic target to sensitize ovarian tumors to platinum therapy.
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http://dx.doi.org/10.1093/narcan/zcab010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984809PMC
March 2021

NAMPT promotes hepatitis B virus replication and liver cancer cell proliferation through the regulation of aerobic glycolysis.

Oncol Lett 2021 May 18;21(5):390. Epub 2021 Mar 18.

Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China.

Nicotinamide phosphoribosyltransferase (NAMPT) is a critical rate-limiting enzyme involved in NAD synthesis that has been shown to contribute to the progression of liver cancer. However, the potential role and mechanism of NAMPT in hepatitis B virus (HBV)-associated liver cancer remain unclear. The present study assessed the expression of NAMPT in HBV-positive and -negative liver cancer cells, and investigated whether HBV-induced NAMPT expression is dependent on HBV X protein (HBx). In addition, the role of NAMPT in HBV replication and transcription, and in HBV-mediated liver cancer cell growth was explored. The effects of NAMPT on the glycolytic pathway were also evaluated. Reverse transcription-quantitative PCR and western blotting results revealed that NAMPT expression levels were significantly higher in HBV-positive liver cancer cells than in HBV-negative liver cancer cells, and this effect was HBx-dependent. Moreover, the activation of NAMPT was demonstrated to be required for HBV replication and transcription. The NAMPT inhibitor FK866 repressed cell survival and promoted cell death in HBV-expressing liver cancer cells, and these effects were attenuated by nicotinamide mononucleotide. Furthermore, the inhibition of NAMPT was associated with decreased glucose uptake, decreased lactate production and decreased ATP levels in HBV-expressing liver cancer cells, indicating that NAMPT may promote the aerobic glycolysis. Collectively, these findings reveal a positive feedback loop in which HBV enhances NAMPT expression and the activation of NAMPT promotes HBV replication and HBV-mediated malignant cell growth in liver cancer. The present study highlights the important role of NAMPT in the regulation of aerobic glycolysis in HBV-mediated liver cancer, and suggests that NAMPT may be a promising treatment target for patients with HBV-associated liver cancer.
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http://dx.doi.org/10.3892/ol.2021.12651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988713PMC
May 2021

Molecular characterization of carbapenem-resistant and virulent plasmids in from patients with bloodstream infections in China.

Emerg Microbes Infect 2021 Dec;10(1):700-709

Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China.

Bloodstream infections (BSIs) caused by carbapenem-resistant (CRKP) are potentially life-threatening and an urgent threat to public health. The present study aims to clarify the characteristics of carbapenemase-encoding and virulent plasmids, and their interactions with the host bacterium. A total of 425 isolates were collected from the blood of BSI patients from nine Chinese hospitals, between 2005 and 2019. Integrated epidemiological and genomic data showed that ST11 and ST307 isolates were associated with nosocomial outbreak and transmission. Comparative analysis of 147 genomes and 39 completely assembled chromosomes revealed extensive interruption of by IS in all carbapenemase-2 (KPC-2)-producing ST11 isolates, leading to activation of the AcrAB-Tolc multidrug efflux pump and a subsequent reduction in susceptibility to the last-resort antibiotic tigecycline and six other antibiotics. We described 29 KPC-2 plasmids showing diverse structures, two virulence plasmids in two KPC-2-producing , and two novel multidrug-resistant (MDR)-virulent plasmids. This study revealed a multifactorial impact of KPC-2 plasmid on , which may be associated with nosocomial dissemination of MDR isolates.
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http://dx.doi.org/10.1080/22221751.2021.1906163DOI Listing
December 2021

Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation.

Eur J Med Chem 2021 Apr 9;216:113265. Epub 2021 Feb 9.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. Electronic address:

Tropomyosin receptor kinase (TRK) represents an attractive oncology target for cancer therapy related to its critical role in cancer formation and progression. NTRK fusions are found to occur in 3.3% of lung cancers, 2.2% of colorectal cancers, 16.7% of thyroid cancers, 2.5% of glioblastomas, and 7.1% of pediatric gliomas. In this paper, we described the discovery of the type-II pan-TRK inhibitor 4c through the structure-based drug design strategy from the original hits 1b and 2b. Compound 4c exhibited excellent in vitro TRKA, TRKB, and TRKC kinase inhibitory activity and anti-proliferative activity against human colorectal carcinoma derived cell line KM12. In the NCI-60 human cancer cell lines screen, compound 4g demonstrated nearly 80% of growth inhibition for KM12, while only minimal inhibitory activity was observed for the remaining 59 cancer cell lines. Western blot analysis demonstrated that 4c and its urea cousin 4k suppressed the TPM3-TRKA autophosphorylation at the concentrations of 100 nM and 10 nM, respectively. The work presented that 2-(4-(thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acetamides could serve as a novel scaffold for the discovery and development of type-II pan-TRK inhibitors for the treatment of TRK driven cancers.
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http://dx.doi.org/10.1016/j.ejmech.2021.113265DOI Listing
April 2021

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division.

Elife 2020 12 21;9. Epub 2020 Dec 21.

Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.

Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote expression of /ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning β-oxidation, reflected by increased acylcarnitines (ACs) and reduced β-hydroxybutyrate. This led to elevated plasma free fatty acids (FFAs), which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here, we demonstrate that loss of hepatocyte proliferation is not only an outcome but also possibly a causative factor for liver pathology.
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http://dx.doi.org/10.7554/eLife.63835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771968PMC
December 2020

Laparoscopic left lateral sectionectomy in pediatric living donor liver transplantation by single-port approach: A case report.

World J Clin Cases 2020 Dec;8(23):6103-6109

Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.

Background: Single-port laparoscopy has been used in a variety of abdominal operations. We report the first case of single-port laparoscopic left lateral sectionectomy in pediatric laparoscopic living donor liver transplantation.

Case Summary: A 28-year-old man volunteered for living liver donation to his daughter who was diagnosed with liver cirrhosis and portal hypertension after the Kasai procedure for biliary atresia. His body mass index was 20.5 kg/m. Liver dynamic computed tomography showed: (1) Left lateral graft volume of 232.76 cm with a graft-to-recipient weight ratio of 2.59%; and (2) Right hepatic artery derived from the superior mesenteric artery. A single-port access system was placed through a transumbilical incision, including four trocars: two 12-mm ports for a camera and endoscopic stapler and two 5-mm working ports. Liver parenchyma was dissected by a Harmonic and Cavitron Ultrasonic Surgical Aspirator, while bipolar was used for coagulation. The bile duct was transected above the bifurcation by indocyanine green fluorescence cholangiography. The specimen was retrieved from the umbilical incision. The total operation time was 4 h without blood transfusion. The final graft weight was 233.6 g with graft-to-recipient weight ratio of 2.60%. The donor was discharged uneventfully on postoperative day 4.

Conclusion: Single-port laparoscopic left lateral sectionectomy is feasible in pediatric laparoscopic living donor liver transplantation in an experienced transplant center.
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http://dx.doi.org/10.12998/wjcc.v8.i23.6103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723710PMC
December 2020

Genomic patterns and characterizations of chromosomally-encoded mcr-1 in Escherichia coli populations.

Gut Pathog 2020 Nov 28;12(1):55. Epub 2020 Nov 28.

Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.

The emergence and transmission of the mobile colistin resistance gene (mcr-1) threatened the extensive use of polymyxin antimicrobials. Accumulated evidence showed that the banning of colistin additive in livestock feed efficiently reduce mcr-1 prevalence, not only in animals but also in humans and environments. However, our previous study has revealed that a small proportion of Escherichia coli could continually carry chromosomally-encoded mcr-1. The chromosomally-encoded events, indicated the existence of stabilized heritage of mcr-1 and revealed a potential threat in the antimicrobial stewardship interventions, are yet to be investigated. In this study, we systematically investigated the genetic basis of chromosomally-encoded mcr-1 in prevalence and potential mechanisms of lineage, plasmid, insertion sequence, and phage. Our results demonstrated that the emergence of chromosomally-encoded mcr-1 could originate from multiple mechanisms, but mainly derived through the recombination of ISApl1/Tn6330. We reported a specific transmission mechanism, which is a phage-like region without lysogenic components, could associate with the emergence and stabilization of chromosomally-encoded mcr-1. These results highlighted the potential origin and risks of chromosomally-encoded mcr-1, which could be a heritable repository and thrive again when confronted with new selective pressures. To the best of our knowledge, this is the first study to systematically reveal the genomic basis of chromosomally-encoded mcr-1, and report a specific transmission pattern involved in phage-like region. Overall, we demonstrate the origin mechanisms and risks of chromosomally-encoded mcr-1. It highlights the need of public attention on chromosome-encoded mcr-1 to prevent from its reemergence.
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http://dx.doi.org/10.1186/s13099-020-00393-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700713PMC
November 2020

Esophageal collateral veins in predicting esophageal variceal recurrence and rebleeding after endoscopic treatment: a systematic review and meta-analysis.

Gastroenterol Rep (Oxf) 2020 Oct 27;8(5):355-361. Epub 2020 Feb 27.

Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, Liaoning, P. R. China.

Background: Endoscopic treatment is recommended for the management of esophageal varices. However, variceal recurrence or rebleeding is common after endoscopic variceal eradication. Our study aimed to systematically evaluate the prevalence of esophageal collateral veins (ECVs) and the association of ECVs with recurrence of esophageal varices or rebleeding from esophageal varices after endoscopic treatment.

Methods: We searched the relevant literature through the PubMed, EMBASE, and Cochrane Library databases. Prevalence of paraesophageal veins (para-EVs), periesophageal veins (peri-EVs), and perforating veins (PVs) were pooled. Risk ratio (RR) and odds ratio (OR) with 95% confidence intervals (CIs) were calculated for cohort studies and case-control studies, respectively. A random-effects model was employed. Heterogeneity among studies was calculated.

Results: Among the 532 retrieved papers, 28 were included. The pooled prevalence of para-EVs, peri-EVs, and PVs in patients with esophageal varices was 73%, 88%, and 54%, respectively. The pooled prevalence of para-EVs and PVs in patients with recurrence of esophageal varices was 87% and 62%, respectively. The risk for recurrence of esophageal varices was significantly increased in patients with PVs (OR=9.79, 95% CI: 1.95-49.22, =0.006 for eight case-control studies), but not in those with para-EVs (OR=4.26, 95% CI: 0.38-38.35, =0.24 for four case-control studies; RR=1.81, 95% CI: 0.83-3.97, =0.14 for three cohort studies). Patients with para-EVs had a significantly higher incidence of rebleeding from esophageal varices (RR=13.00, 95% CI: 2.43-69.56, =0.003 for two cohort studies). Statistically significant heterogeneity was notable across the meta-analyses.

Conclusions: ECVs are common in patients with esophageal varices. Identification of ECVs could be helpful for predicting the recurrence of esophageal varices or rebleeding from esophageal varices after endoscopic treatment.
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http://dx.doi.org/10.1093/gastro/goaa004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603868PMC
October 2020

Microwave-Assisted Copper Catalysis of α-Difluorinated -Diol toward Difluoroalkyl Radical for Hydrodifluoroalkylation of -Quinone Methides.

J Org Chem 2020 10 16;85(19):12785-12796. Epub 2020 Sep 16.

College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, China.

Reported herein is a unified strategy to generate difluoroalkyl radicals from readily prepared α-difluorinated -diols by single electron oxidation. Under microwave irradiation, a catalytic amount of oxidant Cu(OAc) succeeds in the formation of transient difluoroalkyl radicals , for the first time. The reaction features a simple protocol, short reaction time, scalability, and high yield. The synthetic utility of this new methodology was also explored for the synthesis of difluoroalkylated -cyclohexadienones, which is an important core structure in natural products and pharmaceuticals.
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http://dx.doi.org/10.1021/acs.joc.0c01686DOI Listing
October 2020

Strategy Used to Control the Mechanism of Homogeneous Alkyne/Olefin Hydrogenation: AIMD Simulations and DFT Calculations.

J Org Chem 2020 Sep 9;85(18):11626-11634. Epub 2020 Sep 9.

National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, China.

Understanding the mechanism of the catalytic reaction is an effective way to design new high-performance catalysts. The mechanisms of alkyne/olefin hydrogenations catalyzed by a nonclassical Co-N catalyst are explored by ab initio molecular dynamics simulations and density functional theory calculations. From the calculated results, the hydrogenation mechanisms, i.e., molecular or atomic mechanisms, can be effectively controlled via employing the different interaction between the catalyst and substrates. The origination of excellent selectivity toward -olefins for the Co-N catalyst is also taken into account with the help of investigating the olefin hydrogenation process. The mechanism indicates that the negligible energy barrier of rotation is the main reason for highly selective semihydrogenation of a Co-N catalyst, which leads to the -olefin formation. These investigations may provide some useful information and guidelines on the current understanding of the hydrogenation reaction and designing the high-performance catalysts.
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http://dx.doi.org/10.1021/acs.joc.0c01021DOI Listing
September 2020

Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of RET: Design, synthesis and biological evaluation.

Eur J Med Chem 2020 Nov 6;206:112691. Epub 2020 Aug 6.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address:

Gene fusions and point mutations of RET kinase are crucial for driving thoracic cancers, including thyroid cancer and non-small cell lung cancer. Various scaffolds based on different heterocycles have been synthesized and evaluated as RET inhibitors. In this work, we investigate pyrrolo[2,3-d]pyrimidine derivatives for inhibition of RET-wt, drug resistant mutant RET V804M and RET gene fusion driven cell lines. Several compounds were synthesized and the structure activity relationship was extensively studied to optimize the scaffold. Thieno[2,3-d]pyrimidine, a bioisostere of pyrrolo[2,3-d]pyrimidine, was also explored for the effect on RET inhibition. We identified a lead compound, 59, which shows low nanomolar potency against RET-wt and RET V804M. Further 59 shows growth inhibition of LC-2/ad cells which RET-CCDC6 driven. We also determined that 59 is a type 2 inhibitor of RET and demonstrated its ability to inhibit migration of tumor cells. Based on computational studies, we proposed a binding pose of 59 in RET pocket and have quantified the contributions of individual residues for its binding. Together, 59 is an important lead compound which needs further evaluation in biological studies.
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http://dx.doi.org/10.1016/j.ejmech.2020.112691DOI Listing
November 2020

Papillary thyroid carcinoma with hyperthyroidism and multiple metastases: A case report.

Medicine (Baltimore) 2020 Jul;99(30):e21346

Department of Ultrasound.

Rationale: Papillary thyroid carcinoma (PTC) is the most common type of primary thyroid cancer with a low incidence of distant metastases. PTC represents more than 70% to -90% of thyroid malignancies. Distant metastases have only been observed in only 1% to 15% of patients with PTC. In this article, we reported the case of a patient with PTC and hyperthyroidism as well as simultaneous multiple metastases.

Patient Concerns: A 47-year-old man was admitted to our hospital on February 22, 2019, with several neck masses that had been present for 12 months, low back pain for 9 months, and lower limb paraplegia for 3 months.

Diagnoses: According to the patient physical examination, adjuvant examination (e.g., ultrasound, computed tomography, magnetic resonance imaging, blood test, and biopsy) and medical history, the clinical diagnosis was as follows: thyroid papillary carcinoma; cervical lymph node metastasis; multisite bone metastasis (6th and 7th cervical vertebrae, left clavicle proximal, right scapula bone, thoracic vertebrae, lumbar vertebrae, sacral vertebrae, bilateral ilium, and left pubic bone); muscular metastasis (the right medial femoral muscle, the vastus lateralis muscle, left thigh muscle, and the flexor superficialis of the left forearm); possible mediastinal lymph node metastasis; and paraplegia due to the soft-tissue metastasis around the 9th thoracic vertebral spine; and hyperthyroidism (free thyroxine: 36.59 pmol/L, free triiodothyronine: 9.58 pmol/L, thyroid-stimulating hormone: 0.005 μIU/mL, thyroid autoantibody: 2.53 IU/L).

Interventions And Outcomes: The patient refused to undergo further intervention or follow-up.

Lessons: In summary, this is the 1st case of in which a patient with PTC and hyperthyroidism, as well as simultaneous multiple skeletal muscles and bone metastases, lymph node metastasis, and paraplegia was observed. In practice, in cases where patients have PTC and hyperthyroidism, practitioners should perform further examinations to rule out the presence of distant metastases. We believe that the use of ultrasound has a unique advantage in the diagnosis of PTC and skeletal muscle metastasis.
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http://dx.doi.org/10.1097/MD.0000000000021346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386968PMC
July 2020

Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression.

Eur J Med Chem 2020 Oct 12;203:112589. Epub 2020 Jul 12.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. Electronic address:

Aurora Kinase B is a serine-threonine kinase known to be overexpressed in several cancers, with no inhibitors approved for clinical use. Herein, we present the discovery and optimization of a series of novel quinazoline-based Aurora Kinase B inhibitors. The lead inhibitor SP-96 shows sub-nanomolar potency in Aurora B enzymatic assays (IC = 0.316 ± 0.031 nM). We identified the important pharmacophore features resulting in selectivity against receptor tyrosine kinases. Particularly, SP-96 shows >2000 fold selectivity against FLT3 and KIT which is important for normal hematopoiesis. This could diminish the adverse effect of neutropenia reported in the clinical trials of the Aurora B inhibitor Barasertib, which inhibits FLT3 and KIT in addition to Aurora B. Enzyme kinetics of SP-96 shows non-ATP-competitive inhibition which makes it a first-in-class inhibitor. Further, SP-96 shows selective growth inhibition in NCI60 screening, including inhibition of MDA-MD-468, a Triple Negative Breast Cancer cell line.
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http://dx.doi.org/10.1016/j.ejmech.2020.112589DOI Listing
October 2020

Catalyst-Free One-Pot Synthesis of Densely Substituted Pyrazole-Pyrazines as Anti-Colorectal Cancer Agents.

Sci Rep 2020 06 9;10(1):9281. Epub 2020 Jun 9.

College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing, 402160, China.

The first catalyst-free post-Ugi cascade methodology was developed for expeditious access to structurally diverse and complex pyrazole-pyrazines in one-pot. This novel cascade reaction features an intramolecular N2-arylation of pyrazoles with allenes at the C-β position of triple bond. Screening in the colorectal cancer cell lines HCT116 and SW620 validated the feasibility of the methodology for generating bioactive compounds. The lead compound 7h which is active against HCT116 and SW620 with IC of 1.3 and 1.8 µM, respectively, can be synthesized and purified in a gram process synthetic scale in 7 hours. The mechanical studies indicated that compound 7h can induce cell cycle arrest in the G2/M phase and inhibit proliferation and viability in human colon cancer cells. Overall, compound 7h is represented as a promising starting point for the development of new anti-colorectal cancer drugs.
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http://dx.doi.org/10.1038/s41598-020-66137-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283261PMC
June 2020

Portal hypertension in a patient with biliary hamartomas: A case report.

World J Clin Cases 2020 May;8(9):1745-1751

Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China.

Background: Biliary hamartomas (BH) are a rare benign disease caused by malformation of the intrahepatic bile ducts. BH are occasionally diagnosed, but often lack obvious clinical symptoms. They are usually diagnosed by biopsy and imaging tests in clinical practice. Few studies have reported the association of BH with portal hypertension.

Case Summary: A 40-year-old man was repeatedly admitted to our hospital due to hematochezia. The source of bleeding was considered to be gastroesophageal varices and portal hypertensive gastropathy by endoscopy. He had no history of hepatitis virus infection, alcohol abuse, drug-induced liver injury, or autoimmune liver disease. He underwent magnetic resonance imaging, which showed rounded, irregular, low-signal-T1 and high-signal-T2 lesions diffusely distributed on the liver, that were not communicated with the biliary system on magnetic resonance cholangiopancreatography. According to the imaging examination, the patient was considered to have a diagnosis of BH with portal hypertension.

Conclusion: Based on the present case report, BH may be a potential etiology of portal hypertension.
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http://dx.doi.org/10.12998/wjcc.v8.i9.1745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211530PMC
May 2020

ProteoViz: a tool for the analysis and interactive visualization of phosphoproteomics data.

Mol Omics 2020 08 29;16(4):316-326. Epub 2020 Apr 29.

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street (slot 516), Little Rock, AR 72205-7199, USA.

Quantitative proteomics generates large datasets with increasing depth and quantitative information. With the advance of mass spectrometry and increasingly larger data sets, streamlined methodologies and tools for analysis and visualization of phosphoproteomics are needed both at the protein and modified peptide levels. To assist in addressing this need, we developed ProteoViz, which includes a set of R scripts that perform normalization and differential expression analysis of both the proteins and enriched phosphorylated peptides, and identify sequence motifs, kinases, and gene set enrichment pathways. The tool generates interactive visualization plots that allow users to interact with the phosphoproteomics results and quickly identify proteins and phosphorylated peptides of interest for their biological study. The tool also links significant phosphosites with sequence motifs and pathways that will help explain the experimental conditions and guide future experiments. Here, we present the workflow and demonstrate its functionality by analyzing a phosphoproteomic data set from two lymphoma cell lines treated with kinase inhibitors. The scripts and data are freely available at and via the ProteomeXchange with identifier PXD015606.
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http://dx.doi.org/10.1039/c9mo00149bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423749PMC
August 2020

Microwave-assisted efficient and facile synthesis of tetramic acid derivatives via a one-pot post-Ugi cascade reaction.

Beilstein J Org Chem 2020 9;16:663-669. Epub 2020 Apr 9.

College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, China.

A facile microwave-assisted method for the synthesis of tetramic acid derivatives has been developed through an Ugi/Dieckmann cyclization strategy with DBU. This two-step one-pot procedure afforded the targeted tetramic acid analogues in good yields. With commercially available Ugi starting materials, microwave irradiation, a simple operation, excellent yields, and a broad scope, this reaction has the potential to produce a large number of tetramic acid analogues, which cannot be easily accessed by the classic synthetic methods.
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http://dx.doi.org/10.3762/bjoc.16.63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155898PMC
April 2020

Bioisosteric Discovery of NPA101.3, a Second-Generation RET/VEGFR2 Inhibitor Optimized for Single-Agent Polypharmacology.

J Med Chem 2020 05 28;63(9):4506-4516. Epub 2020 Apr 28.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy.

RET receptor tyrosine kinase is a driver oncogene in human cancer. We recently identified the clinical drug candidate Pz-1, which targets RET and VEGFR2. A key metabolite of Pz-1 is its less active demethylated pyrazole analogue. Using bioisosteric substitution methods, here, we report the identification of NPA101.3, lacking the structural liability for demethylation. NPA101.3 showed a selective inhibitory profile and an inhibitory concentration 50 (IC) of <0.003 μM for both RET and VEGFR2. NPA101.3 inhibited phosphorylation of all tested RET oncoproteins as well as VEGFR2 and proliferation of cells transformed by RET. Oral administration of NPA101.3 (10 mg/kg/day) completely prevented formation of tumors induced by RET/C634Y-transformed cells, while it weakened, but did not abrogate, formation of tumors induced by a control oncogene (HRAS/G12V). The balanced synchronous inhibition of both RET and VEGFR2, as well the resistance to demethylation, renders NPA101.3 a potential clinical candidate for RET-driven cancers.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901654PMC
May 2020

MIR210HG promotes cell proliferation and invasion by regulating miR-503-5p/TRAF4 axis in cervical cancer.

Aging (Albany NY) 2020 02 21;12(4):3205-3217. Epub 2020 Feb 21.

Department of Gynecologic and Obstetrics, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan, China.

Long non-coding RNAs (lncRNAs) play important roles in the progression of cervical cancer (CC). However, the roles and underlying molecular mechanisms of lncRNAs in CC remain unclear. In the current study, we discovered a new lncRNA MIR210HG which was upregulated in CC tissues through microarray. The upregulation of MIR210HG was associated with advanced FIGO stage, metastasis, and poor prognosis in CC patients. Function assays showed that MIR210HG inhibition significantly suppressed the proliferation, invasion, and epithelial-mesenchymal transition (EMT) processes in CC and reduced tumor growth in vivo. Mechanistically, we identified that MIR210HG might serve as a competing endogenous RNA (ceRNA) of miR-503-5p to relieve the repressive effect of miR-503-5p on TRAF4 expression in CC cells. In conclusion, we demonstrated that MIR210HG promoted CC progression through regulating the MIR210HG/miR-503-5p/TRAF4 axis, indicating that MIR210HG might act as a novel insight into CC treatment.
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http://dx.doi.org/10.18632/aging.102799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066889PMC
February 2020

Correction: One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction.

Chem Commun (Camb) 2020 Feb 7;56(14):2210. Epub 2020 Feb 7.

College of Pharmacy, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, China.

Correction for 'One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction' by Jie Lei et al., Chem. Commun., 2020, DOI: .
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http://dx.doi.org/10.1039/d0cc90063jDOI Listing
February 2020

Transition State Analogues Enhanced by Fragment-Based Structural Analysis: Bacterial Methylthioadenosine Nucleosidases.

Biochemistry 2020 02 11;59(7):831-835. Epub 2020 Feb 11.

Department of Chemistry , University of Arkansas at Little Rock , Little Rock , Arkansas 72204 , United States.

Transition state analogue inhibitor design (TSID) and fragment-based drug design (FBDD) are drug design approaches typically used independently. Methylthio-DADMe-Immucillin-A (MTDIA) is a tight-binding transition state analogue of bacterial 5'-methylthioadenosine nucleosidases (MTANs). Previously, MTAN structures were found to bind MTDIA and ethylene glycol fragments, but MTDIA modified to contain similar fragments did not enhance affinity. Seventy-five published MTAN structures were analyzed, and co-crystallization fragments were found that might enhance the binding of MTDIA to other bacterial MTANs through contacts external to MTDIA binding. The fragment-modified MTDIAs were tested with Helicobacter pylori MTAN and Staphylococcus aureus MTANs (MTAN and MTAN) as test cases to explore inhibitor optimization by potential contacts beyond the transition state contacts. Replacement of a methyl group with a 2'-ethoxyethanol group in MTDIA improved the dissociation constant 14-fold (0.09 nM vs 1.25 nM) for MTAN and 81-fold for MTAN (0.096 nM vs 7.8 nM). TSID combined with FBDD can be useful in enhancing already powerful inhibitors.
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http://dx.doi.org/10.1021/acs.biochem.9b01092DOI Listing
February 2020

The Skp2 Pathway: A Critical Target for Cancer Therapy.

Semin Cancer Biol 2020 12 1;67(Pt 2):16-33. Epub 2020 Feb 1.

Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC, 27101, USA; Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan. Electronic address:

Strictly regulated protein degradation by ubiquitin-proteasome system (UPS) is essential for various cellular processes whose dysregulation is linked to serious diseases including cancer. Skp2, a well characterized component of Skp2-SCF E3 ligase complex, is able to conjugate both K48-linked ubiquitin chains and K63-linked ubiquitin chains on its diverse substrates, inducing proteasome mediated proteolysis or modulating the function of tagged substrates respectively. Overexpression of Skp2 is observed in various human cancers associated with poor survival and adverse therapeutic outcomes, which in turn suggests that Skp2 engages in tumorigenic activity. To that end, the oncogenic properties of Skp2 are demonstrated by various genetic mouse models, highlighting the potential of Skp2 as a target for tackling cancer. In this article, we will describe the downstream substrates of Skp2 as well as upstream regulators for Skp2-SCF complex activity. We will further summarize the comprehensive oncogenic functions of Skp2 while describing diverse strategies and therapeutic platforms currently available for developing Skp2 inhibitors.
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http://dx.doi.org/10.1016/j.semcancer.2020.01.013DOI Listing
December 2020

One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction.

Chem Commun (Camb) 2020 Feb 23;56(14):2194-2197. Epub 2020 Jan 23.

College of Pharmacy, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, China.

An Ugi, novel pseudo-Knoevenagel, ring expansion cascade reaction was discovered and utilized for the synthesis of aziridinyl succinimides in one-pot. Subsequently, densely functionalized aziridines and maleimides have been designed and synthesized through similar cascade reactions. The target compounds were prepared by means of a mild reaction and a simple operation procedure, which could be applicable to a broad scope of starting materials. This series of novel cascade reactions generates opportunities for the tailored synthesis of a wide range of biologically active scaffolds through tuneable Ugi inputs. Discovery of compound 8i with comparable potency to sorafenib in liver cancer cell lines could provide a new avenue for liver cancer drug discovery.
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http://dx.doi.org/10.1039/c9cc08220dDOI Listing
February 2020

One-step generation of zebrafish carrying a conditional knockout-knockin visible switch via CRISPR/Cas9-mediated intron targeting.

Sci China Life Sci 2020 Jan 20;63(1):59-67. Epub 2019 Dec 20.

Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Chinese Academy of Sciences, Shanghai, 200031, China.

The zebrafish has become a popular vertebrate animal model in biomedical research. However, it is still challenging to make conditional gene knockout (CKO) models in zebrafish due to the low efficiency of homologous recombination (HR). Here we report an efficient non-HR-based method for generating zebrafish carrying a CKO and knockin (KI) switch (zCKOIS) coupled with dual-color fluorescent reporters. Using this strategy, we generated hey2 which served as a hey2 KI reporter with EGFP expression. Upon Cre induction in targeted cells, the hey2 was switched to a non-functional CKO allele hey2associated with TagRFP expression, enabling visualization of the CKO alleles. Thus, simplification of the design, and the visibility and combination of both CKO and KI alleles make our zCKOIS strategy an applicable CKO approach for zebrafish.
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http://dx.doi.org/10.1007/s11427-019-1607-9DOI Listing
January 2020

Structural Characterization of the Aurora Kinase B "DFG-flip" Using Metadynamics.

AAPS J 2019 12 18;22(1):14. Epub 2019 Dec 18.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.

Aurora kinase B (AKB), a Ser/Thr kinase that plays a crucial role in mitosis, is overexpressed in several cancers. Clinical inhibitors targeting AKB bind to the active DFG "in" conformation of the kinase. It would be beneficial, however, to understand if AKB is susceptible to type II kinase inhibitors that bind to the inactive, DFG "out" conformation, since type II inhibitors achieve higher kinome selectivity and higher potency in vivo. The DFG "out" conformation of AKB is not yet experimentally determined which makes the design of type II inhibitors exceedingly difficult. An alternate approach is to simulate the DFG "out" conformation from the experimentally determined DFG "in" conformation using atomistic molecular dynamics (MD) simulation. In this work, we employed metadynamics (MTD) approach to simulate the DFG "out" conformation of AKB by choosing the appropriate collective variables. We examined structural changes during the DFG-flip and determined the interactions crucial to stabilize the kinase in active and inactive states. Interestingly, the MTD approach also identified a unique transition state (DFG "up"), which can be targeted by small molecule inhibitors. Structural insights about these conformations is essential for structure-guided design of next-generation AKB inhibitors. This work also emphasizes the usefulness of MTD simulations in predicting macromolecular conformational changes at reduced computational costs.
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http://dx.doi.org/10.1208/s12248-019-0399-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905835PMC
December 2019

[Impact of Non-middle Hepatic Vein Reconstruction on the Result of Low Graft-to-recipient Weight Ratio Living Donor Liver Transplantation].

Sichuan Da Xue Xue Bao Yi Xue Ban 2019 Sep;50(5):760-764

Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China.

Objective: To analyze of the minimum graft-to-recipient weight ratio (GRWR) required for living donor liver transplantation (LDLT) without middle hepatic vein branch (MHVT) reconstruction.

Methods: We retrospectively collected the clinical data and outcomes of 303 LDLT patients over 16 years from 2001 to 2017. The minimum GRWR of non-middle hepatic vein reconstruction was analyzed by propensity score (PSM).

Results: With PSM analysis, no significant differences were observed in postoperative complications, SFSS, inpatient time, liver function, and coagulation function, but significant differences in 1-year, 3-year and 5-year survival between MHVT reconstruction and non-reconstruction group. The patients with MHVT reconstruction had better short-term and long-term survival than those without reconstruction.

Conclusion: For LDLT patients without HMVT reconstruction, GRWR should be greater than 0.86%; for patients with HMVT reconstruction, GRWR is acceptable between 0.5% and 0.6%.
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September 2019

The Exploration of Chirality for Improved Druggability within the Human Kinome.

J Med Chem 2020 01 9;63(2):441-469. Epub 2019 Oct 9.

Department of Pharmaceutical Sciences, College of Pharmacy , University of Arkansas for Medical Sciences , Little Rock , Arkansas 72205 , United States.

Chirality is important in drug discovery because stereoselective drugs can ameliorate therapeutic difficulties including adverse toxicity and poor pharmacokinetic profiles. The human kinome, a major druggable enzyme class has been exploited to treat a wide range of diseases. However, many kinase inhibitors are planar and overlap in chemical space, which leads to selectivity and toxicity issues. By exploring chirality within the kinome, a new iteration of kinase inhibitors is being developed to better utilize the three-dimensional nature of the kinase active site. Exploration into novel chemical space, in turn, will also improve drug solubility and pharmacokinetic profiles. This perspective explores the role of chirality to improve kinome druggability and will serve as a resource for pioneering kinase inhibitor development to address current therapeutic needs.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00640DOI Listing
January 2020