Publications by authors named "Hailin Zhang"

260 Publications

Case Report: Hemoptysis Caused by Pulmonary Tuberculosis Complicated With Bronchial Artery-Pulmonary Artery Fistula in Children.

Front Pediatr 2021 11;9:587342. Epub 2021 Feb 11.

Department of Pediatric Pulmonology, The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.

Bronchial artery-pulmonary artery fistula secondary to pulmonary tuberculosis is an important cause of hemoptysis in adults, but it's relatively rare in children. Bronchial artery-pulmonary artery fistulas are mostly congenital in children and may have no clinical manifestations in the early stage. Congenital bronchial artery-pulmonary fistula with pulmonary tuberculosis can lead to hemoptysis. From 2016 to 2020, two children with pulmonary tuberculosis complicated with bronchial artery and pulmonary artery fistula were admitted and treated in our hospital. We reminded pediatricians to pay attention to a variety of etiology combined with the possibility of children's hemoptysis.
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http://dx.doi.org/10.3389/fped.2021.587342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904673PMC
February 2021

Development of a rapid field testing method for metals in horizontal directional drilling residuals with XRF sensor.

Sci Rep 2021 Feb 16;11(1):3901. Epub 2021 Feb 16.

U.S. Department of Agriculture, National Soil Erosion Research, West Lafayette, IN, 479072077, USA.

Portable X-ray fluorescence (pXRF) spectrometer allows fast in-situ elemental determination without wet digestion for soils or geological materials, but the use of XRF on wet materials is not well documented. Our objective was to develop a rapid field method using pXRF to measure metals in the residues from horizontal directional drilling (HDD) operations so that proper disposal decisions can be made in-situ. To establish the procedure, we spiked soil samples with 4 concentrations of Cr, Ni, Cu, Zn, As, Cd, and Pb up to 1000 mg kg, and then the metal concentrations were determined by wet chemical method after drying and acid digestion (standard method), and by pXRF, also at laboratory conditions, after drying and at two different moisture conditions. The measurements by pXRF and standard method after drying and after removal of excess water (AREW) were highly correlated with slopes ranging from 0.83 ± 0.01 to 1.08 ± 0.01 (P < 0.001) for all metals. The relationship was better AREW than the saturated paste without removal of excess water and the moisture content affected only the accuracy of As, Cd, and Pb. The procedure established was successfully used for HDD residues collected from 26 states of US with moisture content ranging from 14 to 83% AREW. The pXRF was proven to be a reliable tool for fast detection of common metals in dried soils and HDD residues, and samples containing < 30% moisture content without needing to correct for moisture. If the moisture is > 30%, excess water in samples need to be removed with a commercially available filter press to achieve high accuracy. The developed procedures reduce time of metal detection from days to about an hour which allows drilling operators to make quick decisions on soil or HDD disposal.
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http://dx.doi.org/10.1038/s41598-021-83584-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887265PMC
February 2021

Enhanced antitumor efficacy of a novel oncolytic vaccinia virus encoding a fully monoclonal antibody against T-cell immunoglobulin and ITIM domain (TIGIT).

EBioMedicine 2021 Feb 10;64:103240. Epub 2021 Feb 10.

Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China. Electronic address:

Background: Oncolytic virotherapy with vaccinia virus (VV) can lead to effective anti-tumor immunity by turning "cold" tumors into "hot" tumors. However, its therapeutic potential is affected by the tumor's local immunosuppressive tumor microenvironment (TME). Therefore, it is necessary to explore the use of immune checkpoint inhibitors to arm oncolytic VVs to enhance their anti-tumor efficacy.

Methods: A novel recombinant oncolytic VV, VV-α-TIGIT, which encoded a fully monoclonal antibody against T-cell immunoglobulin and ITIM domain (TIGIT) was generated by homologous recombination with a shuttle plasmid. The anti-tumor efficacy of the VV-α-TIGIT was investigated in several subcutaneous and ascites tumor models.

Findings: The functional α-TIGIT was sufficiently produced and secreted by tumor cells infected with VV-α-TIGIT, which effectively replicated in tumor cells leading to significant oncolysis. Intratumoral injection of VV-α-TIGIT improved anti-tumor efficacy in several murine subcutaneous tumor models compared to VV-Control (without α-TIGIT insertion). Intraperitoneal injection of VV-α-TIGIT achieved approximately 70% of complete tumor regression in an ascites tumor model. At the same time, treatment with VV-α-TIGIT significantly increased the recruitment and activation of T cells in TME. Moreover, the in vivo anti-tumor activity of VV-α-TIGIT was largely dependent on CD8 T cell-mediated immunity. Finally, the tumor-bearing mice cured of VV-α-TIGIT treatment resisted rechallenge with the same tumor cells, suggesting a long-term persistence of tumor-specific immunological memory.

Interpretation: The recombinant oncolytic virus VV-α-TIGIT successfully combines the advantages of oncolytic virotherapy and intratumorally expression of immune checkpoint inhibitor against TIGIT. This novel strategy can provide information on the optimal design of novel antibody-armed oncolytic viruses for cancer immunotherapy.

Funding: This work was supported by the National Natural Science Foundation of China (81773255, 81472820, and 81700037), the Science and Technology Innovation Foundation of Nanjing University (14913414), and the Natural Science Foundation of Jiangsu Province of China (BK20171098).
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http://dx.doi.org/10.1016/j.ebiom.2021.103240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878184PMC
February 2021

Recombinant oncolytic adenovirus expressing a soluble PVR elicits long-term antitumor immune surveillance.

Mol Ther Oncolytics 2021 Mar 17;20:12-22. Epub 2020 Nov 17.

Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.

Oncolytic virotherapy (OVT) has been suggested to be effective. However, the suppressive effects of checkpoints and insufficient costimulatory signals limit OVT-induced antitumor immune responses. In this study, we constructed a replicative adenovirus, Ad5sPVR, that expresses the soluble extracellular domain of poliovirus receptor (sPVR). We showed that sPVR can bind to both T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and CD226, and the binding affinity of sPVR to TIGIT is stronger than that of PVR to CD226. In the H22 hepatocellular carcinoma (HCC) ascites model, Ad5sPVR treatment increased the infiltration of CD8 T cells and the release of interferon (IFN)-γ, exhibiting an antitumor effect with long-term tumor-specific immune surveillance. In line with this, Ad5sPVR also effectively improved antitumor outcomes in solid tumors. In conclusion, while Ad5sPVR plays a role in oncolysis and transforms cold tumors into hot tumors, sPVR expressed by Ad5sPVR can block the PVR/TIGIT checkpoint and activate CD226, thereby greatly improving the efficacy of OVT. This study provides a new way to develop potential oncolytic viral drugs.
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http://dx.doi.org/10.1016/j.omto.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851489PMC
March 2021

Distribution of β-Lactamase Genes and Genetic Context of in Clinical Carbapenemase-Producing Isolates.

Infect Drug Resist 2021 26;14:237-247. Epub 2021 Jan 26.

The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325027, People's Republic of China.

Background: This study was designed to characterize the dissemination mechanism and genetic context of carbapenemase (KPC) genes in carbapenem-resistant (CRKP) isolates.

Methods: A retrospective analysis was performed on CRKP strains isolated from a teaching hospital of Wenzhou Medical University during 2015-2017. Polymerase chain reaction (PCR)-based amplification and whole-genome sequencing (WGS) were used to analyze the genetic context of the gene. Conjugation experiments were performed to evaluate the transferability of -bearing plasmids. Multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were performed to investigate the clonal relatedness of -producing strains.

Results: The gene was identified from 13.61% (40/294) of clinical isolates. Three different sequence types (ST11, ST15 and ST656) and 5 PFGE subtypes (A to E) were classified among them. ST11 was the dominant sequence type (92.50%, 37/40). Plasmid-oriented antibiotic resistance genes, such as extended spectrum-β-lactamases (ESBLs) and other antimicrobial resistance genes, were also found in KPC-positive (KPC-) isolates. Mapping PCR and genomic sequencing revealed that the -bearing sequence regions, which are related to different mobile elements, including Tn1721- and IS26-based transposons, were mainly located in but not restricted to IncFII-like plasmids and were structurally divergent.

Conclusion: The genes related to divergent mobile genetic elements encoded on transferable plasmids may transfer widely, facilitating the spread of carbapenem resistance among bacteria with different genetic backgrounds. The dissemination of -bearing plasmids that collectively carry additional multidrug resistance genes has caused widespread public concern, further limiting the antibiotics available to treat infections caused by KPC-producing pathogens.
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http://dx.doi.org/10.2147/IDR.S290434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847768PMC
January 2021

The Development and Initial Validation of PUMC Localized Scleroderma Facial Aesthetic Index: A Pilot Study.

Aesthetic Plast Surg 2021 Jan 15. Epub 2021 Jan 15.

Department of Dermatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Background: Localized scleroderma (LoS) is an autoimmune connective tissue disorder leading to serious long-term aesthetic impairment on patients. Objective evaluation methods are badly needed to facilitate the evaluation of the surgical treatment on individual patients and clinical studies.

Objective: To develop and assess the reliability and validity of Peking Union Medical College LoS facial aesthetic index (PUMC LoSFAI).

Methods: Twelve experts devoted their time and resources in the development and validation. LoS patients in the stable phase were recruited. Reliability and validity was then assessed. LoS patients were evaluated by two plastic surgeons using PUMC LoSFAI and LoS skin damage index (LoSDI). The PUMC LoSFAI comprises 4 domains for the local assessment (surface area of lesion, dyspigmentation, skin thickness and soft tissue atrophy) and 3 domains for the overall assessment (facial symmetry, proportion and profile) to describe LoS facial aesthetic impairment. Face-Q was completed by patients at each visit.

Results: Thirty-two LoS patients had 96 visits, during which 138 lesions were assessed. PUMC LoSFAI and 7 domains demonstrated substantial to excellent inter- and intra-rater reliability (ICC 0.995, κ 0.72-0.91, r 0.85-0.99, respectively). Seven domains considered to be important to extremely important variables (mean rank 3.2-3.8) had high I-CVI (> 0.78) and S-CVI (0.93). PUMC LoSFAI correlated excellently with LoSDI (r = 0.933, P < 0.001), and correlated fairly with Face-Q (r = - 0.399, P = 0.001).

Conclusions: PUMC LoSFAI was developed and evaluated to play as a tool of aesthetic impairment assessment for LoS patients, which may facilitate the evaluation of the treatment on individual patients and clinical studies. PUMC LoSFAI demonstrated high reliability and validity, and further study in larger patient samples is needed to confirm these preliminary findings.

Level Of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266 .
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http://dx.doi.org/10.1007/s00266-020-02111-4DOI Listing
January 2021

Characterization of florfenicol resistance genes in the coagulase-negative Staphylococcus (CoNS) isolates and genomic features of a multidrug-resistant Staphylococcus lentus strain H29.

Antimicrob Resist Infect Control 2021 01 7;10(1). Epub 2021 Jan 7.

School of Laboratory Medicine and Life Science/Institute of Biomedical Informatics, Wenzhou Medical University, Chashan University Town, Wenzhou, 325035, Zhejiang, China.

Background: With the wide use of florfenicol to prevent and treat the bacterial infection of domestic animals, the emergence of the florfenicol resistance bacteria is increasingly serious. It is very important to elucidate the molecular mechanism of the bacteria's resistance to florfenicol.

Methods: The minimum inhibitory concentration (MIC) levels were determined by the agar dilution method, and polymerase chain reaction was conducted to analyze the distribution of florfenicol resistance genes in 39 CoNS strains isolated from poultry and livestock animals and seafood. The whole genome sequence of one multidrug resistant strain, Staphylococcus lentus H29, was characterized, and comparative genomics analysis of the resistance gene-related sequences was also performed.

Results: As a result, the isolates from the animals showed a higher resistance rate (23/28, 82.1%) and much higher MIC levels to florfenicol than those from seafood. Twenty-seven animal isolates carried 37 florfenicol resistance genes (including 26 fexA, 6 cfr and 5 fexB genes) with one carrying a cfr gene, 16 each harboring a fexA gene, 5 with both a fexA gene and a fexB gene and the other 5 with both a fexA gene and a cfr gene. On the other hand, all 11 isolates from seafood were sensitive to florfenicol, and only 3 carried a fexA gene each. The whole genome sequence of S. lentus H29 was composed of a chromosome and two plasmids (pH29-46, pH29-26) and harbored 11 resistance genes, including 6 genes [cfr, fexA, ant(6)-Ia, aacA-aphD, mecA and mph(C)] encoded on the chromosome, 4 genes [cfr, fexA, aacA-aphD and tcaA] on pH29-46 and 1 gene (fosD) on pH29-26. We found that the S. lentus H29 genome carried two identical copies of the gene arrays of radC-tnpABC-hp-fexA (5671 bp) and IS256-cfr (2690 bp), of which one copy of the two gene arrays was encoded on plasmid pH29-46, while the other was encoded on the chromosome.

Conclusions: The current study revealed the wide distribution of florfenicol resistance genes (cfr, fexA and fexB) in animal bacteria, and to the best of our knowledge, this is the first report that one S. lentus strain carried two identical copies of florfenicol resistance-related gene arrays.
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http://dx.doi.org/10.1186/s13756-020-00869-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791814PMC
January 2021

Piezo2 channel in nodose ganglia neurons is essential in controlling hypertension in a pathway regulated directly by Nedd4-2.

Pharmacol Res 2021 Feb 19;164:105391. Epub 2020 Dec 19.

Department of Pharmacology, Center of Innovative Drug Research and Evaluation, Institute of Medical Science and Health, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China. Electronic address:

Baroreflex plays a crucial role in regulation of arterial blood pressure (BP). Recently, Piezo1 and Piezo2, the mechanically-activated (MA) ion channels, have been identified as baroreceptors. However, the underlying molecular mechanism for regulating these baroreceptors in hypertension remains unknown. In this study, we used spontaneously hypertensive rats (SHR) and NG-Nitro-l-Arginine (L-NNA)- and Angiotensin II (Ang II)-induced hypertensive model rats to determine the role and mechanism of Piezo1 and Piezo2 in hypertension. We found that Piezo2 was dominantly expressed in baroreceptor nodose ganglia (NG) neurons and aortic nerve endings in Wistar-Kyoto (WKY) rats. The expression of Piezo2 not Piezo1 was significantly downregulated in these regions in SHR and hypertensive model rats. Electrophysiological results showed that the rapidly adapting mechanically-activated (RA-MA) currents and the responsive neuron numbers were significantly reduced in baroreceptor NG neurons in SHR. In WKY rats, the arterial BP was elevated by knocking down the expression of Piezo2 or inhibiting MA channel activity by GsMTx4 in NG. Knockdown of Piezo2 in NG also attenuated the baroreflex and increased serum norepinephrine (NE) concentration in WKY rats. Co-immunoprecipitation experiment suggested that Piezo2 interacted with Neural precursor cell-expressed developmentally downregulated gene 4 type 2 (Nedd4-2, also known as Nedd4L); Electrophysiological results showed that Nedd4-2 inhibited Piezo2 MA currents in co-expressed HEK293T cells. Additionally, Nedd4-2 was upregulated in NG baroreceptor neurons in SHR. Collectively, our results demonstrate that Piezo2 not Piezo1 may act as baroreceptor to regulate arterial BP in rats. Nedd4-2 induced downregulation of Piezo2 in baroreceptor NG neurons leads to hypertension in rats. Our findings provide a novel insight into the molecular mechanism for the regulation of baroreceptor Piezo2 and its critical role in the pathogenesis of hypertension.
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http://dx.doi.org/10.1016/j.phrs.2020.105391DOI Listing
February 2021

ATB-targeted delivery of triptolide prodrugs for safer and more effective pancreatic cancer therapy.

Bioorg Med Chem Lett 2021 Feb 17;33:127728. Epub 2020 Dec 17.

Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Wenzhou 325027, China. Electronic address:

Triptolide (TP) is a diterpene epoxide component extracted from Tripterygium wilfordii and has been shown to possess an impressive anticancer effect. However, TP has not yet entered any clinic trials due to the severe adverse effects that resulted from the off-target absorption and distribution found in animal studies. In this study, we designed and synthesized three amino acids (tryptophan, valine, and lysine) based TP prodrugs to target ATB which are highly expressed in pancreatic cancer cells for more effective pancreatic cancer therapy. The stability, uptake profiles, uptake mechanism, and cancer-killing ability were studied in vitro. All three prodrugs showed increased uptake and enhanced cytotoxicity in pancreatic cancer cells, but not in normal pancreatic cells. The difference in killing effect on normal and cancer cells was attributed to pancreatic cancer over-expressed ATB-mediated uptake. Specifically, tryptophan-conjugated TP prodrug (TP-Trp) showed the highest uptake and the best cancer cell killing effect, considered as the best candidate. The present study provided the proof-of-concept of exploiting TP prodrug to target ATB for pancreatic cancer-selective delivery and treatment.
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http://dx.doi.org/10.1016/j.bmcl.2020.127728DOI Listing
February 2021

Drug discovery and formulation development for acute pancreatitis.

Drug Deliv 2020 Dec;27(1):1562-1580

Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Acute pancreatitis is a sudden inflammation and only last for a short time, but might lead to a life-threatening emergency. Traditional drug therapy is an essential supportive method for acute pancreatitis treatment, yet, failed to achieve satisfactory therapeutic outcomes. To date, it is still challenging to develop therapeutic medicine to redress the intricate microenvironment promptly in the inflamed pancreas, and more importantly, avoid multi-organ failure. The understanding of the acute pancreatitis, including the causes, mechanism, and severity judgment, could help the scientists bring up more effective intervention and treatment strategies. New formulation approaches have been investigated to precisely deliver therapeutics to inflammatory lesions in the pancreas, and some even could directly attenuate the pancreatic damages. In this review, we will briefly introduce the involved pathogenesis and underlying mechanisms of acute pancreatitis, as well as the traditional Chinese medicine and the new drug option. Most of all, we will summarize the drug delivery strategies to reduce inflammation and potentially prevent the further development of pancreatitis, with an emphasis on the bifunctional nanoparticles that act as both drug delivery carriers and therapeutics.
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http://dx.doi.org/10.1080/10717544.2020.1840665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598990PMC
December 2020

Pseudomonas species isolated via high-throughput screening significantly protect cotton plants against verticillium wilt.

AMB Express 2020 Oct 28;10(1):193. Epub 2020 Oct 28.

College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310058, China.

Verticillium wilt (VW) caused by Verticillium dahliae is a devastating soil-borne disease that causes severe yield losses in cotton and other major crops worldwide. Here we conducted a high-throughput screening of isolates recovered from 886 plant rhizosphere samples taken from the three main cotton-producing areas of China. Fifteen isolates distributed in different genera of bacteria that showed inhibitory activity against V. dahliae were screened out. Of these, two Pseudomonas strains, P. protegens XY2F4 and P. donghuensis 22G5, showed significant inhibitory action against V. dahliae. Additional comparative genomic analyses and phenotypical assays confirmed that P. protegens XY2F4 and P. donghuensis 22G5 were the strains most efficient at protecting cotton plants against VW due to specific biological control products they produced. Importantly, we identified a significant efficacy of the natural tropolone compound 7-hydroxytropolone (7-HT) against VW. By phenotypical assay using the wild-type 22G5 and its mutant strain in 7-HT production, we revealed that the 7-HT produced by P. donghuensis is the major substance protecting cotton against VW. This study reveals that Pseudomonas specifically has gene clusters that allow the production of effective antipathogenic metabolites that can now be used as new agents in the biocontrol of VW.
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http://dx.doi.org/10.1186/s13568-020-01132-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593376PMC
October 2020

Codon optimization with deep learning to enhance protein expression.

Sci Rep 2020 10 19;10(1):17617. Epub 2020 Oct 19.

Chengdu Institute of Computer Applications, Chinese Academy of Sciences, Chengdu, 610041, China.

Heterologous expression is the main approach for recombinant protein production ingenetic synthesis, for which codon optimization is necessary. The existing optimization methods are based on biological indexes. In this paper, we propose a novel codon optimization method based on deep learning. First, we introduce the concept of codon boxes, via which DNA sequences can be recoded into codon box sequences while ignoring the order of bases. Then, the problem of codon optimization can be converted to sequence annotation of corresponding amino acids with codon boxes. The codon optimization models for Escherichia Coli were trained by the Bidirectional Long-Short-Term Memory Conditional Random Field. Theoretically, deep learning is a good method to obtain the distribution characteristics of DNA. In addition to the comparison of the codon adaptation index, protein expression experiments for plasmodium falciparum candidate vaccine and polymerase acidic protein were implemented for comparison with the original sequences and the optimized sequences from Genewiz and ThermoFisher. The results show that our method for enhancing protein expression is efficient and competitive.
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http://dx.doi.org/10.1038/s41598-020-74091-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572362PMC
October 2020

The roles of co-composted biochar (COMBI) in improving soil quality, crop productivity, and toxic metal amelioration.

J Environ Manage 2021 Jan 10;277:111443. Epub 2020 Oct 10.

Plant and Soil Sciences Department, Oklahoma State University, 371 Agricultural Hall, Stillwater, OK, 74078, USA.

The use of co-composted biochar (COMBI) made by the addition of biochar at the beginning of the composting process has greatly increased in agriculture during the last decade. There are more benefits of using the co-composting end product COMBI than using compost and biochar separately or the mixture of the two products. We conducted an extensive review of the production of several COMBIs and their contribution to the composting process and biochar properties as well as the further use of COMBIs in agricultural lands to improve soil health and increase crop yields, and to remediate areas severely contaminated with potentially toxic metals (PTMs). Although the number of researches focused on COMBI production and its application is so far limited, there is enough evidence to elucidate the importance of creating such products to promote sustainable agriculture and environmental safety. Even if a few drawbacks or side effects are found, they are outweighed by the many benefits achieved with COMBIs production and application in comparison to other amendments. The quality of both biochar and compost is largely improved in so many ways during the co-composting process, which in turn improved soil health and crop yields of up to 300% in some particular cases. This work improved the overall understanding of COMBI production and application in agriculture. Based on the review, we suggested future researches to better understand the mechanisms of COMBI long-term application to promote awareness on its role over time through alterations in its surface chemistry, ionic nutrient adsorption, supply (aging effect), and environmental implications.
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http://dx.doi.org/10.1016/j.jenvman.2020.111443DOI Listing
January 2021

Extracellular Vesicles-Mimetic Encapsulation Improves Oncolytic Viro-Immunotherapy in Tumors With Low Coxsackie and Adenovirus Receptor.

Front Bioeng Biotechnol 2020 16;8:574007. Epub 2020 Sep 16.

Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.

The oncolytic adenovirus (Adv) exhibited poor infection efficiency in tumor cells with low coxsackie and adenovirus receptor (CAR) on the cell surface, which limits the therapeutic efficacy of the Adv-mediated cancer gene therapy. In addition, the abundant adenovirus neutralizing antibodies also abrogate the viral infection of cancer cells. Therefore, novel strategies are required to overcome these two major hurdles to improve the Adv-mediated cancer virotherapy. We constructed a recombinant adenovirus expressing the extracellular domain of PD1 (Ad5-P). The 293T cells expressing VSV-G protein on the cell surface (293T-VSV-G) were infected with Ad5-P. Then Ad5-P infected 293T-VSV-G cells were harvested and squeezed stepwisely through a serial of polycarbonate membranes. Next, the extracellular vesicles-mimetic (EVM) encapsulated Ad5-P (EVM/VSV-G Ad5-P) were collected by density gradient centrifugation. In cell lines with low CAR expression, EVM/VSV-G Ad5-P showed a significantly improved infection efficiency, oncolytic ability, and soluble PD-1 production. In passively immunized mice with Ad5 neutralizing antibody, EVM/VSV-G Ad5-P successfully escaped from antibodies, and the soluble PD-1expression of Ad5-P was significantly prolonged. Finally, EVM/VSV-G Ad5-P treatment significantly improved the antitumor immune responses and prolonged survival of mice with HCC ascites. The EVM/VSV-G Ad5-P not only bypasses the limitation of low CAR expression in tumor cells to improve the viral entry, but also significantly protects the virus from the neutralization antibodies. The EVM encapsulation technology can be successfully used for loading of non-enveloped viruses to generate the extracellular vesicle-mimetic encapsulated viral particles. Our results provide a novel strategy in OVs manufacture to improve the efficacy of tumor oncolytic virotherapy.
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http://dx.doi.org/10.3389/fbioe.2020.574007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525182PMC
September 2020

Transporter-Targeted Nano-Sized Vehicles for Enhanced and Site-Specific Drug Delivery.

Cancers (Basel) 2020 Oct 1;12(10). Epub 2020 Oct 1.

Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang 325027, China.

Nano-devices are recognized as increasingly attractive to deliver therapeutics to target cells. The specificity of this approach can be improved by modifying the surface of the delivery vehicles such that they are recognized by the target cells. In the past, cell-surface receptors were exploited for this purpose, but plasma membrane transporters also hold similar potential. Selective transporters are often highly expressed in biological barriers (e.g., intestinal barrier, blood-brain barrier, and blood-retinal barrier) in a site-specific manner, and play a key role in the vectorial transfer of nutrients. Similarly, selective transporters are also overexpressed in the plasma membrane of specific cell types under pathological states to meet the biological needs demanded by such conditions. Nano-drug delivery systems could be strategically modified to make them recognizable by these transporters to enhance the transfer of drugs across the biological barriers or to selectively expose specific cell types to therapeutic drugs. Here, we provide a comprehensive review and detailed evaluation of the recent advances in the field of transporter-targeted nano-drug delivery systems. We specifically focus on areas related to intestinal absorption, transfer across blood-brain barrier, tumor-cell selective targeting, ocular drug delivery, identification of the transporters appropriate for this purpose, and details of the rationale for the approach.
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http://dx.doi.org/10.3390/cancers12102837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599460PMC
October 2020

Liraglutide activates nature killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma.

Transl Oncol 2021 Jan 23;14(1):100872. Epub 2020 Sep 23.

Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. Electronic address:

Inflammatory IL-6/STAT3 signaling is constitutively activated in diverse cancers and is associated with malignant cell proliferation, invasion and escape of antitumor immunosurveillance. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is commonly used to treat insulin-resistant diabetes. In this study, for the first time, we showed that liraglutide remarkably improved the antitumor immune responses in hepatocellular carcinoma (HCC). Furthermore, we showed that the antitumor activity was mediated by nature killer cells (NKs) but not CD8 T cells. Finally, we showed that liraglutide enhanced NK-mediated cytotoxicity by suppressing the IL-6/STAT3 signaling pathway in HCC cells. Our findings unveil a novel therapeutic role of liraglutide by manipulating the innate immunity in cancer therapy.
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http://dx.doi.org/10.1016/j.tranon.2020.100872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516274PMC
January 2021

Characterization of a Novel Chromosomal Class C β-Lactamase, YOC-1, and Comparative Genomics Analysis of a Multidrug Resistance Plasmid in W13.

Front Microbiol 2020 20;11:2021. Epub 2020 Aug 20.

The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.

, a member of the family Enterobacteriaceae, is usually isolated from environmental samples and generally resistant to early generations of cephalosporins. To characterize the resistance mechanism of strain W13 isolated from the sewage of an animal farm, whole genome sequencing, comparative genomics analysis and molecular cloning were performed. The results showed that a novel chromosomally encoded class C β-lactamase gene with the ability to confer resistance to β-lactam antibiotics, designated , was identified in the genome of W13. Kinetic analysis revealed that the β-lactamase YOC-1 has a broad spectrum of substrates, including penicillins, cefazolin, cefoxitin and cefotaxime. The two functionally characterized β-lactamases with the highest amino acid identities to YOC-1 were CDA-1 (71.69%) and CMY-2 (70.65%). The genetic context of the -encoding region was unique compared with the sequences in the NCBI nucleotide database. The plasmid pRYW13-125 of W13 harbored 11 resistance genes (, , , , , , , , , and ) within an ∼34 kb multidrug resistance region; these genes were all related to mobile genetic elements. The multidrug resistance region of pYRW13-125 shared the highest identities with those of two plasmids from clinical isolates, indicating the possibility of horizontal transfer of these resistance genes between bacteria of various origins.
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http://dx.doi.org/10.3389/fmicb.2020.02021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468467PMC
August 2020

Activation of TMEM16A by natural product canthaxanthin promotes gastrointestinal contraction.

FASEB J 2020 Oct 19;34(10):13430-13444. Epub 2020 Aug 19.

Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin, China.

Transmembrane 16A (TMEM16A), also known as anoctamin 1, is the molecular basis of the calcium-activated chloride channels. TMEM16A is present in interstitial cells of Cajal, which are the pacemaker cells that control smooth muscle contraction. TMEM16A is implicated in gastrointestinal disorders. Activation of TMEM16A is believed to promote the gastrointestinal muscle contraction. Here, we report a highly efficient, nontoxic, and selective activator of TMEM16A, canthaxanthin (CX). The study using molecular docking and site-directed mutation revealed that CX-specific binging site in TMEM16A is K769. CX was also found to promote the contraction of smooth muscle cells in gastrointestinal tract through activation of TMEM16A channels, which provides an excellent basis for development of CX as a chemical tool and potential therapeutic for gastrointestinal dysfunction.
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http://dx.doi.org/10.1096/fj.202000443RRDOI Listing
October 2020

Keystone-designed perforator island flaps for reconstruction after chest keloid excision: A retrospective case series.

J Cosmet Dermatol 2021 Mar 10;20(3):937-942. Epub 2020 Sep 10.

Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.

Objective: We retrospectively evaluated the efficacy and safety of keystone-designed perforator island flaps for chest keloid reconstruction.

Methods: We reviewed consecutive patients who received keystone flap reconstruction after chest keloid resection between January 2017 and February 2018. The patient demographic data, defect size, flap size, complications, and recurrence were recorded.

Results: Thirty-eight patients were evaluated in this retrospective case series. After keloid resection, dimension of wound defects was 5.5-9.5 cm × 9.5-12.5 cm, with an average dimension of 7.3 cm × 10.7 cm. The dimension of keystone flaps was between 6-10 cm × 20-34.5 cm, with an average dimension of 7.5 cm × 25.5 cm. The flaps healed smoothly without any complication. There was no keloid recurrence with 15 months of follow-up. 89.4% of the patients had good outcome with no apparent scarring, and 10.6% patients had satisfactory outcome with localized scarring.

Conclusions: Keystone-designed perforator island flap is an effective and reliable method for reconstruction following chest keloid resection.
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http://dx.doi.org/10.1111/jocd.13684DOI Listing
March 2021

Discovery of Potent Small-Molecule SIRT6 Activators: Structure-Activity Relationship and Anti-Pancreatic Ductal Adenocarcinoma Activity.

J Med Chem 2020 09 9;63(18):10474-10495. Epub 2020 Sep 9.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.

SIRT6 activation is thought to be a promising target for the treatment of many diseases, particularly cancer. Herein, we report the discovery of a series of new small-molecule SIRT6 activators. Structure-activity relationship analyses led to the identification of the most potent compound, 2-(1-benzofuran-2-yl)--(diphenylmethyl) quinoline-4-carboxamide (), which showed an EC value of 0.58 ± 0.12 μM and an EC value of 5.35 ± 0.69 μM against SIRT6-dependent peptide deacetylation in FLUOR DE LYS assay. It exhibited weak or no activity against other HDAC family members as well as 415 kinases, indicating good selectivity for SIRT6. significantly inhibited the proliferation and migration of pancreatic ductal adenocarcinoma (PDAC) cells . It also markedly suppressed the tumor growth in a PDAC tumor xenograft model. This compound showed attractive pharmacokinetic properties. Overall, could be a good lead compound for the treatment of PDAC, and it is worthy of further study.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01183DOI Listing
September 2020

The role of surface hydroxyls on the radiolysis of gibbsite and boehmite nanoplatelets.

J Hazard Mater 2020 Nov 24;398:122853. Epub 2020 May 24.

Physical Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, United States.

Understanding mechanistic pathways to radiolytic hydrogen generation by metal oxyhydroxide nanomaterials is challenging because of the difficulties of distinguishing key locations of OH bond scission, from structural interiors to hydroxylated surfaces to physi-sorbed water molecules. Here we exploited the interface-selectivity of vibrational sum frequency generation (VSFG) to isolate surface versus bulk hydroxyl groups for gibbsite and boehmite nanoplatelets before and after Co irradiation at dose levels of approximately 7.0 and 29.6 Mrad. While high-resolution microscopy revealed no effect on particle bulk and surface structures, VSFG results clearly indicated up to 83% and 94% radiation-induced surface OH bond scission for gibbsite and boehmite, respectively, a substantially higher proportion than observed for interior OH groups by IR and Raman spectroscopy. Electron paramagnetic spectroscopy revealed that the major radiolysis products bound in the mineral structures are trapped electrons, O, O and possibly F-centers in gibbsite, and H, O and O in boehmite, which persist on the time frame of several months. The entrapped radiolysis products appear to be highly stable, enduring re-hydration of particle surfaces, and likely reflect a permanent adjustment in the thermodynamic stabilities of these nanomaterials.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122853DOI Listing
November 2020

Inhibition of M/K7 Currents Contributes to Chloroquine-Induced Itch in Mice.

Front Mol Neurosci 2020 30;13:105. Epub 2020 Jun 30.

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.

M/K7 potassium channels play a key role in regulation of neuronal excitability. Modulation of neuronal excitability of primary sensory neurons determines the itch sensation induced by a variety of itch-causing substances including chloroquine (CQ). In the present study, we demonstrate that suppression of M/K7 channel activity contributes to generation of itch in mice. CQ enhances excitability of the primary sensory neurons through inhibiting M/K7 potassium currents in a Ca influx-dependent manner. Specific M/K7 channel opener retigabine (RTG) or tannic acid (TA) not only reverses the CQ-induced enhancement of neuronal excitability but also suppresses the CQ-induced itch behavior. Systemic application of RTG or TA also significantly inhibits the itch behavior induced by a variety of pruritogens. Taken together, our findings provide novel insight into the molecular basis of CQ-induced itch sensation in mammals that can be applied to the development of strategies to mitigate itch behavior.
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http://dx.doi.org/10.3389/fnmol.2020.00105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339983PMC
June 2020

Rice nitrogen use efficiency does not link to ammonia volatilization in paddy fields.

Sci Total Environ 2020 Nov 22;741:140433. Epub 2020 Jun 22.

National Key Laboratory of Soil and Sustainable Agriculture, Institute of Soil Science, Chinese Academy of Sciences, Nanjing 210008, China. Electronic address:

Ammonia (NH) volatilization is a major pathway of nitrogen (N) losses from paddy fields, and could be potentially mitigated by cultivation of high nitrogen use efficiency (high-NUE) rice cultivars. However, the relationship between NUE and NH volatilization has not been validated under field conditions. A field experiment was conducted to evaluate the impact of four rice cultivars with different NUE [Wuyunjing 23 (W23), Zhendao 11 (Z11), Wuyujing 3 (W3), and Aoyusi 386 (A386)] on NH volatilization, as well as the related mechanisms. Two high-NUE rice cultivars W23 and Z11 was not more effective in reducing total NH volatilization from the paddy field compared to cultivar A386 with the lowest NUE. Cultivar A386 had 12.7-17.8% and 35.7-54.1% lower NH volatilization than other three rice cultivars at tillering fertilization stage (TFS) and panicle fertilization stage (PFS), respectively, mainly due to its greater shoot N accumulation, root biomass and volume at TFS and its greater shoot biomass, leaf area index and shoot N accumulation at PFS. There was no significant difference in NH volatilization among W23, Z11 and W3 at TFS. However, premature senescence phenomenon at later growth stages of A386 eventually led to its lowest NUE among the four rice cultivars. Our results suggest that NUE of rice does not link to NH volatilization from paddy fields. In order to make high-NUE rice cultivars also effective in mitigating NH volatilization, future breeding works should aim to improve N uptake capability and canopy structure at early tillering and panicle development stages while prevent premature senescence of rice plants to maintain high yields.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140433DOI Listing
November 2020

Determining the Genetic Characteristics of Resistance and Virulence of the "Epidermidis Cluster Group" Through Pan-Genome Analysis.

Front Cell Infect Microbiol 2020 12;10:274. Epub 2020 Jun 12.

The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.

, and belong to the "Epidermidis Cluster Group" (ECG) and are generally opportunistic pathogens. In this work, whole genome sequencing, molecular cloning and pan-genome analysis were performed to investigate the genetic characteristics of the resistance, virulence and genome structures of 69 ECG strains, including a clinical isolate ( SY333) obtained in this work. Two resistance genes ( and ) encoded on the plasmids pSY333-41 and pSY333-45 of SY333 were confirmed to be functional. The region in ECG exhibited three distinct structures, and these chromosome- and plasmid-encoded operons seemed to follow two different evolutionary paths. Pan-genome analysis revealed their pan-genomes tend to be "open." For the virulence-related factors, the genes involved in primary attachment were observed almost exclusively in , while the genes associated with intercellular aggregation were observed more frequently in and . The type VII secretion system was present in all strains of and some of but not in . Moreover, the locus (iron regulated surface determinant) was first found to be encoded on the genomes of and . These findings suggested that the plasmid and chromosome encoded operons of ECG species underwent different evolution paths, as well as they differed in the abundance of virulence genes associated with adherence, invasion, secretion system and immune evasion. Identification of loci in and indicated their ability to acquire heme as nutrient iron during infection.
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http://dx.doi.org/10.3389/fcimb.2020.00274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303328PMC
June 2020

Time-resolved mRNA and miRNA expression profiling reveals crucial coregulation of molecular pathways involved in epithelial-pneumococcal interactions.

Immunol Cell Biol 2020 Oct 20;98(9):726-742. Epub 2020 Jul 20.

Department of Pediatric Pulmonology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Streptococcus pneumoniae is a major causative agent of pneumonia worldwide and its complex interaction with the lung epithelium has not been thoroughly characterized. In this study, we exploited both RNA-sequencing and microRNA (miRNA)-sequencing approaches to monitor the transcriptional changes in human lung alveolar epithelial cells infected by S. pneumoniae in a time-resolved manner. A total of 1330 differentially expressed (DE) genes and 45 DE miRNAs were identified in all comparisons during the infection process. Clustering analysis showed that all DE genes were grouped into six clusters, several of which were primarily involved in inflammatory or immune responses. In addition, target gene enrichment analyses identified 11 transcription factors that were predicted to link at least one of four clusters, revealing transcriptional coregulation of multiple processes or pathways by common transcription factors. Notably, pharmacological treatment suggested that phosphorylation of p65 is important for optimal transcriptional regulation of target genes in epithelial cells exposed to pathogens. Furthermore, network-based clustering analysis separated the DE genes negatively regulated by DE miRNAs into two functional modules (M1 and M2), with an enrichment in immune responses and apoptotic signaling pathways for M1. Integrated network analyses of potential regulatory interactions in M1 revealed that multiple DE genes related to immunity and apoptosis were regulated by multiple miRNAs, indicating the coordinated regulation of multiple genes by multiple miRNAs. In conclusion, time-series expression profiling of messenger RNA and miRNA provides a wealth of information for global transcriptional changes, and offers comprehensive insight into the molecular mechanisms underlying host-pathogen interactions.
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http://dx.doi.org/10.1111/imcb.12371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586809PMC
October 2020

Prevalence of Aminoglycoside Resistance Genes and Molecular Characterization of a Novel Gene, , among Clinical Isolates of the Enterobacter cloacae Complex from a Chinese Teaching Hospital.

Antimicrob Agents Chemother 2020 08 20;64(9). Epub 2020 Aug 20.

Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China

Members of the complex are important opportunistic human pathogens capable of causing a wide variety of infections. During recent decades, aminoglycoside-resistant complex isolates have increasingly been reported and have become a major concern. Here, we employed high-throughput sequencing in combination with specific PCR assays to investigate the prevalence of aminoglycoside resistance genes among 170 isolates of the complex collected from a teaching hospital in Wenzhou, China. A total of 12 known genes [, , , , , , , , , , , and ] and 1 novel gene [] were identified, with (71.18%), (55.29%), and (52.35%) being the most prevalent, and was detected with a positive rate of 21.76% (37/170). The gene was 810 bp in length and encoded a protein that shared 72 to 78% identities with previously known AAC(3)-II aminoglycoside 3--acetyltransferases. The MICs of gentamicin and tobramycin were 512 μg/ml and 64 μg/ml, respectively, when was cloned into DH5α. All -positive isolates exerted broad aminoglycoside resistance profiles, mediated by the coexistence of multiple resistance genes. Moreover, aminoglycoside resistance and resistance genes were found to be transferable in most strains (24/37). Nevertheless, pulsed-field gel electrophoresis (PFGE) and dendrogram analysis showed clonal diversity among these isolates. S1 nuclease PFGE, Southern hybridization, and whole-genome sequencing indicated that was located on transferable as well as nontransferable plasmids of various sizes. The analysis of the genetic environment suggested that is embedded within a class 1 integron, with IS playing an important role in its mobility.
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http://dx.doi.org/10.1128/AAC.00852-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449223PMC
August 2020

Procyanidin B1, a novel and specific inhibitor of Kv10.1 channel, suppresses the evolution of hepatoma.

Biochem Pharmacol 2020 08 10;178:114089. Epub 2020 Jun 10.

Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China. Electronic address:

Recently, we and other groups revealed that aberrant expression of Kv10.1 channel, a voltage-gated potassium ion channel, contributes to a variety of tumorigenesis process.Potent and selective inhibitor of Kv10.1 is urgently needed, both as pharmacological tools for studying the physiological functions of this enigmatic channel and as potential leads for development of anti-tumor drugs. In this study, Procyanidin B1, a natural compound extracted from the grape seed, was identified as a potent, specific inhibitor, which can inhibit the Kv10.1 channel in a concentration-dependent manner (IC = 10.38 ± 0.87 μM), but has negligible effects on other potassium channels, including Kir2.1, HERG or KCNQ1. It was demonstrated that Procyanidin B1 directly binds to Kv10.1 channel and inhibits its currents, without increasing intracellular Ca. Further, three amino acids, I550, T552, and Q557 in the C-linker domain of Kv10.1 were found critical for forming the binding pocket of Procyanidin B1 with Kv10.1 channel.In addition, Procyanidin B1 inhibits migration and proliferation of liver cancer cells (HuH-7 cells, HepG2 cells) through inhibiting Kv10.1, but not in Kv10.1 negatively expressed cell lines. Next, we assayed the tumor suppressing effect of Procyanidin B1 on cell line-derived xenograft mouse model. Our data showed that 15 mg/kg Procyanidin B1 can significantly suppress the growth of the tumor (HepG2) with an inhibition rate of about 60.25%. Compared with cisplatin, Procyanidin B1 has no side effect on the normal metabolismof the mice. The present work indicated that Procyanidin B1 is a proming liver cancer anti-tumor drug, and also confirmed that Kv10.1 can serve as a potential, tumor-specific drug target.
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http://dx.doi.org/10.1016/j.bcp.2020.114089DOI Listing
August 2020

Management of gestational gigantomastia with breast reconstruction after mastectomy: case report and literature review.

J Int Med Res 2020 Jun;48(6):300060520920463

Department of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China.

Gestational gigantomastia (GGM) is a rare complication of pregnancy. The etiology of GGM is yet to be fully established. Treatment methods for GGM include medical therapy and surgery. If medical treatment is unsuccessful, surgery may be required. Currently available surgical interventions are either breast reduction or mastectomy with delayed reconstruction. We report a case of a 25-year-old woman (G1P1) who presented with massive enlargement of both breasts during puerperium. Because of the limited effect of medical therapy, surgical intervention was considered to be the first choice. Bilateral mastectomies with grafting of the nipple-areola complex and immediate bilateral tissue expander implantation were performed. Reconstruction was fully completed 8 months after the initial procedure by replacing tissue expanders with definitive implants. Despite being a benign condition, GGM can turn into a serious problem. GGM can be successfully reconstructed by mastectomy with delayed reconstruction and grafting of the nipple-areola complex.
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http://dx.doi.org/10.1177/0300060520920463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294380PMC
June 2020

Resveratrol inhibits proliferation and promotes apoptosis of keloid fibroblasts by targeting HIF-1α.

J Plast Surg Hand Surg 2020 Oct 4;54(5):290-296. Epub 2020 Jun 4.

Department of Plastic Surgery, Peking Union Medical College Hospital, Beijing, China.

A keloid is characterized by red, tickling, hard, and irregular raised tissues, and it tends to outgrow its origin. It frequently occurs in young adults and appears to be refractory to prevailing therapies. Resveratrol is a new drug that has anti-proliferative effect. In this study, keloid-derived fibroblasts were cultured under hypoxia environment and was treated by resveratrol. CCK-8 assay and Annexin V-FITC were used to evaluate cell activity and apoptosis level. Western blot and RT-qPCR were also used to assess the expression of HIF-α, Collagen I and Collagen III. Besides, siRNA was also used to explore the mechanisms of resveratrol's effect. In this study, hypoxia promotes proliferation and inhibits apoptosis of keloid fibroblasts. These findings highlight the potential obstacle in treating keloids. Furthermore, we demonstrated that resveratrol could reverse the effect of hypoxia on keloids through down-regulation of HIF-1α. Moreover, collagen synthesis in keloid fibroblasts was also inhibited by resveratrol, which corresponded with HIF-1α suppression. These results provide evidence for resveratrol's treatment effect against keloids through inhibiting cell proliferation and promoting cell apoptosis, while, HIF-1α may play the key role in this process.
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http://dx.doi.org/10.1080/2000656X.2020.1771719DOI Listing
October 2020

TMEM16A-inhibitor loaded pH-responsive nanoparticles: A novel dual-targeting antitumor therapy for lung adenocarcinoma.

Biochem Pharmacol 2020 08 31;178:114062. Epub 2020 May 31.

State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300130, China; Key Laboratory of Electromagnetic Field and Electrical Apparatus Reliability of Hebei Province, Hebei University of Technology, Tianjin 300130, China; Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China. Electronic address:

To overcome the adverse effects of conventional chemotherapy for cancers, various nanoparticles based drug delivery systems have been developed. However, nanoparticles delivering drugs directly to kill tumor cells still faced with challenges, because tumors possessed adopt complex mechanism to resist damages, which compromised the therapeutic efficacy. TMEM16A/CaCCs (Calcium activates chloride channels) has been identified to be overexpressed in lung adenocarcinoma which can serve as a novel tumor specific drug target in our previous work. Here, we developed a novel dual-targeted antitumor strategy via designing a novel nano-assembled, pH-sensitive drug-delivery system loading with specific inhibitors of TMEM16A against lung adenocarcinoma. For validation, we assayed the novel dual-targeting therapy on xenograft mouse model which exhibited significant antitumor activity and not affect mouse body weight. The dual targeting therapy accomplished in this study will shed light on the development of advanced antitumor strategy.
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http://dx.doi.org/10.1016/j.bcp.2020.114062DOI Listing
August 2020