Publications by authors named "Dongmei Zhao"

149 Publications

Parasexual reproduction in : Simple sequence repeat molecular evidence for haploidization.

Mycologia 2021 Jun 14:1-7. Epub 2021 Jun 14.

College of Plant Protection, Hebei Agricultural University, Baoding, China.

Multiple alleles were constantly detected in isolates by simple sequence repeat (SSR) analysis, and sectors were also observed in their subcultures. These preliminary results and observations point to a possible parasexual cycle in . In this study, codominant SSR markers were used as molecular markers on the chromosomes of and single-conidium subculture was used to simulate the mitosis process of in nature. The number of alleles at locus As-95236 changed from 2 to 1 as a molecular marker for haploidy of parasexuality of . Fifty monosporic F1 strains were tested. The results showed that two parent strains lost allele with a haploid probability of 38%. For F2 strains, the results showed that all four F1 strains lost allele with a haploid probability of 75%. Since sexual recombination of has not been found so far, the allele lost in the subcultures of isolates provides molecular evidence for the existence of parasexual reproduction in .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00275514.2021.1922243DOI Listing
June 2021

The regulation of miR-320a/XBP1 axis through LINC00963 for endoplasmic reticulum stress and autophagy in diffuse large B-cell lymphoma.

Cancer Cell Int 2021 Jun 10;21(1):305. Epub 2021 Jun 10.

School of Basic Medicine, Jiamusi University, Jiamusi, 154007, Heilongjiang, China.

Background: This study incorporates fundamental research referring to considerable amounts of gene-sequencing data and bioinformatics tools to analyze the pathological mechanisms of diffuse large B-cell lymphoma (DLBCL).

Methods: A lncRNA-miRNA-mRNA ceRNA network of DLBCL was constructed through database analysis combining GTEx and TCGA. qPCR was used to detect the expression of LINC00963 and miR-320a in DLBCL cell lines. After LINC00963 or miR-320a overexpression in vitro, western blot was performed to assess the protein levels of UPR sensors (GRP78, p-IRE1, IRE1, active ATF6, ATF4 and XBP1), along with apoptosis markers (Bcl-2, Bax, caspase 3) and autophagy indicators (Beclin1, LC3II, LC3I and p62). Additionally, the expression of LC3 was analyzed through immunofluorescence (IF) assay.  RESULTS: Following LINC00963 overexpression in vitro, SUDHL4 cell line showed a marked increase in the level of UPR-related GRP78, p-IRE1 and spliced XBP-1/XBP-1(s), apoptosis-related Bax and cleaved caspase 3, as well as autophagy-related Beclin1 and LC3II, whereas miR-320a mimic greatly diminished the effects of LINC00963 overexpression. Moreover, LINC00963 targeted miR-320a while miR-320a bound to the 3'UTR of XBP1. It was also found that LINC00963 overexpression resulted in significantly delayed tumor growth in a xenograft model of DLBCL.  CONCLUSION: Mechanistically, LINC00963/miR-320a regulated XBP1-apoptosis pathway and autophagy, implying the therapeutic potential of this pathway for selective targeting. The data presented here illustrated the mechanism of LINC00963/miR-320a/XBP1 in DLBCL for the first time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12935-021-01992-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194177PMC
June 2021

Corrigendum to "Strategies for the development of highly selective cytochrome P450 inhibitors: Several CYP targets in current research" [Bioorg. Med. Chem. Lett. 29 (2019) 2016-2024].

Bioorg Med Chem Lett 2021 Aug 27;45:128140. Epub 2021 May 27.

Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2021.128140DOI Listing
August 2021

Design, synthesis, and biological evaluation of 5-aminotetrahydroquinoline-based LSD1 inhibitors acting on Asp375.

Arch Pharm (Weinheim) 2021 May 13:e2100102. Epub 2021 May 13.

Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.

The abnormal expression of lysine-specific histone demethylase 1 (LSD1) is associated with different cancer types, and LSD1 inhibitory activity seems to have high therapeutic potential in cancer treatment. Here, we report the design, synthesis, and biochemical evaluation of novel 5-aminotetrahydroquinoline-based LSD1 inhibitors. Among them, compounds A6, A8, B1-B5, and C4 showed preferable inhibitory effects on LSD1, with IC  = 0.19-0.82 µM. Several potent compounds were selected to evaluate their antiproliferative activity on A549 cells and MCF-7 cells with a high expression of LSD1. The potential binding modes of the compounds were revealed through molecular docking to rationalize the potency of compounds toward LSD1. Our data recognized that the 5-aminotetrahydroquinoline scaffold may serve as a starting point for developing potent LSD1 inhibitors for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ardp.202100102DOI Listing
May 2021

Design, synthesis and biological evaluation of novel benzofuran derivatives as potent LSD1 inhibitors.

Eur J Med Chem 2021 Aug 24;220:113501. Epub 2021 Apr 24.

Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. In particular, the representative compound 17i exhibited excellent LSD1 inhibition at the molecular levels with IC = 0.065 μM, as well as anti-proliferation against MCF-7, MGC-803, H460, A549 and THP-1 tumor cells with IC values of 2.90 ± 0.32, 5.85 ± 0.35, 2.06 ± 0.27, 5.74 ± 1.03 and 6.15 ± 0.49 μM, respectively. The binding modes of these compounds were rationalized by molecular docking. Meanwhile, a preliminary druggability evaluation showed that compound 17i displayed favorable liver microsomal stability and weak inhibitory activity against CYPs at 10 μM. Remarkably, H460 xenograft tumors studies revealed that 17i demonstrated robust in vivo antitumor efficacy without significant side effects. All the results demonstrated that compound 17i could represent a promising lead for further development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2021.113501DOI Listing
August 2021

Impact of the COVID-19 Pandemic on Children with ASD and Their Families: An Online Survey in China.

Psychol Res Behav Manag 2021 4;14:289-297. Epub 2021 Mar 4.

Department of Maternal and Child Health, School of Public Health, Sun Yat-Sen University, Guangdong, Guangzhou, 510080, People's Republic of China.

Background: The COVID-19 pandemic and lockdown will have short-term and long-term psychosocial and mental health implications for children. Children with autism may have some specific needs for support because of their difficulties in social communication, stereotyped behavior patterns, and other specificities brought about by autism.

Purpose: The purpose of this study was to investigate the impact of the COVID-19 pandemic on ASD children and their families.

Patients And Methods: A total of 406 parents of ASD children completed an online survey investigating basic information; sleep, outdoor activities, and rehabilitation training; ASD children's frequency of abnormal behaviors; and stress and emotional status of parents.

Results: 50.3% of the parents thought their children had sleep problems, and 47.3% of the parents thought their children's outdoor activity time was reduced. About 40% of parents think that their children have improved cognitive ability, language expression, and understanding. 36.2% of the families reported that their children's emotional and social performance became worse. 60.8% of parents reported that their children's training intensity decreased. The most common abnormal behaviors observed in children with ASD were being easily distracted, losing temper, and crying. 81.3% of parents did not have anxiety, but 98% of parents reported that family training was under pressure.

Conclusion: The main impact of the COVID-19 pandemic on children with ASD is that they do not have access to professional rehabilitation training. These families need more medical support, especially in family training, to help parents improve the social and emotional control skills of ASD children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/PRBM.S293426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939504PMC
March 2021

Captopril potentiated meropenem activity against MBL-producing carbapenem-resistant Klebsiella pneumoniae: in vitro and in vivo study.

J Inorg Biochem 2021 May 20;218:111381. Epub 2021 Feb 20.

Department of Infectious Disease, The First Affilated Hospital of Anhui Medical University, Hefei, Anhui, China; Department of Infectious Diseases, The Chaohu Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Anhui Center for Surveillance of Bacterial Resistance, Hefei, Anhui, China; Institute of Bacterial Resistance, Anhui Medical University, Hefei, Anhui, China. Electronic address:

This study investigated whether captopril can reverse drug resistance in metallo-β-lactamase (MBL)-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) and increase their sensitivity to antimicrobial agents. And also aimed to further characterize the affinity of captopril for imipenemase 4 (IMP-4) to explore the drug resistance treatment of MBL-producing bacteria. Five clinically isolated MBL-producing strains of CRKP were screened and the combined effects of captopril and meropenem were examined in vitro and in vivo to analyze whether captopril can reverse antimicrobial resistance in drug-resistant bacteria. Additionally, enzyme inhibition kinetics was analyzed to characterize the affinity of captopril for IMP-4. In MBL-producing Klebsiella pneumoniae, combined treatment with captopril significantly reduced the minimum inhibitory concentration (MIC) of carbapenems to 1 μg/mL at least, and captopril inhibited New-Delhi metallo-β-lactamase 1 (NDM-1) and IMP-4 in a concentration-dependent manner in vitro. Following the infection of Galleria mellonella by IMP-expressing bacteria, the survival rates were significantly higher in the combination treatment group than in the monotherapy groups. And the bacterial load in the combination treatment group was significantly lower than those in the monotherapy groups and IMP-4-producing bacteria were more sensitive to the combination treatment than NDM-1-producing bacteria. Additionally, enzyme inhibition kinetics firstly illustrated that the half-maximal inhibitory concentration of captopril for IMP-4 was 26.34 μM, and the dissociation constant was 37.14 μM. In brief, captopril potentiated meropenem activity and restored its efficacy against MBL-producing CRKP. Additionally, analysis of enzyme inhibition kinetics confirmed that captopril has good inhibitory effects on IMP-4 activity. Therefore, captopril or its derivatives may have clinical utility for overcoming antibiotic resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jinorgbio.2021.111381DOI Listing
May 2021

Outcome study of five cases receiving in vitro fertilization after treatment of intrauterine platelet-rich plasma (PRP) for chronic endometritis.

Panminerva Med 2021 Jan 20. Epub 2021 Jan 20.

Reproductive Medicine Center, Qingdao Women and Children's Hospital, Qingdao, China -

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23736/S0031-0808.20.04247-0DOI Listing
January 2021

A Study on Differences between Simplified and Traditional Chinese Based on Complex Network Analysis of the Word Co-Occurrence Networks.

Comput Intell Neurosci 2020 3;2020:8863847. Epub 2020 Dec 3.

Department of Artificial Intelligence, School of Informatics, Xiamen University, Xiamen 361005, China.

Currently, most work on comparing differences between simplified and traditional Chinese only focuses on the character or lexical level, without taking the global differences into consideration. In order to solve this problem, this paper proposes to use complex network analysis of word co-occurrence networks, which have been successfully applied to the language analysis research and can tackle global characters and explore the differences between simplified and traditional Chinese. Specially, we first constructed a word co-occurrence network for simplified and traditional Chinese using selected news corpora. Then, the complex network analysis methods were performed, including network statistics analysis, kernel lexicon comparison, and motif analysis, to gain a global understanding of these networks. After that, the networks were compared based on the properties obtained. Through comparison, we can obtain three interesting results: first, the co-occurrence networks of simplified Chinese and traditional Chinese are both small-world and scale-free networks. However, given the same corpus size, the co-occurrence networks of traditional Chinese tend to have more nodes, which may be due to a large number of one-to-many character/word mappings from simplified Chinese to traditional Chinese; second, since traditional Chinese retains more ancient Chinese words and uses fewer weak verbs, the traditional Chinese kernel lexicons have more entries than the simplified Chinese kernel lexicons; third, motif analysis shows that there is no difference between the simplified Chinese network and the corresponding traditional Chinese network, which means that simplified and traditional Chinese are semantically consistent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8863847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728479PMC
December 2020

Discovery of a series of 1H-pyrrolo[2,3-b]pyridine compounds as potent TNIK inhibitors.

Bioorg Med Chem Lett 2021 02 24;33:127749. Epub 2020 Dec 24.

Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address:

In an in-house screening, 1H-pyrrolo[2,3-b]pyridine scaffold was found to have high inhibition on TNIK. Several series of compounds were designed and synthesized, among which some compounds had potent TNIK inhibition with IC values lower than 1 nM. Some compounds showed concentration-dependent characteristics of IL-2 inhibition. These results provided new applications of TNIK inhibitors and new prospects of TNIK as a drug target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127749DOI Listing
February 2021

hPMSCs protects against D-galactose-induced oxidative damage of CD4 T cells through activating Akt-mediated Nrf2 antioxidant signaling.

Stem Cell Res Ther 2020 11 4;11(1):468. Epub 2020 Nov 4.

Department of Immunology, School of Basic Medicine, Binzhou Medical University, Yantai, People's Republic of China.

Background: Mesenchymal stem cells (MSCs) were considered a regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of CD4 T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related CD4 T cell senescence and identified the underlying mechanisms using a D-gal-induced mouse aging model.

Methods: In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, D-gal group, hPMSC group, and PBS group. In in vitro experiment, human naive CD4 T (CD4CD45RA) cells were prepared using a naive CD4 T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive CD4 T cell were co-cultured with hPMSCs for 72 h in the absence or presence of anti-CD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-β-gal stain. The expression of aging-related proteins was detected by Western blotting, RT-PCR, and confocal microscopy.

Results: We found that hPMSC treatment markedly decreased the ROS level, SA-β-gal-positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression, and aging-related protein (P16 and P21) expression in senescent CD4 T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC, and NQO1) in senescent CD4 T cells. Moreover, in vitro studies revealed that hPMSCs attenuated CD4 T cell senescence by upregulating the Akt/GSK-3β/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent CD4 T cells.

Conclusions: Our results indicate that hPMSCs attenuate D-gal-induced CD4 T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3β/Fyn pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13287-020-01993-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641865PMC
November 2020

Downregulated Recycling Process but Not De Novo Synthesis of Glutathione Limits Antioxidant Capacity of Erythrocytes in Hypoxia.

Oxid Med Cell Longev 2020 4;2020:7834252. Epub 2020 Sep 4.

Department of Anatomy, School of Basic Medicine, Binzhou Medical University, Yantai, China.

Red blood cells (RBCs) are susceptible to sustained free radical damage during circulation, while the changes of antioxidant capacity and regulatory mechanism of RBCs under different oxygen gradients remain unclear. Here, we investigated the changes of oxidative damage and antioxidant capacity of RBCs in different oxygen gradients and identified the underlying mechanisms using an in vitro model of the hypoxanthine/xanthine oxidase (HX/XO) system. In the present study, we reported that the hypoxic RBCs showed much higher oxidative stress injury and lower antioxidant capacity compared with normoxic RBCs. In addition, we found that the disturbance of the recycling process, but not de novo synthesis of glutathione (GSH), accounted for the significantly decreased antioxidant capacity of hypoxic RBCs compared to normoxic RBCs. We further elucidated the underlying molecular mechanism by which oxidative phosphorylation of Band 3 blocked the hexose monophosphate pathway (HMP) and decreased NADPH production aggravating the dysfunction of GSH synthesis in hypoxic RBCs under oxidative conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/7834252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492869PMC
May 2021

Beneficial phytoestrogenic effects of resveratrol on polycystic ovary syndromein rat model.

Gynecol Endocrinol 2021 Apr 27;37(4):337-341. Epub 2020 Aug 27.

Reproductive Medicine Center, Yantai Yuhuangding Hospital, Yantai, China.

Aims: The effective treatment of polycystic ovary syndrome (PCOS)-related hormonal disorders necessitates the development of novel treatment strategies. Resveratrol is found in certain food products, and is known to exhibit phytoestrogen properties. The present study was to assess whether resveratrol exhibits beneficial phytoestrogenic effects and associated hormonal modulation in a rat model of PCOS.

Materials And Methods: This model was established by administering oral letrozole to female Sprague-Dawley (SD) rats prior to randomizing them into control, model and resveratrol treatment groups (40, 80, or 160 mg/kg). Animals were treated for 30 days, after which time ovarian tissues were collected and evaluated hematoxylin and eosin staining. In addition, serum levels of estradiol and adiponectin were assessed ELISA, and ovarian expression of nesfatin-1 and aromatase was assessed through RT-PCR and western blotting.

Results: We found that resveratrol administration was associated with increased levels of plasma adiponectin and estradiol levels and restoration of normal ovarian morphology in PCOS model animals. In addition, this treatment was linked to the increased ovarian expression of nesfatin-1 and aromatase at the RNA and protein levels.

Conclusions: Together things findings suggest that resveratrol may represent an effective tool for treating PCOS owing to its phytoestrogenic properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09513590.2020.1812569DOI Listing
April 2021

Development and Validation of a Model for Predicting the Risk of Death in Patients with Infection: A Retrospective Study.

Infect Drug Resist 2020 10;13:2761-2772. Epub 2020 Aug 10.

Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.

Purpose: This study aimed to develop and validate a personalized prediction model of death risk in patients with () infection and thus guide clinical research and support clinical decision-making.

Patients And Methods: The development group is comprised of 350 patients with infection admitted between January 2013 and December 2015 in The First Affiliated Hospital of Anhui Medical University. Further, 272 patients in the validation group were admitted between January 2016 and December 2018. The univariate and multivariate logistic regression analyses were used to determine the independent risk factors for death with infection. The nomogram prediction model was established based on the regression coefficients. The discrimination of the proposed prediction model was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curves and decision curve analysis (DCA). The calibration diagram was used to evaluate the calibration degree of this model.

Results: The infectious source, carbapenem-resistant (CRAB), hypoalbuminemia, Charlson comorbidity index (CCI), and mechanical ventilation (MV) were independent risk factors for death. The AUC of the ROC curve of the two groups was 0.768 and 0.792, respectively. The net income was higher when the probability was between 30% and 80%, showing a strong discrimination capacity of the proposed model. The calibration curve swung around the 45° oblique line, indicating a high degree of calibration.

Conclusion: The proposed model helped predict the risk of death from infection, improve the early identification of patients with a higher risk of death, and guide clinical treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IDR.S253143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428379PMC
August 2020

Oligosaccharide attenuates aging-related liver dysfunction by activating Nrf2 antioxidant signaling.

Food Sci Nutr 2020 Jul 5;8(7):3872-3881. Epub 2020 Jun 5.

Department of Anatomy School of Basic Medicine Binzhou Medical University Yantai China.

Chitosan oligosaccharide (COS) is the depolymerized product of chitosan possessing various biological activities and protective effects against inflammation and oxidative injury. The aim of the present study was to investigate the antioxidant effects of COS supplements on aging-related liver dysfunction. We found that COS treatment significantly attenuated elevated liver function biomarkers and oxidative stress biomarkers and decreased antioxidative enzyme activities in liver tissues in D-galactose (D-gal)-treated mice. Furthermore, COS treatment significantly upregulated the expression of Nrf2 and its downstream target genes HO-1, NQO1, and CAT. Moreover, in vitro experiments showed that COS treatment played a vital role in protecting HO-exposed L02 cells against oxidative stress by activating Nrf2 antioxidant signaling. These data indicate that COS could protect against D-gal-induced hepatic aging by activating Nrf2 antioxidant signaling, which may provide novel applications for the prevention and treatment of aging-related hepatic dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/fsn3.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382186PMC
July 2020

Discovery of 7H-pyrrolo[2,3-d]pyridine derivatives as potent FAK inhibitors: Design, synthesis, biological evaluation and molecular docking study.

Bioorg Chem 2020 09 14;102:104092. Epub 2020 Jul 14.

Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.

Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase responsible for development of various tumor types. Aiming to explore new potent inhibitors, two series of 2,4-disubstituted-7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized on the base of structure-based design strategy. Biological evaluation indicated that most of these new compounds could potently inhibit FAK kinase, leading to the promising inhibitors against the proliferation of U-87MG, A-549, and MDA-MB-231 cancer cell lines. Among them, the optimized compound 18h potently inhibited the enzyme (IC = 19.1 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC values of 0.35, 0.24, and 0.34 μM, respectively. Compound 18h is a multi-target kinase inhibitor. Furthermore, compound 18h also exhibited relatively less cytotoxicity (IC = 3.72 μM) toward a normal human cell line, HK2. According to the flow cytometry and wound healing assay results, compound 18h effectively induced apoptosis and G0/G1 phase arrest of MDA-MB-231 cells and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. The docking study of compound 18h was performed to elucidate its possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors. Collectively, these data support the further development of compound 18h as a lead compound for FAK-targeted anticancer drug discovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2020.104092DOI Listing
September 2020

Discovery of 2,4-diaminopyrimidine derivatives targeting p21-activated kinase 4: Biological evaluation and docking studies.

Arch Pharm (Weinheim) 2020 Oct 6;353(10):e2000097. Epub 2020 Jul 6.

Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.

In this study, novel 2,4-diaminopyrimidine derivatives targeting p21-activated kinase 4 (PAK4) were discovered and evaluated for their biological activity against PAK4. Among the derivatives studied, promising compounds A2, B6, and B8 displayed the highest inhibitory activities against PAK4 (IC  = 18.4, 5.9, and 20.4 nM, respectively). From the cellular assay, compound B6 exhibited the highest potency with an IC value of 2.533 μM against A549 cells. Some compounds were selected for computational ADME (absorption, distribution, metabolism, and elimination) properties and molecular docking studies against PAK4. The detailed structure-activity relationship based on the biochemical activities and molecular docking studies were explored. According to the docking studies, compound B6 had the lowest docking score (docking energy: -7.593 kcal/mol). The molecular docking simulation indicated the binding mode between compound B6 and PAK4. All these results suggest compound B6 as a useful candidate for the development of a PAK4 inhibitor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ardp.202000097DOI Listing
October 2020

Antifungal Effects of Volatiles Produced by Against in Potato.

Front Microbiol 2020 17;11:1196. Epub 2020 Jun 17.

College of Plant Protection, Hebei Agricultural University, Baoding, China.

Antifungal activities of plant-beneficial have been widely studied in recent years. Numerous studies have studied the antifungal mechanisms of soluble non-volatile bioactive compounds such as lipopeptides and proteins produced by against soil-borne diseases. However, the antagonistic mechanisms of volatile organic compounds (VOCs) from against airborne phytopathogens are still largely unknown, and the function of pathogenic genes has not been well identified. Here, we first isolated a strain with strong antifungal activity and finally identified it as ZD01. Then, the antagonistic mechanisms of VOCs produced by strain ZD01, against , an airborne fungal pathogen that can cause early blight diseases of potato, were studied. We showed that VOCs produced by strain ZD01 can reduce the colony size and mycelial penetration and can cause serious morphological changes of . Scanning electron microscope (SEM) observation showed that VOCs released by ZD01 could cause more flaccid and gapped hyphae of . Also, we found that VOCs produced by ZD01 can inhibit the conidia germination and reduce the lesion areas and number of significantly. Meanwhile, based on gas chromatography/mass spectrometry (GC/MS) analysis, 29 volatile compounds produced by strain ZD01 were identified. Out of 29 identified VOCs, 9 VOCs showed complete growth inhibition activities against . Moreover, we identified two virulence-associated genes ( and ) in . is a key gene that regulates the mycelial growth, penetration, sporulation, and virulence in . In addition, plays a significant role in the SOD synthetic pathway in . Results from qRT-PCR showed that the transcriptional expression of these two genes was down-regulated after being treated by VOCs produced by ZD01. These results are useful for a better understanding of the biocontrol mechanism of and offer a potential method for potato early blight disease control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2020.01196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311636PMC
June 2020

Risk Factors, Molecular Epidemiology, and Outcomes of Carbapenem-Resistant Infection for Hospital-Acquired Pneumonia: A Matched Case-Control Study in Eastern China During 2015-2017.

Microb Drug Resist 2021 Feb 2;27(2):204-211. Epub 2020 Jul 2.

Department of Clinical Laboratory and The First Affiliated Hospital of Anhui Medical University, Hefei, China.

This study was conducted to acknowledge microbiological and clinical characteristics of hospital-acquired pneumonia (HAP) caused by carbapenem-resistant (CRKP). A retrospective, 1:1 matched (age, gender, specimen source, and ward) case-control study was conducted during 2015-2017 in a tertiary teaching hospital in Anhui, China. Multivariate logistic regression analysis demonstrated that prior central venous catheter use, sputum suction, continuous renal replacement therapy, and exposure to fluroquinolones were independent risk factors for the morbidity of CRKP infection for HAP. Treatment failure for infection was an independent risk factor for crude in-hospital mortality, while the use of fluroquinolones may improve the effective treatment for infection ( = 0.040). Among 74 CRKP strains, 85.1% of them were positive for the production of KPC-2, and one of them was detected for co-harboring and . Separately, sequence type (ST) 11 (81.1%) was the predominant ST in this study, and ST11 CRKP isolates were related with higher detection rate of and lower resistance rate to trimethoprim/sulfamethoxazole when compared with non-ST11 ones. Moreover, resistance to carbapenem was associated with higher mortality (35.1%) and hospitalization costs for HAP patients with infection. Invasive procedures may increase the morbidity of CRKP infection for HAP. Prior exposure to fluroquinolones is associated with the development of resistance, but as a targeted treatment it may be effective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/mdr.2020.0162DOI Listing
February 2021

Construction and Evaluation of Molecular Models: Guide and Design of Novel SE Inhibitors.

ACS Med Chem Lett 2020 Jun 11;11(6):1152-1159. Epub 2020 May 11.

Institute of BioPharmaceutical Research, Liaocheng University, No. 1 Hunan Road, Liaocheng City, 252059 Shandong Province, China.

Squalene epoxidase (SE) was considered an important antifungal target to block ergosterol synthesis. In this study, molecular models of CASE including the homology model and the SBP were constructed, respectively. Three representative SE inhibitors were selected and docked into the active site of CASE. Subsequently, the novel SE inhibitors were designed based on the analysis of the inhibitor binding mode and the distribution of pharmacophore features. These compounds were further synthesized and tested . They exhibited a certain degree of antifungal activity, especially compound , which also has a significant inhibitory effect on resistant fungi. Further analysis found that compound could inhibit SE, which is similar to naftifine. The study proved the rationality of the molecular models; they can help us design and discover more potent antifungal SE inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.0c00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294727PMC
June 2020

Proton Transfer Can Govern Regioselectivity Assisted by Iron Catalysis.

iScience 2020 Jun 1;23(6):101214. Epub 2020 Jun 1.

State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Center for Excellence in Molecular Synthesis, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P.R. China. Electronic address:

Ortho-selective aromatic C-H functionalization is frequently used in organic synthesis and chemical/pharmaceutical industries. However, this reaction relies heavily on the use of directing groups suffering from limited substrate scope and extra steps to put on and remove the directing/protecting groups. Herein we present the previously neglected concept that enables good to nearly complete selective ortho position. Proton transfer was utilized to tune the electron density on the aryl ring and determine the positional selectivity of electrophilic substitution. Consistently with deuteration experiments and DFT studies, this work demonstrates that acid-promoted proton transfer directs accelerated ortho-selective halogenation of NH/OH contained aromatic amines/phenols with excellent selectivity (>40 examples; up to 98:2 ortho/para selectivity). The application potential of this Fe-catalyzed method is demonstrated by the convenient synthesis of three alkaloids and tizanidine. This report raises the possibility that proton transfer could serve as the basis of developing new selective C-H functionalization reactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2020.101214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298526PMC
June 2020

Heavy N ion transfer in doubly charged NAr van der Waals cluster.

Nat Commun 2020 Jun 12;11(1):2987. Epub 2020 Jun 12.

Institute of Modern Physics, Chinese Academy of Sciences, 730000, Lanzhou, China.

Van der Waals clusters are weakly bound atomic/molecular systems and are an important medium for understanding micro-environmental chemical phenomena in bio-systems. The presence of neighboring atoms may open channels otherwise forbidden in isolated atoms/molecules. In hydrogen-bond clusters, proton transfer plays a crucial role, which involves mass and charge migration over large distances within the cluster and results in its fragmentation. Here we report an exotic transfer channel involving a heavy N ion observed in a doubly charged cluster produced by 1 MeV Ne ions: (NAr)→N+NAr. The neighboring Ar atom decreases the [Formula: see text] barrier height and width, resulting in significant shorter lifetimes of the metastable molecular ion state [Formula: see text]([Formula: see text]). Consequently, the breakup of the covalent N-N bond, the tunneling out of the N ion from the [Formula: see text] potential well, as well as the formation of an N-Ar bound system take place almost simultaneously, resulting in a Coulomb explosion of N and NAr ion pairs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-16749-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293282PMC
June 2020

Dissecting the effect of continuous cropping of potato on soil bacterial communities as revealed by high-throughput sequencing.

PLoS One 2020 29;15(5):e0233356. Epub 2020 May 29.

College of Plant Protection, Agricultural University of Hebei, Baoding City, Hebei Province, China.

Plant rhizosphere-associated bacterial communities play key roles in affecting host health in response to diverse biotic stresses. Currently, the effect of continuous cropping of potato on soil bacterial communities and physiochemical parameters has not been well documented. Herein, we compared bacterial composition and diversity in rotationally and continuously (5, 10, and 30 years) cropped soils, and clarified the correlations between soil properties and the bacterial communities revealed by Illumina MiSeq sequencing. Our results demonstrated that Proteobacteria, Actinobacteria and Firmicutes were the predominant phyla in all the tested soil samples. While the abundance of Proteobacteria showed an increase, the abundance of Actinobacteria and Firmicutes displayed a reduction with the increase of continuous cropping years. At the genus level, as continuous cropping years increasing, the abundance of Pseudarthrobacter, Bacillus and Pseudomonas decreased, but the abundance of Rhodanobacte, Sphingobium, Mizugakiibacter and Devosia increased. Our results also demonstrated that the abundance of plant growth-promoting rhizobacteria in the rotationally cropped soil was significantly higher than that of continuously cropped soil. Furthermore, our results showed that soil organic matter, available nitrogen, available phosphorus and available potassium were significantly correlated with bacterial community distribution. Overall, our work provides a comprehensive view of altered structure and composition of bacterial communities between the continuously cropped soil and rotationally cropped soil.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233356PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259506PMC
August 2020

Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats.

Sci Transl Med 2020 04;12(540)

Henan University affiliated Huaihe Hospital, Kaifeng 475004, P.R. China.

Myocardial infarction (MI) is a leading cause of death worldwide for which there is no cure. Although cardiac cell death is a well-recognized pathological mechanism of MI, therapeutic blockade of cell death to treat MI is not straightforward. Death receptor 5 (DR5) and its ligand TRAIL [tumor necrosis factor (TNF)-related apoptosis-inducing ligand] are up-regulated in MI, but their roles in pathological remodeling are unknown. Here, we report that blocking TRAIL with a soluble DR5 immunoglobulin fusion protein diminished MI by preventing cardiac cell death and inflammation in rats, pigs, and monkeys. Mechanistically, TRAIL induced the death of cardiomyocytes and recruited and activated leukocytes, directly and indirectly causing cardiac injury. Transcriptome profiling revealed increased expression of inflammatory cytokines in infarcted heart tissue, which was markedly reduced by TRAIL blockade. Together, our findings indicate that TRAIL mediates MI directly by targeting cardiomyocytes and indirectly by affecting myeloid cells, supporting TRAIL blockade as a potential therapeutic strategy for treating MI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aaw3172DOI Listing
April 2020

Inhibition of EZH2 attenuates inhibitory synaptic transmission via the pro-inflammatory pathway in rats.

Neuropharmacology 2020 07 13;171:108101. Epub 2020 Apr 13.

Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Provincial Cancer Hospital, Zhengzhou, 450008, China.

Enhancer of zeste homolog 2 (EZH2), a subunit of the polycomb repressive complex 2 (PRC2), is associated with seizure development and epileptogenesis, however, the underlying mechanism of the process remains to be elucidated. This study focused on exploring whether EZH2 regulated gamma-aminobutyric acid (GABA)-mediated neurotransmission during seizure generation. Hyperthermia-induced seizures were generated in Sprague-Dawley (SD) rats using a hot (43.5 °C) bath method, and seizure severity was evaluated according to the Racine scale. The effect of treatment with the EZH2 pharmacological inhibitor GSK 126 on the GABA and pro-inflammatory cytokine levels was tested using enzyme-linked immunosorbent assay (ELISA). Miniature inhibitory postsynaptic currents (mIPSCs) were recorded using whole-cell patch clamp. In this study, our results showed that intracerebroventricular (i.c.v) injection of the EZH2 pharmacological inhibitor GSK 126 (10 nM) increased seizure severity and shortened seizure latency in a rat model of FS, and these effects were accompanied by reduced GABA content. Furthermore, GSK 126 (1 μM) treatment decreased the mean amplitude and frequency of the mIPSCs in cultured hippocampal neurons subjected to hyperthermia. Importantly, the same results were also obtained in cultured neurons infected with lentivirus carrying EZH2 shRNA. In addition, a significant increase in the pro-inflammatory cytokine (IL-1β and TNF-α) levels was observed in rats after GSK 126 treatment, and IL-1β administration increased seizure severity, suggesting that the inflammatory response was involved in the regulation of seizure development by EZH2. This study helps clarify the role of EZH2 in FS and supports EZH2 administration as an effective target for the management of seizure generation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2020.108101DOI Listing
July 2020

Design, synthesis and biological evaluation of tetrahydroquinoline-based reversible LSD1 inhibitors.

Eur J Med Chem 2020 May 21;194:112243. Epub 2020 Mar 21.

Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.

The targeted regulation of LSD1, which is highly expressed in a variety of tumor cells, is a promising cancer therapy strategy. Several LSD1 inhibitors are currently under clinical evaluation, and most of these inhibitors are irreversible. Here, we report the design, synthesis and biochemical evaluation of novel tetrahydroquinoline-based reversible LSD1 inhibitors. Compounds 18s and 18x, which are selective to LSD1 over MAO-A/B, exhibit excellent LSD1 inhibition at the molecular levels with IC = 55 nM and 540 nM, respectively. The classic Lineweaver-Burk plots revealed that compound 18s could reversibly bind the LSD1 enzyme in a noncompetitive manner. Molecular docking was used to reveal the potential binding-mode of the compounds and interpret the structure-activity relationships. Furthermore, compounds 18s and 18x significantly inhibited proliferation (IC = 1.13 μM and 1.15 μM, respectively) and induced apoptosis in MGC-803 cells with high expression of LSD1. Compound 18x showed acceptable liver microsomal stability. Meanwhile, 18x did not appear to inhibit CYPs at 10 μM in vitro. Remarkably, the oral administration of compound 18x can inhibit the growth of MGC-803 xenograft tumors without significant side effects. Our findings suggest that tetrahydroquinoline-based LSD1 inhibitors deserve further investigation for the treatment of LSD1 overexpressing cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2020.112243DOI Listing
May 2020

[Diagnosis of Bainbridge-Ropers syndrome due to de novo ASXL3 variant by high throughput sequencing].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2020 Apr;37(4):452-454

Jinan Pediatric Research Institute, Qilu Children's Hospital of Shandong University, Jinan, Shandong 250022, China.

Objective: To explore the clinical and genetic features of a patient with mental retardation.

Methods: G-Banding chromosomal karyotyping and high-throughput sequencing was carried out for the child. Suspected variant was validated in his family by Sanger sequencing and bioinformatic analysis.

Results: The patient was found to carry a de novo heterozygous c.4090G>T (p.Gly1364X) variant of the ASXL3 gene, which was known to predispose to Bainbridge-Ropers syndrome.

Conclusion: The nonsense c.4090G>T (p.Gly1364X) variant probably accounts for the disease in this patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2020.04.022DOI Listing
April 2020

Enhancement of anammox bacterial activity by sodium glutamate.

Chemosphere 2020 Apr 7;244:125570. Epub 2019 Dec 7.

Low Carbon Water Environmental Technology Research Center, School of Environment & Natural Resources, Renmin University of China, Beijing, 100872, China.

In this paper, the enhancement of sodium glutamate (SG) on activity of anaerobic ammonia oxidizing (anammox) bacteria was investigated by batch tests. The results illustrated that SG played an important role in enhancing anammox bacterial activity when the SG dosage ranged from 0.50 to 1.25 mM, and the optimal SG concentration was 1.00 mM. The performance of anammox was the best and the total nitrogen removal rate (TNRR) was 138.2 mg N g·VSS·d when the concentration of SG was 1.00 mM. The results of EPS and anammox bacterial biomass measurement indicated that protein (PN), polysaccharide (PS), total EPS and the bacterial abundance reached the maximum of 1.00 mM SG addition. Compared to the control tests, the EPS content and bacterial abundance increased by 38.2% and 75.8%, respectively. In addition, the cloning results showed that the community structure of anammox bacteria evolved in species level of Candidatus Brocadia genus under the condition of SG enhancement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chemosphere.2019.125570DOI Listing
April 2020

Molecular docking, 3D-QSAR, and molecular dynamics simulations of thieno[3,2-b]pyrrole derivatives against anticancer targets of KDM1A/LSD1.

J Biomol Struct Dyn 2021 Mar 21;39(4):1189-1202. Epub 2020 Feb 21.

Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, P.R. China.

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which has been proposed as a promising target for anticancer drug development. Extensive research on LSD1 inhibitors has been performed since its discovery. In order to get more information for lead identification and optimization, we carried out a molecular modeling study on a set of 43 thieno[3,2-b]pyrrole competitive inhibitors of LSD1 using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations. Based on the co-crystallized conformer-based alignment (CCBA) method, 3D-QSAR model of thieno[3,2-b]pyrrole derivatives as LSD1 inhibitors was established. The significant statistics ( = 0.595, = 0.959, = 0.846) of the 3D-QSAR indicated the good predictive power and statistical reliability of this model. Based on the corresponding contour maps six LSD1 inhibitors were designed and their activities were predicted by 3D-QSAR model. Meanwhile, molecular docking was performed to simulate the probable binding modes between ligands and LSD1 protein. The molecular interactions mainly contributions to the binding affinity for LSD1 inhibitions were further supplemented by 100 ns MD simulations and binding free energy calculation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07391102.2020.1726819DOI Listing
March 2021

Refining critical regions in 15q24 microdeletion syndrome pertaining to autism.

Am J Med Genet B Neuropsychiatr Genet 2020 06 18;183(4):217-226. Epub 2020 Jan 18.

Pediatric Research Institute, Qilu Children's Hospital of Shandong University, Ji'nan, China.

Chromosome 15q24 microdeletion syndrome is characterized by developmental delay, facial dysmorphism, hearing loss, hypotonia, recurrent infection, and other congenital malformations including microcephaly, scoliosis, joint laxity, digital anomalies, as well as sometimes having autism spectrum disorder (ASD) and attention deficit hyperactivity disorder. Here, we report a boy with a 2.58-Mb de novo deletion at chromosome 15q24. He is diagnosed with ASD and having multiple phenotypes similar to those reported in cases having 15q24 microdeletion syndrome. To delineate the critical genes and region that might be responsible for these phenotypes, we reviewed all previously published cases. We observe a potential minimum critical region of 650 kb (LCR15q24A-B) affecting NEO1 among other genes that might pertinent to individuals with ASD carrying this deletion. In contrast, a previously defined minimum critical region downstream of the 650-kb interval (LCR15q24B-D) is more likely associated with the developmental delay, facial dysmorphism, recurrent infection, and other congenital malformations. As a result, the ASD phenotype in this individual is potentially attributed by genes particularly NEO1 within the newly proposed critical region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.32778DOI Listing
June 2020