Publications by authors named "Kexin Liu"

282 Publications

The effects of incorporation of the counterparts and mimics of L-lysine on the antimicrobial activity, hemolytic activity, cytotoxicity and tryptic stability of antimicrobial peptide polybia-MPII.

Amino Acids 2021 Nov 26. Epub 2021 Nov 26.

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, West Donggang Road 199, Lanzhou, 730000, China.

Due to the limited effects of conventional antibiotics on the increasing emergence of drug-resistant bacteria and fungi, novel antimicrobial agents were urgently needed to alleviate this phenomenon. Nowadays, antimicrobial peptides are believed to be a promising candidate for a new generation of antimicrobial drugs. Antimicrobial peptide polybia-MPII (MPII) was first isolated from the venom of the social wasp Polybia paulista with a broad spectrum of antimicrobial activity. In the present study, the counterparts and mimics of cationic amino acids of Lys, such as Arg, His, Orn, Dab and Dap were employed to substitute Lys in the sequence of MPII. The effects of the incorporation of these amino acids on its antimicrobial activity, hemolytic activity, cytotoxicity, enzyme stability and therapeutic potential were explored. Our results showed that although the incorporation of Arg could improve its antimicrobial activity, there is no improvement in enzyme stability. The incorporation of His makes MPII exert its antimicrobial activity in a pH-dependent manner. Notably, incorporating Dap could effectively decrease its hemolytic activity and cytotoxicity and enhance its enzyme stability against trypsin. In conclusion, this study would provide an effective strategy to improve the bioavailability and metabolic stability of AMPs while decrease their hemolytic activity and cytotoxicity.
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http://dx.doi.org/10.1007/s00726-021-03099-0DOI Listing
November 2021

Isoliquiritigenin-mediated miR-23a-3p inhibition activates PGC-1α to alleviate alcoholic liver injury.

Phytomedicine 2021 Nov 5:153845. Epub 2021 Nov 5.

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China. Electronic address:

Background: Alcoholic liver disease (ALD), one of the most prevalent forms of liver disease, has received wide attention worldwide. However, limited efficient and appropriate therapeutic agents were responded to ALD. Isoliquiritigenin (ISL), a flavonoid isolated from liquorice, possesses multiple pharmacological activities.

Purpose: The current study investigated the hepatoprotective effect of ISL against ALD and further elucidate the involvement of miR-23a-3p/peroxisome proliferative activated receptor-γ coactivator 1 alpha (PGC-1α) in vivo and in vitro experiments.

Study Design And Methods: In the study, H&E and Oil Red O staining were employed to detect liver histopathological changes and the accumulation of lipid droplets. Quantitative real-time PCR, bioinformatics, luciferase assay, immunofluorescence staining, reactive oxygen species (ROS), Western blot, and siRNA were used to further explore the mechanism of ISL protection.

Results: ISL significantly reduced the liver-to-body weight ratios and biochemical index. The staining results showed that ISL remarkedly ameliorated the histopathological changes in the liver. Furthermore, ISL promoted fatty acid metabolism via induction in the expression of PGC-1α-target genes PPARα, CPT1α, and ACADs, and inhibited the ROS, TNF-α, IL-1β, and IL-6 expression. Bioinformatics and Luciferase assay analysis confirmed that miR-23a-3p might bind to PGC-1α mRNA in ALD. Significantly, the expression of miR-23a-3p was increased in the ALD, which was significantly decreased by ISL. In addition, the miR-23a-3p inhibitor also promoted lipid metabolism in ALD via PGC-1α activation.

Conclusions: We first demonstrated that ISL could alleviate ALD, and further verified that ISL exerted protective effects through modulating miR-23a-3p/PGC-1α-mediated lipid metabolism in vivo and in vitro.
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http://dx.doi.org/10.1016/j.phymed.2021.153845DOI Listing
November 2021

Mating-type genes control sexual reproduction, conidial germination and virulence in Cochliobolus lunatus.

Phytopathology 2021 Nov 5. Epub 2021 Nov 5.

Shenyang Agricultural University, College of Plant Protection, 120 Dongling Road, Shenyang, Liaoning,China, Shenyang, Liaoning, China, 110866;

Cochliobolus lunatus (anamorph: Curvularia lunata) is a major pathogenic fungus that causes the Curvularia leaf spot of maize. ClMAT1-1-1 and ClMAT1-2-1, the C. lunatus orthologs of Cochliobolus heterostrophus ChMAT1-1-1 and ChMAT1-2-1, were investigated in the present study to uncover their functions in C. lunatus. Southern blot analysis showed that these mating-type MAT genes exist in the C. lunatus genome as a single copy. ClMAT1-1-1 and ClMAT1-2-1 were knocked out and complemented to generate ΔClmat1-1-1 and ΔClmat1-2-1, ΔClmat1-1-1-C and ΔClmat1-2-1-C, respectively. The mutant strains had defective sexual development and failed to produce pseudothecia. There were no significant differences in growth rate or conidia production between the mutant and wild-type strains. However, the aerial mycelia and mycelial dry weight of ΔClmat1-1-1 and ΔClmat1-2-1 were lower than that of wild type, suggesting that MAT genes affect asexual development. ClMAT genes were involved in the responses to cell wall integrity and osmotic adaptation. ΔClmat1-2-1 had a lower conidial germination rate than the wild-type strain CX-3. The virulence of ΔClmat1-2-1 and ΔClmat1-1-1 was also reduced compared to the wild type. Complementary strains could restore all the phenotypes.
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http://dx.doi.org/10.1094/PHYTO-02-21-0063-RDOI Listing
November 2021

Exogenous Citrulline and Glutamine Contribute to Reverse the Resistance of to Apramycin.

Front Microbiol 2021 14;12:759170. Epub 2021 Oct 14.

National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, China.

Antibiotic resistance is an increasing concern for human and animal health worldwide. Recently, the concept of reverting bacterial resistance by changing the metabolic state of antibiotic-resistant bacteria has emerged. In this study, we investigated the reversal of Apramycin resistance in . First, non-targeted metabonomics were used to identify key differential metabolites of drug-resistant bacteria. Then, the reversal effect of exogenous substances was verified and . Finally, the underlying mechanism was studied. The results showed that the metabolites citrulline and glutamine were significantly reduced in Apramycin-resistant . When citrulline and glutamine were added to the culture medium of drug-resistant , the killing effect of Apramycin was restored markedly. Mechanistic studies showed that citrulline and glutamine promoted the Tricarboxylic acid cycle, produced more NADH in the bacteria, and increased the proton-motive force, thus promoting Apramycin entry into the bacterial cells, and killing the drug-resistant bacteria. This study provides a useful method to manage infections by antibiotic-resistant bacteria.
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http://dx.doi.org/10.3389/fmicb.2021.759170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552007PMC
October 2021

Molecular level precision and high molecular weight peptide dendrimers for drug-specific delivery.

J Mater Chem B 2021 Oct 27;9(41):8594-8603. Epub 2021 Oct 27.

Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Zhejiang Key Laboratory of Smart Biomaterials, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China.

Peptide dendrimers have a broad application in biomedical science due to their biocompatibility, diversity, and multifunctionality, but the precision synthesis of high-molecule weight peptide dendrimers remains challenging. We here report the facile and liquid-phase synthesis of molecular level precision and amino-acid built-in polylysine (PLL) dendrimers with molecular weights as high as ∼60 kDa. Three types of polyhedral oligosilsesquioxane (POSS)-cored PLL dendrimers with phenylalanine, tyrosine, or histidine as building blocks were synthesized. The precise structures of the dendrimers were confirmed by MALDI-TOF MS, GPC, and H NMR spectroscopy. The interior functionalized peptide dendrimers improved the encapsulation capability of SN38 and sustained the release profiles. Enhanced molecular interactions between the peptide dendrimers and drugs were explored by both NMR experiments and computer simulations. The peptide dendrimer/SN38 formulations showed potent antitumor activity against multiple cancer cell lines. We believe that this strategy can be applied to the synthesis of tailor-made functional peptide dendrimers for drug-specific delivery and other diverse biomedical applications.
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http://dx.doi.org/10.1039/d1tb01157jDOI Listing
October 2021

Gastrointestinal microbiome and gluten in celiac disease.

Ann Med 2021 12;53(1):1797-1805

Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.

Coeliac disease (CD), also known as gluten sensitive enteropathy, is an autoimmune intestinal disease induced by gluten in genetically susceptible individuals. Gluten is a common ingredient in daily diet and is one of the main environmental factors to induce coeliac disease. Adhering to gluten free diet (GFD) is an effective method for treating CD. Microbiota plays an extremely important role in maintaining human health, and diet is the main factor to regulate the composition and function of gut microbiota. Recent studies have shown that gluten metabolism is closely related to gastrointestinal tract (GIT) microbiota. With the increasing prevalence of coeliac disease, there is a need for alternative treatments to GFD. In this review, biological medication of gluten, relationship between gluten and gut microflora, effect of GFD on GIT microflora, and effect of probiotics on CD were reviewed. By analysing the research progress on relationship between gluten and gastrointestinal microbiome in coeliac disease, this review tried to explore the prospective and potential mechanism of microecological agents in treating coeliac disease.
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http://dx.doi.org/10.1080/07853890.2021.1990392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519548PMC
December 2021

Diterpenoid alkaloids from Delphinium forrestii var. viride and their anti-inflammation activity.

Phytochemistry 2021 Dec 7;192:112971. Epub 2021 Oct 7.

Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address:

Six undescribed diterpenoid alkaloids including five C-diterpenoid alkaloids forrestlines A-E, and one C-diterpenoid alkaloid forrestline F, together with nine known alkaloids have been isolated from the whole herbs of Delphinium forrestii var. vride. Their structures were elucidated by spectroscopic data, and their inhibitory activities on NO production stimulated by LPS in RAW264.7 macrophage cells were determined. Then, forrestline F, with the strongest inhibitory activity (IC of 9.57 ± 1.43 μM), was selected to study its possible anti-inflammatory mechanism. ELISA results showed that forrestline F suppressed inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosisfactor-α (TNF-α), and interleukin-6 (IL-6). Moreover, forrestline F could down-regulate LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by western blotting assay. It also inhibited expression of phosphorylation of MAPKs (including p-p38, p-ERK and p-JNK), and NF-κB p65, and decreased ROS accumulation by upregulating the expression of HO-1 expression via nuclear translocation of Nrf2. In conclusion, forrestline F showed anti-inflammatory effect by inhibiting NF-κB/MAPK and Nrf2/HO-1 signaling pathway. Therefore, forrestline F could be a promising molecule for the development of anti-inflammatory agents in the future.
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http://dx.doi.org/10.1016/j.phytochem.2021.112971DOI Listing
December 2021

Short-wavelength blue light contributes to the pyroptosis of human lens epithelial cells (hLECs).

Exp Eye Res 2021 Nov 5;212:108786. Epub 2021 Oct 5.

Eye Hospital, The First Affiliated Hospital of Harbin Medical University, China. Electronic address:

Purpose: The purpose of this study is to examine the effect of short-wavelength blue light (SWBL) on cultured human lens epithelial cells (hLECs). The pathogenesis of cataracts after SWBL exposure is discussed.

Methods: HLE-B3 hLECs were randomly divided into 3 groups: the NC group, which was grown in a dark incubator; the acetyl (Ac)-Tyr-Val-Ala-Asp-chloromethyl ketone (AC-YVAD-CMK) treatment group; and the SWBL exposure group. After SWBL (2500 lux) irradiation (for 8, 16, 24, and 32 h), caspase-1 and gasdermin D (GSDMD) expression levels in HLE-B3 hLECs were examined using ELISA, immunofluorescence staining, and Western blotting analyses. Double-positive staining of hLECs for activated and inhibited caspase-1 was used to determine pyroptosis in HLE-B3 hLECs.

Results: SWBL led to hLEC death, but a caspase-1 inhibitor suppressed cell death. The flow cytometry results also confirmed the dose-dependent effect of SWBL irradiation on the pyroptotic death of hLECs. Caspase-1 and GSDMD expression levels in all hLEC groups changed with blue light exposure times (8, 16, 24, and 32 h) and were higher in the AC-YVAD-CMK and SWBL exposure groups than in the NC group. The immunofluorescence results revealed higher GSDMD-N expression in the cell membrane of both the AC-YVAD-CMK and SWBL exposure groups than in the NC group.

Conclusions: Based on the data, SWBL induces pyroptotic programmed cell death by activating the GSDMD signalling axis in HLE-B3 hLECs. These results provide new insights into the exploitation of new candidates for the prevention of cataracts.
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http://dx.doi.org/10.1016/j.exer.2021.108786DOI Listing
November 2021

Source apportionment of carbonaceous aerosols in diverse atmospheric environments of China by dual-carbon isotope method.

Sci Total Environ 2022 Feb 29;806(Pt 2):150654. Epub 2021 Sep 29.

Keck Carbon Cycle AMS Laboratory, Department of Earth System Science, University of California, Irvine, CA 92697-3100, USA.

Carbonaceous aerosols are major components in PM of both polluted and clean atmosphere. Accurate source apportionment of carbonaceous aerosols may support effective PM control. Dual-carbon isotope method (C and C) was adopted to identify the contribution of three main air pollution sources biogenic and biomass (f), liquid fossil (f) and coal (f). The aerosol samples were collected at three types of sites with distinctly different degree of air pollution: urban, rural and regional background. The seasonal variation of source apportionment of the carbonaceous aerosols in urban Beijing was discussed. Modern biogenic and biomass made an absolute dominance of 92.9 ± 0.5% contribution to the carbonaceous aerosols at the background site Mt. Yulong due to long-range transport from Southeast Asia. The three main sources contributed jointly to the atmospheric carbonaceous aerosols at the rural site Wangdu and the urban site Beijing. The biogenic and biomass source was the major contribution in summer (47.0 ± 0.3%) and autumn (49.3 ± 0.3%) of Beijing, while coal source increased from summer (26.8 ± 13.8%) to autumn (34.7 ± 11.5%). Heating significantly increased the coal source to the dominant contribution (47.0 ± 16.9%) in winter of Beijing. Separate day and night time coal contributions were used to evaluate the two origins of coal combustion: industrial use vs. residential use. The results of source apportionment for carbonaceous aerosols provide scientific support for the prevention and control of air pollution.
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http://dx.doi.org/10.1016/j.scitotenv.2021.150654DOI Listing
February 2022

Isoliquiritigenin alleviates LPS/ D-GalN-induced acute liver failure by activating the PGC-1α/ Nrf2 pathway to reduce oxidative stress and inflammatory response.

Int Immunopharmacol 2021 Nov 20;100:108159. Epub 2021 Sep 20.

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China. Electronic address:

Acute liver failure (ALF) is a dramatic liver disease characterized by large areas of inflammation. However, there are no available effective targeted drugs for ALF treatment. In the study, serum biochemical index and H&E were used to explore the amelioration of the liver histopathological changes. The oxidative stress kits, quantitative real-time PCR, western blot, immunohistochemistry, immunofluorescence staining, reactive oxygen species (ROS), and siRNA were used to elucidate the mechanisms underlying isoliquiritigenin (ISL) protection. The results showed that ISL significantly improved the liver pathological changes. Furthermore, ISL reduced oxidative stress by altering the expression of PGC-1α, Nrf2, HO-1, NQO1, Keap1, GCLC, and GCLM in damaged hepatocytes. Moreover, the levels of inflammation-related genes including NLRP3 inflammasome, IL-1β, IL-6, TNF-α, iNOS, and Mip-2 were repressed by ISL. In addition, ISL alleviated LPS/D-GalN-induced hepatocytes apoptosis by increasing the Bcl-2/Bax ratio and suppressing the expression of cleaved caspase-3. Further in vivo and in vitro evidence proved the involvement of the PGC-1α/Nrf2 signaling pathway in ISL protection. In conclusion, ISL improves the ability of anti-oxidative stress, alleviates inflammatory reaction, apoptosis, and inhibits NLRP3 inflammasome to protect lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced ALF through activating the PGC-1α/Nrf2 pathway, which provides the possibility for the treatment of ALF.
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http://dx.doi.org/10.1016/j.intimp.2021.108159DOI Listing
November 2021

TiO-modified fibrous core-shell mesoporous material to selectively enrich endogenous phosphopeptides with proteins exclusion prior to CE-MS analysis.

Talanta 2021 Dec 24;235:122737. Epub 2021 Jul 24.

Key Laboratory of Nanobiosensing and Nanobioanalysis at Universities of Jilin Province, Department of Chemistry, Northeast Normal University, 5268 Renmin Street, Changchun, Jilin Province, 130024, China. Electronic address:

As an important post-translational modification of proteins, phosphorylation plays a key role in regulating a variety of complicated biological reactions. Owing to the fact that phosphopeptides are low abundant and the ionization efficiency could be suppressed in mass spectroscopic detection, highly efficient and selective enrichment methods are essential to identify protein phosphorylation by mass spectrometry. Here, we develop novel titanium oxide coated core shell mesoporous silica ([email protected]) nanocomposites for enrichment of phosphopeptides with simultaneous exclusion of massive proteins. The [email protected] nanocomposites have essential features, including uniform 1.0 μm diameter, 120 nm thick shell, 7.0 nm mesopores perpendicular to the surface, large surface area of 77 m/g and pore volume of 0.15 cm/g, therefore can greatly improve the sensitivity for identifying phosphopeptides by capillary electrophoresis-mass spectrometry. The proposed [email protected] nanocomposites are applied for analysis of β-casein tryptic digest and bovine serum albumin (BSA) protein mixture, respectively. The results show that the number of phosphopeptides detected is tremendously increased by using [email protected] nanocomposite, proving selectively enriching phosphopeptides due to the size-exclusive and specific interaction of the TiO-modified mesopores. The enrichment of the phosphopeptides is achieved even for the digests at very low concentration of β-casein (1 fmol/μL). This research would open up a promising idea to utilize mesoporous materials in peptidomics analysis.
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http://dx.doi.org/10.1016/j.talanta.2021.122737DOI Listing
December 2021

Linear-Dendritic Polymer-Platinum Complexes Forming Well-Defined Nanocapsules for Acid-Responsive Drug Delivery.

ACS Appl Mater Interfaces 2021 Sep 9;13(37):44028-44040. Epub 2021 Sep 9.

Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Zhejiang Key Laboratory of Smart Biomaterials, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China.

Polymeric nanocapsules hold considerable applications in cancer drug delivery, but the synthesis of well-defined nanocapsules with a tunable drug release property remains a significant challenge in fabrication. Herein, we demonstrate a supramolecular complexation strategy to assemble small molecular platinum (Pt) compounds into well-defined nanocapsules with high drug loading, acidity-sensitivity, and tunable Pt releasing profile. The design utilizes poly(ethylene glycol)-dendritic polylysine-G4/amides to complex with Pt compounds, forming stable nanocapsules with diameters approximately ∼20 nm and membrane thickness around several nanometers. The stability, drug content, and release profiles are tunable by tailoring the dendritic structure. The designated polymer-Pt nanocapsules, PEG-G4/MSA-Pt, showed sustained blood retention, preferential tumor accumulation, enhanced cellular uptake, lysosomal drug release, and nuclear delivery capability. PEG-G4/MSA-Pt showed enhanced antitumor efficacy compared to free cisplatin and other nanocapsules, which stopped the progression of both A549 cell xenografts and patient-derived xenografts (PDXs) of hepatocellular carcinoma on a mice tumor model. Thus, we believe this strategy is promising for developing Pt-based nanomedicine for cancer drug delivery.
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http://dx.doi.org/10.1021/acsami.1c12156DOI Listing
September 2021

Clinical Characteristics, Prognosis, and Gender Disparities in Young Patients With Acute Myocardial Infarction.

Front Cardiovasc Med 2021 12;8:720378. Epub 2021 Aug 12.

Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Young people hold a stable or increasing percentage of patients with acute myocardial infarction (AMI) in many countries. However, data on clinical characteristics and outcomes of young AMI patients were insufficient. This study aimed to analyze clinical characteristics, prognosis, and gender disparities in patients aged ≤45 years with AMI. A total of 24,125 patients from China Acute Myocardial Infarction registry were included in this study. Clinical characteristics, managements, and in-hospital and 2-year outcomes were compared between patients aged ≤45 years and those aged >45 years. Predictors of all-cause death were obtained using multivariate regression models. Gender disparities of AMI were analyzed among young patients. Of 24,125 patients, 2,042 (8.5%, 116 female) were aged ≤45 years. Compared with patients aged >45 years, young patients were more often male, current smokers, and more likely to have medical history of hyperlipidemia. Smoking (72.1%) was the major modifiable risk factor in patients aged ≤45 years. Young patients received more evidence-based medications and had significantly lower risk of both in-hospital and 2-year adverse events than older patients. Education level and left ventricular ejection fraction were independent predictors of 2-year mortality in young patients. Moreover, symptom onset to admission time of young women was significantly longer than that of young men. Young women were less likely to receive percutaneous coronary intervention and suffered higher risk of in-hospital adverse events than young men (adjusted odds ratio for death: 5.767, 95% confidence interval 1.580-21.049, = 0.0080; adjusted odds ratio for the composite of death, re-infarction, and stroke: 3.981, 95% confidence interval 1.150-13.784, = 0.0292). Young women who survived at discharge had a higher 2-year cumulative incidence of death (3.8 vs 1.4%, = 0.0412). Patients aged ≤45 years constituted a non-negligible proportion of AMI patients, with higher prevalence of smoking and hyperlipidemia but better care and prognosis compared with older patients. There were significant gender disparities of managements and outcomes in young patients. More efforts to improve quality of care in young women are needed.
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http://dx.doi.org/10.3389/fcvm.2021.720378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387867PMC
August 2021

Yangonin modulates lipid homeostasis, ameliorates cholestasis and cellular senescence in alcoholic liver disease via activating nuclear receptor FXR.

Phytomedicine 2021 Sep 17;90:153629. Epub 2021 Jun 17.

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China. Electronic address:

Background: Alcoholic liver disease (ALD) is a progressive disease beginning with simple steatosis but can progress to alcoholic steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. The morbidity of ALD is on the rise and has been a large burden on global healthcare system. It is unfortunately that there are currently no approved therapeutic drugs against ALD. Hence, it is of utmost urgency to develop the efficacious therapies. The ability of many molecular targets against ALD is under investigation. Farnesoid X receptor (FXR), a member of the ligand-activated transcription factor superfamily, has been recently demonstrated to have a crucial role in the pathogenesis and progression of ALD.

Purpose: The purpose of the study is to determine whether Yangonin (YAN), a FXR agonist previously demonstrated by us, exerts the hepatoprotective effects against ALD and further to clarify the mechanisms in vitro and in vivo.

Study Design: The alcoholic liver disease model induced by Lieber-Decarli liquid diet was established with or without Yan treatment.

Methods: We determined the liver to body weight ratios, the body weight, serum and hepatic biochemical indicators. The alleviation of the liver histopathological progression was evaluated by H&E and immunohistochemical staining. Western blot and quantitative real-time PCR were used to demonstrate YAN treatment-mediated alleviation mechanisms of ALD.

Results: The data indicated that YAN existed hepatoprotective activity against ALD via FXR activation. YAN improved the lipid homeostasis by decreasing hepatic lipogenesis and increasing fatty acid β-oxidation and lipoprotein lipolysis through modulating the related protein. Also, YAN ameliorated ethanol-induced cholestasis via inhibiting bile acid uptake transporter Ntcp and inducing bile acid efflux transporter Bsep and Mrp2 expression. Besides, YAN improved bile acid homeostasis via inducing Sult2a1 expression and inhibiting Cyp7a1 and Cyp8b1 expression. Furthermore, YAN attenuated ethanol-triggered hepatocyte damage by inhibiting cellular senescence marker P16, P21 and Hmga1 expression. Also, YAN alleviated ethanol-induced inflammation by down-regulating the inflammation-related gene IL-6, IL-1β and TNF-α expression. Notably, the protective effects of YAN were cancelled by FXR siRNA in vitro and FXR antagonist GS in vivo.

Conclusions: YAN exerted significant hepatoprotective effects against liver injury triggered by ethanol via FXR-mediated target gene modulation.
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http://dx.doi.org/10.1016/j.phymed.2021.153629DOI Listing
September 2021

Determination of the panel of reference genes for quantitative real-time PCR in fetal and adult rat intestines.

Reprod Toxicol 2021 09 6;104:68-75. Epub 2021 Jul 6.

Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. Electronic address:

In quantitative real-time PCR (qRT-PCR) detection, the stability of reference genes varies with different organs, tissue locations, sex and developmental stages. This study aimed to screen out and determine the optimal panel of reference genes of the intestine in pre- and post-natal rats of different sex. We used qRT-PCR to detect the mRNA expression of six commonly used reference genes (ACTB, GAPDH, HPRT1, B2M, RPLPO and SDHA) in rat intestines at gestational day 21 (GD21) and postnatal week 12 (PW12). Using GeNorm, BestKeeper and NormFinder software comprehensively analyzed the stability of candidate reference genes and screened out stable reference genes. Further, we used the pathological model of prenatal dexamethasone exposure (PDE) to verify the stability of the selected panel of reference genes. Based on the results of the software analysis, the optimal panel of reference genes in the fetal rat intestine was SDHA + ACTB, and the adult rat small intestine and colon were ACTB + HPRT1 and RPLP0 + GAPDH, respectively. There was no significant sex difference in the above results. Besides, in the PDE model, the results were consistent with those under physiological conditions. Therefore, the stability of intestinal reference genes in fetal rats and adult rats was different, and the intestinal reference genes of adult rats were intestinal segments-specific. The selected panel of reference genes was still stable under pathological conditions. This study determined the optimal panel of reference genes of pre- and post-natal rat intestines and provided reliable reference genes for the qRT-PCR analysis of rat intestines.
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http://dx.doi.org/10.1016/j.reprotox.2021.07.001DOI Listing
September 2021

[Simultaneous and rapid determination of malachite green and leucomalachite green by a label-free colorimetric aptasensor].

Se Pu 2020 Nov;38(11):1332-1339

Agricultural College of Yanbian University, Yanji 133002, China.

A label-free colorimetric aptasensor, using a bispecific aptamer (A3) as a sensing probe, gold nanoparticles (AuNPs) as an indicator, and NaCl solution as an aggregation inducer, was successfully developed for the simultaneous, rapid and visual detection of malachite green (MG) and leucomalachite green (LMG) in aquatic products. This method is based on the aptamer A3 having bispecific binding ability with MG and LMG, making it an ideal recognition receptor for MG and LMG. It can adsorb on the AuNPs and protect AuNPs against salt-induced aggregation, maintaining the red color of the solution. When MG or LMG was added to a solution, aggregation of AuNPs was specifically induced by desorption of aptamer from the AuNPs surface upon formation of the aptamer-target complex. Therefore, the salt could trigger aggregation of AuNPs and the solution color was changed from red to blue. This color change allowed the qualitative determination of MG and LMG visually, and quantitative determination by measuring the ratio of the absorbances at 520 nm and 650 nm. In this study, 50 μL of the nucleic acid aptamer A3 (final concentrations 150 nmol/L) and 150 μL of AuNPs (final concentrations 1.25 nmol/L) were incubated at room temperature (RT) for 6 min, then 50 μL of the sample was added and incubated at RT for 30 min, and finally 50 μL NaCl solution (final concentrations 150 mmol/L) was added. After 4 min, the solution color change was observed, and the absorbances at 520 nm and 650 nm were measured. Under the optimal conditions, MG and LMG could be detected specifically without any cross-reactivity with sulfadiazine (SDZ) and nitrofurantoin (NFT). The absorbance were related to the concentrations of MG and LMG, and a good linear relationship was obtained in the range of 0-17.5 μmol/L. The correlation coefficients () were 0.9938 and 0.9715, respectively. The limits of detection of MG and LMG were 6.93 nmol/L and 6.38 nmol/L, respectively. The spiked recoveries of MG and LMG ranged from 88.60% to 93.30% and 101.80% to 107.00%, respectively. The relative standard deviations (RSDs) of MG and LMG ranged from 2.27% to 3.55% and 2.62% to 3.75%, respectively. This colorimetric method is simple, rapid, sensitive, and allows visual, and it can provide a new method for the simultaneous and rapid determination of the MG and LMG in aquatic products.
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http://dx.doi.org/10.3724/SP.J.1123.2020.04010DOI Listing
November 2020

Mixture of controlled-release and conventional urea fertilizer application changed soil aggregate stability, humic acid molecular composition, and maize nitrogen uptake.

Sci Total Environ 2021 Oct 15;789:147778. Epub 2021 May 15.

National Engineering Laboratory for Efficient Utilization of Soil and Fertilizer Resources, College of Recourses and Environment, Shandong Agricultural University, Taian, Shandong 271018, China.

Controlled-release urea (CRU) fertilizer application has been shown to improve crop yield and nitrogen (N) use efficiency. However, its effects when mixed with conventional urea fertilizer on soil aggregate stability, humic acid (HA) molecular composition and crop N uptake remain unclear. Soil and plant samples were collected from a long-term (2008-2019) experiment on field maize (Zea mays L., 'Zhengdan 958') which included two types of fertilizers [conventional urea fertilizer (CUF), blended CUF with CRU fertilizer (CRF)], four N application rates (0, 150, 300 and 450 kg ha), each in three replicates. The results showed that at 300 kg N ha, compared to CUF treatment, the CRF treatment significantly improved soil aggregate characteristics [aggregate content with particle size larger than 0.25 mm (R) by 9.6%, mean weight diameter by 19.8%, and geometric mean diameter by 21.7%]. CRF treatment also increased HA content by 5.5%, fulvic acid (FA) by 5.5%, lignin-like molecules by 0.94 times, and protein-like molecules by 3.69 times. At grain-filling stage, CRF treatments significantly increased the sum of soil NH-N and NO-N content by 23.3-24.5%, sap bleeding rate by 12.8-18.2% and N delivery rate through bleeding sap by 60.6-87.7% compared to CUF treatments at the same N application rate. At the same rate of N application, the CRF treatments significantly improved the average yield during three growing seasons by 9.4-14.0% in contrast with CUF treatments. The regression equations showed that the maximum yield was 8294 kg ha for CUF at the application rate of 312 kg N ha while it was 9890 kg ha for CRF at the application rate of 286 kg N ha. We conclude that the long-term application of CRF changed the HA molecular structure, enhanced the water stable aggregates, improved crop N uptake, and increased economically viable maize yield.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147778DOI Listing
October 2021

Consensus of Stochastic Dynamical Multiagent Systems in Directed Networks via PI Protocols.

IEEE Trans Neural Netw Learn Syst 2021 May 28;PP. Epub 2021 May 28.

With the rapid development of swarm intelligence, the consensus of multiagent systems (MASs) has attracted substantial attention due to its broad range of applications in the practical world. Inspired by the considerable gap between control theory and engineering practices, this article is aimed at addressing the mean square consensus problems for stochastic dynamical nonlinear MASs in directed networks by designing proportional-integral (PI) protocols. In light of the general algebraic connectivity, consensus underlying PI protocols for a directed strongly connected network is investigated, and due to the M-matrix approaches, consensus with PI protocols for a directed network containing a spanning tree is studied. By constructing appropriate Lyapunov functions, combining with the stochastic analysis technique and LaSalle's invariant principles, some sufficient conditions are derived under which the stochastic dynamical MASs realize consensus in mean square. Numerical simulations are finally presented to illustrate the validity of the main results.
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http://dx.doi.org/10.1109/TNNLS.2021.3080122DOI Listing
May 2021

Luteolin ameliorates LPS-induced acute liver injury by inhibiting TXNIP-NLRP3 inflammasome in mice.

Phytomedicine 2021 Jul 5;87:153586. Epub 2021 May 5.

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China. Electronic address:

Background: Chemical liver injury is one of the main causes of acute liver failure and death. To date, however, treatment strategies for acute liver injury have been limited. Therefore, there is an urgent need to find new therapeutic targets and effective drugs. NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a complex of multiple proteins that has been shown to induce cell death under inflammatory and stress pathologic conditions and is thought to provide new targets for the treatment of a variety of diseases.

Purpose: The purpose of this study was to investigate whether luteolin has a protective effect on the liver and further elucidate whether it is realized through the thioredoxin interacting protein (TXNIP)-NLRP3 axis.

Study Design: Acute hepatic injury in mice caused by intraperitoneal injection of lipopolysaccharide (LPS) was treated with or without luteolin.

Methods: Male C57BL/6 mice and mouse primary hepatocytes were selected. TXNIP protein knockdown was achieved by siRNA, qPCR and Western blot were performed to explore the mechanism of luteolin in alleviating acute liver injury.

Results: The results indicated that luteolin had a markedly protective effect on acute liver injury induced by LPS in mice by inhibiting the TXNIP-NLRP3 axis. Luteolin inhibits NLRP3 inflammasome activation by suppressing TXNIP, apoptosis associated speck-like protein containing a CARD domain (ASC), caspase-1, interleukin-1β (IL-1β) and IL-18 to reduce liver injury. In addition, luteolin inhibits LPS-induced liver inflammation by inhibiting the production of inflammation-related gene tumor necrosis factor-α (TNF-α), IL-10, and IL-6. What's more, luteolin alleviated LPS-induced hepatocyte injury by inhibiting oxidative stress and regulating MDA, SOD, and GSH levels. However, the protective effect of luteolin on acute LPS-induced liver injury in mice was blocked by si-TXNIP in vitro.

Conclusions: These combined data showed that luteolin may alleviate LPS-induced liver injury through the TXNIP-NLPR3 axis, providing new therapeutic targets and therapeutic drugs for subsequent studies.
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http://dx.doi.org/10.1016/j.phymed.2021.153586DOI Listing
July 2021

Nonlinear response of SIA to emission changes and chemical processes over eastern and central China during a heavy haze month.

Sci Total Environ 2021 Sep 14;788:147747. Epub 2021 May 14.

Wuhan Environmental Monitoring Center, Wuhan 430015, China.

This study used a chemical transport model to investigate the response of secondary inorganic aerosols (SIA) to chemical processes and its precursor emissions over northern and southern city-clusters of China in January 2014. Unexpectedly, SIA concentrations with low levels of precursor emissions were much higher over the southern regions than those over the northern region with high levels of precursor emissions, based on ground observations and high-precision simulations. The sensitivity analysis of chemical processes suggests that the gas-phase chemistry was a critical factor determining the SIA pattern, especially the higher efficiency of nitrogen conversion to nitrate in southern cities controlled by favorable meteorological elements than that in northern city. However, the heterogeneous process led to the decrease of SIA in southern regions by 3% to 36% and the increasing of SIA in NCP by 26.9%, mainly attributing to the impact on nitrate. The reason was that sulfate enhancement by the heterogeneous reactions can compete ammonia (NH) and the excessive nitric acid converted into nitrogen oxide (NO), leading to nitrate decrease in southern regions under NH-deficient regimes. Moreover, through sensitivity experiments of precursor emission reduction by 20%, NH control was found to be the most effective for reducing SIA concentrations comparing to sulfur dioxide (SO) and NO reduction and a more remarkable decrease of SIA was in southern regions by 10% to 15% than that in northern region by 6.7%. The effect of the synergy control of precursors emission varied in different city-clusters, inferring that the control strategy aimed at improving air quality should be implemented based on specific characteristics of precursors emission in different regions of China.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147747DOI Listing
September 2021

An optimized analog of antimicrobial peptide Jelleine-1 shows enhanced antimicrobial activity against multidrug resistant P. aeruginosa and negligible toxicity in vitro and in vivo.

Eur J Med Chem 2021 Jul 7;219:113433. Epub 2021 Apr 7.

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, West Donggang Road 199, Lanzhou, 730000, China. Electronic address:

Due to the threat of escalating multi-drug resistant gram-negative bacteria to human health and life, novel antimicrobial agents against gram-negative pathogens are urgently needed. As antimicrobial peptides are not prone to induce bacteria resistance, they are believed to be one kind of promising class of potential antimicrobial agent candidates to combat multi-drug resistant bacteria for long-term use. Jelleine-1, first isolated from the royal jelly of honeybees, is a typical amphiphilic antimicrobial peptide and shows broad antimicrobial spectrum and negligible toxicity. To promote its antimicrobial activity and extend its potential of clinical use against multi-drug resistant gram-negative bacteria, novel analogs of jelleine-1 were designed, synthesized and their antimicrobial functions and toxicity were examined in this study. Our results showed that fine tuning of the cationic charge, polarity, and basicity of the sequence through amino acids substitution at position 3, 5, 7 and maintaining position 1, 4, 6, 8 unchanged could improve the bioactivity of jelleine-1 significantly. Meanwhile, we also found that the substitution of phenylalanine by tryptophan also could improve the antimicrobial activity of jelleine-1. Among all the analogs, analog 15, which is enriched in arginine and leucine, showed the most potent antimicrobial activity against both gram-negative and gram-positive bacteria, especially to multi-drug resistant Pseudomonas aeruginosa in vivo and in vitro. In addition, analog 15 also showed potent inhibition of the formation of multi-drug resistant P. aeruginosa biofilm and negligible toxicity, which was certified by MTT, hemolysis, blood assay, and biochemical analysis.
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http://dx.doi.org/10.1016/j.ejmech.2021.113433DOI Listing
July 2021

Ultraviolet-cured polyethylene oxide-based composite electrolyte enabling stable cycling of lithium battery at low temperature.

J Colloid Interface Sci 2021 Aug 15;596:257-266. Epub 2021 Mar 15.

Research Centre of Nanoscience and Nanotechnology, Shanghai University, Shanghai 200444, China; Emerging Industries Institute, Shanghai University, Jiaxing, Zhejiang 314006, China. Electronic address:

The room and low-temperature performances of solid-state lithium batteries are crucial to expand their practical application. Polyethylene oxide (PEO) has received great attention as the most representative polymer electrolyte matrix. However, most PEO-based solid-state batteries need to operate at high temperature due to low room temperature ionic conductivity. Improving the ionic conductivity by adding plasticizers or reducing the crystallinity of PEO often compromises its mechanical strength. Here, an amorphous PEO-based composite solid-state electrolyte is obtained by ultraviolet (UV) polymerizing PEO and methacryloyloxypropyltrimethoxy silane (KH570)-modified SiO which demonstrates both satisfactory mechanical performance and high ionic conductivity at room (3.37 × 10 S cm) and low temperatures (1.73 × 10 S cm at 0 °C). In this electrolyte, the crystallinity of PEO is reduced through cross-linking, and therefore provides a fast Li ions transfer area. Moreover, the KH570-modified SiO inorganic particles promote the dissociation of lithium salts by Lewis acid centers to increase the ionic conductivity. Importantly, this kind of cross-linking networks endows the final electrolyte much higher mechanical strength than the pure PEO polymer electrolyte or PEO-inorganic filler blended systems. The solid-state LiFePO/Li cell assembled with this electrolyte exhibits excellent cycling performance and high capacity at room and low temperatures.
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http://dx.doi.org/10.1016/j.jcis.2021.02.095DOI Listing
August 2021

Unexpected Deprotonation from a Chemically Inert OH Group Promoted by Metal Ions in Lanthanide-Erythritol Complexes.

Inorg Chem 2021 Apr 12;60(7):5172-5182. Epub 2021 Mar 12.

Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Rare Earth Materials Chemistry and Applications, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

Single-crystal structures of five lanthanide-erythritol complexes are reported. The analysis of the chemical compositions and scrutinization of structural features in the single-crystal data of the complexes led us to find that unexpected deprotonation occurs on the OH group of erythritol of three complexes. Considering these complexes were prepared in acidic environments, where spontaneous ionization on an OH group is suppressed, we suggest metal ions play an important role in promoting the proton transfer. To find out why the chemically inert OH is activated, the single-crystal structures of 63 rare-earth complexes containing organic ligands with multiple hydroxyl groups (OLMHs) were surveyed. The formation of μ-bridges turns out to be directly relevant to the occurrence of deprotonation. When an OH group from an OLMH molecule participates in the formation of a μ-bridge, the polarization ability of the metal ions becomes strong enough to promote the deprotonation on the OH group. The above structural characteristics may be useful in the rational design of catalysts that can activate the chemically inert OH group and promote the relevant chemical conversions.
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http://dx.doi.org/10.1021/acs.inorgchem.1c00179DOI Listing
April 2021

Silver Nanoparticles Attenuate the Antimicrobial Activity of the Innate Immune System by Inhibiting Neutrophil-Mediated Phagocytosis and Reactive Oxygen Species Production.

Int J Nanomedicine 2021 18;16:1345-1360. Epub 2021 Feb 18.

Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.

Purpose: Despite the extensive development of antibacterial biomaterials, there are few reports on the effects of materials on the antibacterial ability of the immune system, and in particular of neutrophils. In this study, we observe differences between the in vivo and in vitro anti-infective efficacies of silver nanoparticles (AgNPs). The present study was designed to further explore the mechanism for this inconsistency using ex vivo models and in vitro experiments.

Methods: AgNPs were synthesized using the polyol process and characterized by transmission electron microscopy and X-ray photoelectron spectroscopy. The antibacterial ability of AgNPs and neutrophils was tested by the spread-plate method. The infected air pouch model was prepared to detect the antimicrobial ability of AgNPs in vivo. Furthermore, blood-AgNPs-bacteria co-culture model and reactive oxygen species (ROS) measurement were used to evaluate the effect of AgNPs to neutrophil-mediated phagocytosis and ROS production.

Results: The antibacterial experiments in vitro showed that AgNPs had superior antibacterial properties in cell compatible concentration. While, AgNPs had no significant antibacterial effect in vivo, and pathological section in AgNPs group indicated less neutrophil infiltration in inflammatory site than group. Furthermore, AgNPs were found to reduce the phagocytosis of neutrophils and inhibit their ability to produce ROS and superoxide during ex vivo and in vitro experiments.

Conclusion: This study selects AgNPs as the representative of inorganic nano-biomaterials and reveals the phenomenon and the mechanism underlying the significant AgNPs-induced inhibition of the antibacterial ability of neutrophils, and may have a certain enlightening effect on the development of biomaterials in the future. In the fabrication of antibacterial biomaterials, however, attention should be paid to both cell and immune system safety to make the antibacterial properties of the biomaterials and innate immune system complement each other and jointly promote the host's ability to resist the invasion of pathogenic microorganisms.
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http://dx.doi.org/10.2147/IJN.S292482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901559PMC
March 2021

Comparison of the Inhibitory Effects of Clotrimazole and Ketoconazole against Human Carboxylesterase 2.

Curr Drug Metab 2021 ;22(5):391-398

College of Pharmacy, Dalian Medical University, Dalian, 116044, China.

Background: Both clotrimazole and ketoconazole have been verified to have an inhibitory effect on CYP3A4. hCE2 is an enzyme closely related to the side effects of several anti-cancer drugs. However, the interactions between hCE2, clotrimazole, and ketoconazole remain unclear.

Objective: The objective of this study was to investigate and compare the inhibition behaviors of the two antifungal agents, ketoconazole and clotrimazole, on the human liver microsome hCE2 and to explore their underlying mechanism.

Methods: The inhibitory effects were investigated in human liver microsomes (HLMs) using fluorescein diacetate (FD), N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN) and irinotecan (CPT- 11) as substrates of hCE2.

Results: Clotrimazole significantly inhibited the hCE2 activity, which was manifested by attenuated fluorescence when the substrates were FD and NCEN. The inhibitory effect of clotrimazole towards hCE2 was much stronger than that of ketoconazole, and the inhibitory behaviors displayed substrate-dependent inhibition. The IC value of clotrimazole, with CPT-11 as the substate, increased by 5 and 37 times more than that with FD and NCEN, respectively. Furthermore, the inhibitions of clotrimazole towards hCE2-mediated hydrolysis of FD, NCEN, and CPT-11 were all in competitive mode with the Ki values of 0.483 μM, 8.63 μM, and 29.0 μM, respectively. Molecular docking result of clotrimazole binding to hCE2 illustrated that clotrimazole could efficiently orient itself in the Z site cavity of hCE2.

Conclusion: Clotrimazole displayed a strong inhibitory effect against hCE2, which might be used as a potential combined agent co-administrated with CPT-11 to alleviate the hCE2-mediated severe side effects.
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http://dx.doi.org/10.2174/1389200222666210210115509DOI Listing
January 2021

Catalpol-Induced AMPK Activation Alleviates Cisplatin-Induced Nephrotoxicity through the Mitochondrial-Dependent Pathway without Compromising Its Anticancer Properties.

Oxid Med Cell Longev 2021 15;2021:7467156. Epub 2021 Jan 15.

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning, China.

Nephrotoxicity is a common complication of cisplatin chemotherapy and, thus, limits the clinical application of cisplatin. In this work, the effects of catalpol (CAT), a bioactive ingredient extracted from Rehmannia glutinosa, on cisplatin-induced nephrotoxicity and antitumor efficacy were comprehensively investigated. Specifically, the protective effect of CAT on cisplatin-induced injury was explored in mice and HK-2 cells. , CAT administration strikingly suppressed cisplatin-induced renal dysfunction, morphology damage, apoptosis, and inflammation. , CAT induced activation of adenosine 5'-monophosphate- (AMP-) activated protein kinase (AMPK), improved mitochondrial function, and decreased generation of cellular reactive oxygen species (ROS), leading to a reduction in inflammation and apoptosis, which ultimately protected from cisplatin-induced injury. However, the beneficial effects of CAT were mostly blocked by coincubation with compound C. Furthermore, molecular docking results indicated that CAT had a higher affinity for AMPK than other AMPK activators such as danthron, phenformin, and metformin. Importantly, CAT possessed the ability to reverse drug resistance without compromising the antitumor properties of cisplatin. These findings suggest that CAT exerts positive effects against cisplatin-induced renal injury through reversing drug resistance via the mitochondrial-dependent pathway without affecting the anticancer activity of cisplatin.
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http://dx.doi.org/10.1155/2021/7467156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826214PMC
September 2021

Prenatal dexamethasone exposure induces nonalcoholic fatty liver disease in male rat offspring via the miR-122/YY1/ACE2-MAS1 pathway.

Biochem Pharmacol 2021 03 16;185:114420. Epub 2021 Jan 16.

Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, China. Electronic address:

Epidemiological studies have shown that nonalcoholic fatty liver disease (NAFLD) has an intrauterine developmental origin. We aimed to demonstrate that NAFLD is caused by prenatal dexamethasone exposure (PDE) in adult male rat offspring and to investigate the intrauterine programming mechanism. Liver samples were obtained on gestational day (GD) 21 and postnatal week (PW) 28. The effects and epigenetic mechanism of dexamethasone were studied with bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and other cell models. In the PDE group, lipid accumulation increased, triglyceride synthesis-related gene expression increased, and oxidation-related gene expression decreased in livers of adult male rat offspring. In utero, hepatic triglyceride synthesis increased and oxidative function decreased in PDE fetal male rats. Moreover, low hepatic miR-122 expression, high Yin Yang-1 (YY1) expression and angiotensin-converting enzyme 2 (ACE2)-Mas receptor (MAS1) signaling pathway inhibition were observed before and after birth. At the cellular level, dexamethasone (100-2500 nM) elevated the intracellular triglyceride content, increased triglyceride synthesis-related gene expression and decreased oxidation-related gene expression. Dexamethasone treatment also decreased miR-122 expression, increased YY1 expression and inhibited the ACE2-MAS1 signaling pathway. Interference or overexpression of glucocorticoid receptor (GR), miR-122, YY1 and ACE2 could reverse the changes in downstream gene expression. In summary, PDE could induce NAFLD in adult male rat offspring. The programming mechanism included inhibition of miR-122 expression after GR activation, and dexamethasone increased hepatocyte YY1 expression; these effects resulted in ACE2-MAS1 signaling pathway inhibition, which led to increased hepatic triglyceride synthesis and decreased oxidative function. The increased triglyceride synthesis and decreased oxidative function of hepatocytes caused by low miR-122 expression due to dexamethasone could continue postnatally, eventually leading to NAFLD in adult rat offspring.
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http://dx.doi.org/10.1016/j.bcp.2021.114420DOI Listing
March 2021

Panel of suitable reference genes and its gender differences of fetal rat liver under physiological conditions and exposure to dexamethasone during pregnancy.

Reprod Toxicol 2021 03 14;100:74-82. Epub 2021 Jan 14.

Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. Electronic address:

The panel of suitable reference genes in the fetal liver have not been reported. In this study, five commonly used reference genes (GAPDH, β-actin, Rn18 s, Rpl13a, and Rps29) were firstly selected as candidates. Bestkeeper, GeNorm, and NormFinder software were then used to screen out the panel of suitable reference genes of male and female fetal rat liver under physiological and prenatal dexamethasone exposure (PDE) conditions. Finally, we verified the reliability of the screened panel of reference genes by standardizing sterol regulatory element binding protein 1c (SREBP1c) expression with different reference genes. The results showed that GAPDH + Rn18 s and GAPDH + Rpl13a were respectively the panel of suitable reference genes in male and female rat fetal liver under the physiological model, while Rn18 s + Rps29 and GAPDH + Rn18 s were respectively under the PDE model. The results showed that different reference genes affected the statistical results of SREBP1c expression, and the screened panel of suitable reference genes under the PDE model had smaller intragroup differences, when compared with other reference genes under physiological and PDE models. In conclusion, we screened and determined that the panel of suitable reference genes were GAPDH + Rn18 s and Rn18 s + Rps29 in the male rat fetal liver under physiological and PDE models, while they were GAPDH + Rpl13a and GAPDH + Rn18 s in the females, and confirmed that the selection of the panel of suitable reference genes in the fetal liver had gender differences and pathological model specificity.
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http://dx.doi.org/10.1016/j.reprotox.2021.01.005DOI Listing
March 2021

Identifying the Dominant Contribution of Human Cytochrome P450 2J2 to the Metabolism of Rivaroxaban, an Oral Anticoagulant.

Cardiovasc Drugs Ther 2021 Jan 7. Epub 2021 Jan 7.

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.

Purpose: Rivaroxaban, an oral anticoagulant, undergoes the metabolism mediated by human cytochrome P450 (CYP). The present study is to quantitatively analyze and compare the contributions of multiple CYPs in the metabolism of rivaroxaban to provide new information for medication safety.

Methods: The metabolic stability of rivaroxaban in the presence of human liver microsomes (HLMs) and recombinant CYPs was systematically evaluated to estimate the participation of various CYP isoforms. Furthermore, the catalytic efficiency of CYP isoforms was compared via metabolic kinetic studies of rivaroxaban with recombinant CYP isoenzymes, as well as via CYP-specific inhibitory studies. Additionally, docking simulations were used to illustrate molecular interactions.

Results: Multiple CYP isoforms were involved in the hydroxylation of rivaroxaban, with decreasing catalytic rates as follows: CYP2J2 > 3A4 > 2D6 > 4F3 > 1A1 > 3A5 > 3A7 > 2A6 > 2E1 > 2C9 > 2C19. Among the CYPs, 2J2, 3A4, 2D6, and 4F3 were the four major isoforms responsible for rivaroxaban metabolism. Notably, the intrinsic clearance of rivaroxaban catalyzed by CYP2J2 was nearly 39-, 64-, and 100-fold that catalyzed by CYP3A4, 2D6, and 4F3, respectively. In addition, rivaroxaban hydroxylation was inhibited by 41.1% in the presence of the CYP2J2-specific inhibitor danazol, which was comparable to the inhibition rate of 43.3% by the CYP3A-specific inhibitor ketoconazole in mixed HLMs. Furthermore, molecular simulations showed that rivaroxaban is principally bound to CYP2J2 by π-alkyl bonds, carbon-hydrogen bonds, and alkyl interactions.

Conclusion: CYP2J2 dominated the hydroxylation of rivaroxaban, which may provide new insight into clinical drug interactions involving rivaroxaban.
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http://dx.doi.org/10.1007/s10557-020-07129-zDOI Listing
January 2021

The PGE2 receptor EP3 plays a positive role in the activation of hypothalamic-pituitary-adrenal axis and neuronal activity in the hypothalamus under immobilization stress.

Brain Res Bull 2021 03 25;168:45-51. Epub 2020 Dec 25.

Department of Animal Physiology, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471003, PR China. Electronic address:

Background: Prostaglandin E2 (PGE2) binds to four receptor subtypes (EP1, EP2, EP3 and EP4) and plays an important role in response to stress. However, the identity of the receptor(s) responsible for PGE2 regulation of neuronal activity and signaling through activation of the hypothalamic-pituitary-adrenal (HPA) axis under immobilization stress is unknown.

Purpose: The present study aimed to investigate the role of the hypothalamic PGE2 receptors in the activation of the HPA axis and neuronal activity in a rat model of stress.

Methods: Stress was induced by immobilization of the animals, after which the stress-induced profile of PGE2 receptor signaling in the rat hypothalamus was determined by real-time polymerase chain reaction and immunohistochemistry. The effect of a selective EP3 receptor antagonist on corticosterone concentrations and c-Fos immunoreactivity was measured.

Results: Expression of EP2 and EP3 receptor genes, but not EP1 and EP4, was increased following immobilization stress. The EP3 receptor was localized to the paraventricular nucleus (PVN) of the hypothalamus, and the integrated density of the EP3 receptor was increased after immobilization stress. Rats given L-798,106, a selective antagonist of the EP3 receptor, showed significant attenuation of stress-increased serum corticosterone levels. EP3 antagonist also significantly suppressed the increase in the gene expression of c-Fos and the number of c-Fos-immunoreactive cells in the PVN of the hypothalamus following immobilization stress.

Conclusions: These results suggest that immobilization stress may result in increased activation of the HPA axis and neuronal activity through regulating the function of the EP3 receptor.
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http://dx.doi.org/10.1016/j.brainresbull.2020.12.014DOI Listing
March 2021
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