Publications by authors named "Chunling Wang"

219 Publications

Physical and Chemical Compatibility of Etomidate and Propofol Injectable Emulsions.

Pharmacology 2021 Oct 13:1-14. Epub 2021 Oct 13.

Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, China.

Introduction: The mixture of etomidate and propofol is widely used in clinical practice to improve efficacy of general anesthesia and to minimize side effects. As a thermodynamically unstable system, emulsion is prone to destabilization through mechanisms including coalescence, flocculation, and creaming. Such unwanted phenomenon can induce fat embolism after intravenous administration. This study was aimed to investigate the physical and chemical stability of the mixture of etomidate and propofol in the dosage form of emulsion.

Methods: This compatibility study focused on the critical quality attributes (CQAs) of drug-containing emulsions, such as appearance, pH, particle size and distribution, zeta potential, the observation under centrifugation, and drug content and impurity.

Results: As the results, there were no significant changes in the CQAs of the mixed emulsions up to 24 h after mixing at refrigeration temperature (4°C), room temperature (25°C), and body temperature (37°C).

Conclusions: These results demonstrate that etomidate emulsion is physically and chemically compatible with propofol emulsions up to 24 h at 4°C, 25°C, and 37°C, suggesting that etomidate and propofol can be administrated in mixture without adversely affecting product characteristics, at least in vitro.
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http://dx.doi.org/10.1159/000519236DOI Listing
October 2021

Matrine ameliorates the inflammatory response and lipid metabolism in vascular smooth muscle cells through the NF-κB pathway.

Exp Ther Med 2021 Nov 16;22(5):1309. Epub 2021 Sep 16.

Department of Emergency Medicine, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China.

Atherosclerosis is a chronic inflammatory disease associated with inflammatory responses and the uncontrolled proliferation and excessive apoptosis of vascular smooth muscle cells. However, the effects of matrine on the inflammatory response, abnormal lipid metabolism and cell proliferation and apoptosis marker proteins in human aortic vascular smooth muscle cells (HAVSMCs) have not been elucidated. Therefore, the present study aimed to investigate the effect of matrine on an model of atherosclerosis using HAVSMCs. The HAVSMCs were divided into normal, model and matrine groups. The model group was treated with oxidized low-density lipoprotein (oxLDL), the matrine group was treated with oxLDL and matrine and the normal group was treated with physiological saline. Total cholesterol (TC), free cholesterol (FC) and cholesterol ester (CE) levels were measured in the cell supernatant. In addition, the relative mRNA levels of inflammatory factors were quantified using reverse transcription-quantitative PCR, and the cell proliferation and apoptosis rates were evaluated using Cell Counting Kit-8 and flow cytometry assays, respectively. The expression levels of proteins associated with proliferation and apoptosis were also determined using western blotting. The levels of TC, FC and CE and the mRNA levels of IL-1β, IL-6, and TNF-α in the matrine group were lower than those in the model group, but higher than those in the normal group. After 48 and 96 h of treatment, the cell proliferation and apoptotic rates were lower in the matrine group compared with the model group. The relative expression levels of Ki-67, proliferating cell nuclear antigen and Bax were decreased, while that of Bcl-2 was increased in the matrine group compared with the model group. In addition, the relative protein expression of nuclear factor κB (NF-κB) in the matrine group was lower than that in the model group, but higher than that in the normal group. In summary, matrine inhibited activation of the NF-κB pathway and reduced cell proliferation and apoptosis in the oxLDL-induced atherosclerosis model, and exhibited anti-inflammatory effects. These results suggest that matrine attenuated abnormal biological reactions in HAVSMCs through the NF-κB pathway.
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http://dx.doi.org/10.3892/etm.2021.10744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461614PMC
November 2021

Structural characterization of polysaccharide from yellow sweet potato and ameliorates DSS-induced mice colitis by active GPR41/MEK/ERK 1/2 signaling pathway.

Int J Biol Macromol 2021 Sep 29;192:278-288. Epub 2021 Sep 29.

State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Food Nutrition and Safety, Ministry of Education, College of Food Engineering and Biotechnology, Tianjin University of Science and Technology, No.29, 13th Avenue, Tianjin Economy Technological Development Area, Tianjin 300457, People's Republic of China. Electronic address:

A polysaccharide isolated from yellow sweet potato (Ipomoea batatas (L.) Lam.) consisted of Rha, Ara, Gal, Glc, GalA, GlcA with the ratio of 1.00, 2.00, 3.63, 1.21, 1.17, 1.14, respectively. The molecular weight (Mw) of RSPP-A was determinted to be 2.51×10 kDa. Methylation, Nuclear Magnetic Resonance (NMR) (1D & 2D) and Fourier transform infrared spectroscopy (FT-IR) analysis indicated that RSPP-A possessed six glycosidic bonds including α-L-Araf-(1→, →5)-α-L-Araf-(1→, →6)-β-D-Galp-(1→, β-D-Glcp-(1→, →3)-α-L-Araf-(1→, →3)-α-L-Rhap-(1→. In dextran sulfate sodium (DSS) induced mouse-acute-colitis model, the results indicated that RSPP-A could down- regulate the secretion of IL-6 and IL-1β, and promote the secretion of IL-10 in serum and colon, which also suggested that RSPP-A could enhance the contents of short chain fatty acids(SCFAs) and up-regulate the expression of G protein-coupled receptor (GPR41) in colon. Moreover, the expression of Mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase 1/2 (ERK1/2) were up-regulated in colon after intervention with RSPP-A, result from above suggested that the anti-inflammatory activity might be related to the production of SCFA, activating GPR41/MEK/ERK1/2 signaling pathway.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.09.175DOI Listing
September 2021

Imaging-Based Body Fat Distribution in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Front Endocrinol (Lausanne) 2021 9;12:697223. Epub 2021 Sep 9.

School of Medicine, Cheeloo College of Medicine, Shandong University, Ji'nan, China.

Background: Women with polycystic ovary syndrome (PCOS) are generally considered to be central obese and at higher risks of metabolic disturbances. Imaging methods are the golden standards for detecting body fat distribution. However, evidence based on magnetic resonance imaging (MRI) and computed tomography (CT) is conflicting. This study systematically reviewed the imaging-based body fat distribution in PCOS patients and quantitatively evaluated the difference in body fat distribution between PCOS and BMI-matched controls.

Methods: PUBMED, EMBASE, and Web of Science were searched up to December 2019, and studies quantitatively compared body fat distribution by MRI, CT, ultrasound, or X-ray absorptiometry (DXA) between women with PCOS and their BMI-matched controls were included. Two researchers independently reviewed the articles, extract data and evaluated the study quality based on Newcastle-Ottawa Scale (NOS).

Results: 47 studies were included in systematic review and 39 were eligible for meta-analysis. Compared to BMI-matched controls, higher accumulations of visceral fat (SMD 0.41; 95%CI: 0.23-0.59), abdominal subcutaneous fat (SMD 0.31; 95%CI: 0.20-0.41), total body fat (SMD 0.19; 95% CI: 0.06-0.32), trunk fat (SMD 0.47; 95% CI: 0.17-0.77), and android fat (SMD 0. 36; 95% CI: 0.06-0.66) were identified in PCOS group. However, no significant difference was identified in all the above outcomes in subgroups only including studies using golden standards MRI or CT to evaluate body fat distribution (SMD 0.19; 95%CI: -0.04-0.41 for visceral fat; SMD 0.15; 95%CI: -0.01-0.31 for abdominal subcutaneous fat). Moreover, meta-regression and subgroup analyses showed that young and non-obese patients were more likely to accumulate android fat.

Conclusions: PCOS women seem to have abdominal fat accumulation when compared with BMI-matched controls. However, MRI- and CT- assessed fat distribution was similar between PCOS and controls, suggesting central obesity may be independent of PCOS. These findings will help us reappraise the relationship between PCOS and abnormal fat deposition and develop specialized lifestyle interventions for PCOS patients.

Systematic Review Registration: PROSPERO, identifier CRD42018102983.
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http://dx.doi.org/10.3389/fendo.2021.697223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458943PMC
September 2021

Comparative study between two bleeding grading systems of immune thrombocytopenia purpura.

Hematology 2021 Dec;26(1):769-774

Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, People's Republic of China.

Objective: To explore the relationship between platelet count and bleeding score in immune thrombocytopenia purpura (ITP) and compare the clinical practicability of two bleeding grading systems with adult patients with ITP.

Methods: A total of 204 patients were retrospectively analyzed with the ITP bleeding scale (IBLS) and the ITP bleeding assessment tool (version 2016) (ITP-2016). The correlation between the two bleeding score systems and the relations among the platelet counts were respectively analyzed.

Results: (1) There is a linear relationship between platelet count and bleeding score, no matter which scoring system it is based on (rs = -0.429,  < 0.001; rs = -0.331,  < 0.001, the analysis of the number of sites of Grade 1/2 bleeding were done; and rs = -0.466,  < 0.05, the analysis between platelet count and bleeding score by ITP-2016 respectively). (2) Platelet count and bleeding scores are negatively correlated in those with extremely low platelet counts ( < 10*10/L). The number of sites of Grade 2 bleeding and the ITP-2016 scores are negatively correlated with platelet counts (rs = -0.15 and rs = -0.244,  < 0.05, respectively). Significantly, there is no correlation between the platelet count and bleeding scores when the platelet count is more than 10*10/L. (3) It takes less time to score with ITP-2016 than IBLS ( = -3.825,  < 0.001).

Conclusions: There is good responsiveness, strong assessment consistency, close correlation between ITP-2016 and IBLS. ITP-2016 takes less time-consuming in clinical application. It can be used as an effective tool of condition judgement, risk assessment and efficacy evaluation of patients with ITP.
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http://dx.doi.org/10.1080/16078454.2021.1978753DOI Listing
December 2021

Intraoperative use of low-dose dexmedetomidine for the prevention of emergence agitation following general anaesthesia in elderly patients: a randomized controlled trial.

Aging Clin Exp Res 2021 Sep 22. Epub 2021 Sep 22.

Department of Anesthesiology, Affiliated Hospital of Weifang Medical University, Weifang, 261000, China.

Objective: To clarify the effect of an intraoperative low-dose dexmedetomidine infusion on emergence agitation following general anaesthesia in elderly patients.

Methods: Eighty elderly patients (> 64-years-old) following elective general anaesthesia for radical cancer surgeries were randomly allocated into two groups (n = 40 each): the dexmedetomidine group (Group D) and the normal saline group (Group C). Anaesthesia was maintained with continuous intravenous infusion of dexmedetomidine at - 0.2 µg kg h in Group D, and an equal volume of normal saline (0.5 ml kg h) was given in Group C. All patients were observed for 30 min in the post-anaesthesia care unit (PACU), AFPS and NRS were recorded every 2 min, and the total doses of nalbuphine and fentanyl were calculated in the PACU. MAP and HR were recorded at the time of 10 min (T1), 20 min (T2), 30 min (T3) after dexmedetomidine or saline pumping, and before extubation (T4), immediately after extubation (T5), and 5 min after extubation (T6). We also documented some durations, including anaesthesia duration (D1), surgery duration (D2), duration from the end of surgery to extubation (D3), and emergence agitation duration (D4).

Results: The MAP in Group C was significantly higher than that in Group D (P < 0.05), and there were no significant changes between the two groups in HR and MAP within each time point and D1, D2, D3, and D4. The incidence of agitation, NRS score and total dose of nalbuphine and fentanyl were all lower in Group D than in Group C (P < 0.05).

Conclusion: An intraoperative low-dose dexmedetomidine continuous infusion can reduce emergence agitation following general anaesthesia in elderly patients (> 64-years-old), remain stable in terms of haemodynamics, and not lead to delays in anaesthesia recovery time and extubation time.
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http://dx.doi.org/10.1007/s40520-021-01984-yDOI Listing
September 2021

Transcriptomic Analysis Provides Insights into Foliar Zinc Application Induced Upregulation in 2-Acetyl-1-pyrroline and Related Transcriptional Regulatory Mechanism in Fragrant Rice.

J Agric Food Chem 2021 Sep 16;69(38):11350-11360. Epub 2021 Sep 16.

Department of Crop Science and Technology, College of Agriculture, South China Agricultural University, Guangzhou 510642, P. R. China.

The involvement of zinc (Zn) in terms of aroma formation has been rarely investigated. This study shows that the regulation of 2-acetyl-1-pyrroline (2AP) biosynthesis was evaluated in two different rice cultivars under foliar Zn application. The results showed that the 2AP and Zn contents in leaves and grains were improved substantially under foliar Zn application. The 2AP content was positively related to the expression gene, contents of proline, 1-pyrroline, and Δ1-pyrroline-5-carboxylate (P5C), and the activity of pyrroline-5-carboxylate synthase (P5CS) under Zn application in fragrant rice. Multiple transcription factors (TFs) were differently expressed, such as , , and , to play a role under Zn treatments in fragrant rice, suggesting the crucial role of 46 differently expressed TFs in 2AP improvements in fragrant rice. Furthermore, this study showed that the optimal foliar Zn application at a concentration of 30 mg L could increase the 2AP content of aromatic rice and keep the yield stable or increase the yield. TFs were involved in regulating to promote the 2AP formation in aromatic rice under the foliar Zn application. However, the relationship between 2AP biosynthesis pathway genes and TFs in fragrant rice remains to be further studied.
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http://dx.doi.org/10.1021/acs.jafc.1c03655DOI Listing
September 2021

Comprehensive evaluation of protein-coding sORFs prediction based on a random sequence strategy.

Front Biosci (Landmark Ed) 2021 Aug;26(8):272-278

Shandong Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, 253023 Dezhou, Shandong, China.

: Small open reading frames (sORFs) with protein-coding ability present unprecedented challenge for genome annotation because of their short sequence and low expression level. In the past decade, only several prediction methods have been proposed for discovery of protein-coding sORFs and lack of objective and uniform negative datasets has become an important obstacle to sORFs prediction. The prediction efficiency of current sORFs prediction methods needs to be further evaluated to provide better research strategies for protein-coding sORFs discovery. : In this work, nine mainstream existing methods for predicting protein-coding potential of ORFs are comprehensively evaluated based on a random sequence strategy. : The results show that the current methods perform poorly on different sORFs datasets. For comparison, a sequence based prediction algorithm trained on prokaryotic sORFs is proposed and its better prediction performance indicates that the random sequence strategy can provide feasible ideas for protein-coding sORFs predictions. : As a kind of important functional genomic element, discovery of protein-coding sORFs has shed light on the dark proteomes. This evaluation work indicates that there is an urgent need for developing specialized prediction tools for protein-coding sORFs in both eukaryotes and prokaryotes. It is expected that the present work may provide novel ideas for future sORFs researches.
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http://dx.doi.org/10.52586/4943DOI Listing
August 2021

The Protective Effect of Docosahexaenoic Acid on PC12 Cells in Oxidative Stress Induced by HO through the TrkB-Erk1/2-CREB Pathway.

ACS Chem Neurosci 2021 09 25;12(18):3433-3444. Epub 2021 Aug 25.

"State Key Laboratory of Food Nutrition and Safety", Key Laboratory of Food Nutrition and Safety, Ministry of Education, College of Food Engineering and Biotechnology, Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin Economy Technological Development Area, Tianjin 300457, People's Republic of China.

Docosahexaenoic acid (DHA) has attracted plenty of interest in the prevention of neurodegenerative diseases. Although the beneficial effects of DHA on the central nervous system function are recognized, more information on the molecular mechanisms involved in its neuroprotective effects is required. The present study aimed to evaluate the effects of DHA on the function of mitochondria, neurite growth-related proteins signaling pathway, and neural signal transmission. In this study, PC12 cells were treated with HO (400 μM) to establish an oxidative damage model. Results showed that DHA improved the viability and morphology of PC12 cells. DHA significantly increased the antioxidant capacity, mitochondrial membrane potential, and activity of ATPase in the cells. Furthermore, the phosphorylation levels of tyrosine kinase receptor (BTrkB), phospholipase C-γ1 (PLCγ1), calcium/calmodulin-dependent protein kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), and cAMP-response element-binding protein (CREB) were upregulated by DHA. The damage on F-actin induced by HO was reversed by DHA, indicating that DHA could protect neurite outgrowth. In addition, DHA increased the content of acetylcholine and γ-aminobutyric acid while decreasing glutamic acid. These results revealed that DHA could protect PC12 cells from damage induced by HO through the TrkB-ERK1/2-CREB pathway.
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http://dx.doi.org/10.1021/acschemneuro.1c00421DOI Listing
September 2021

Distinct Pathways in Visible-Light Driven Thermo-Photo Catalytic Methane Conversion.

J Phys Chem Lett 2021 Aug 2;12(31):7459-7465. Epub 2021 Aug 2.

Department of Materials Science and Engineering, Michigan Technological University, Houghton, Michigan 49931, United States.

The utilization of visible light for direct photocatalytic methane conversion remains a huge challenge. Here, we developed a thermo-photo catalytic process with a visible-light-responsive Pt/WO catalyst and realized highly efficient visible-light driven methane conversion for the first time. The conversion efficiency was enhanced by 4.6 and 14.7 times compared to room-temperature photocatalysis and thermal catalysis at 150 °C, respectively. Furthermore, the production of liquid oxygenates (mainly CHOH) was found to proceed via photocatalysis with high apparent quantum efficiencies of 5.9%, 4.5%, and 1.9% at 350, 420, and 450 nm, respectively, while CO evolution was contributed by photoassisted thermal catalysis. Solid isotope evidence further confirmed that CHOH, HCHO, and CO were produced via parallel rather than sequential reactions. These observations provide a valuable guide for designing a visible-light driven system for methane conversion with high efficiency and controllable selectivity.
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http://dx.doi.org/10.1021/acs.jpclett.1c02053DOI Listing
August 2021

RNA demethylation increases the yield and biomass of rice and potato plants in field trials.

Nat Biotechnol 2021 Jul 22. Epub 2021 Jul 22.

Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.

RNA N-methyladenosine (mA) modifications are essential in plants. Here, we show that transgenic expression of the human RNA demethylase FTO in rice caused a more than threefold increase in grain yield under greenhouse conditions. In field trials, transgenic expression of FTO in rice and potato caused ~50% increases in yield and biomass. We demonstrate that the presence of FTO stimulates root meristem cell proliferation and tiller bud formation and promotes photosynthetic efficiency and drought tolerance but has no effect on mature cell size, shoot meristem cell proliferation, root diameter, plant height or ploidy. FTO mediates substantial mA demethylation (around 7% of demethylation in poly(A) RNA and around 35% decrease of mA in non-ribosomal nuclear RNA) in plant RNA, inducing chromatin openness and transcriptional activation. Therefore, modulation of plant RNA mA methylation is a promising strategy to dramatically improve plant growth and crop yield.
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http://dx.doi.org/10.1038/s41587-021-00982-9DOI Listing
July 2021

Highly efficient visible-light photocatalytic ethane oxidation into ethyl hydroperoxide as a radical reservoir.

Chem Sci 2021 Mar 18;12(16):5825-5833. Epub 2021 Mar 18.

School of Environmental Science and Engineering, Shanghai Jiao Tong University Shanghai 200240 China.

Photocatalytic ethane conversion into value-added chemicals is a great challenge especially under visible light irradiation. The production of ethyl hydroperoxide (CHCHOOH), which is a promising radical reservoir for regulating the oxidative stress in cells, is even more challenging due to its facile decomposition. Here, we demonstrated a design of a highly efficient visible-light-responsive photocatalyst, Au/WO, for ethane oxidation into CHCHOOH, achieving an impressive yield of 1887 μmol g in two hours under visible light irradiation at room temperature for the first time. Furthermore, thermal energy was introduced into the photocatalytic system to increase the driving force for ethane oxidation, enhancing CHCHOOH production by six times to 11 233 μmol g at 100 °C and achieving a significant apparent quantum efficiency of 17.9% at 450 nm. In addition, trapping active species and isotope-labeling reactants revealed the reaction pathway. These findings pave the way for scalable ethane conversion into CHCHOOH as a potential anticancer drug.
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http://dx.doi.org/10.1039/d1sc00694kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179680PMC
March 2021

On-line screening of indoleamine 2,3-dioxygenase 1 inhibitors by partial filling capillary electrophoresis combined with rapid polarity switching.

J Chromatogr A 2021 Aug 18;1651:462305. Epub 2021 Jun 18.

Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, KU Leuven - University of Leuven, Leuven, Belgium. Electronic address:

Indoleamine 2,3-dioxygenase 1 (IDO1) has been shown to play an important role in the immune escape process of tumors, and therefore is considered as a promising target for tumor immunotherapy. In this study, off-line and on-line capillary electrophoresis methods were developed for IDO1 inhibitors screening from natural product extracts. The optimized separation conditions of CE were achieved with 32 mM sodium tetraborate (pH 9.22) as background electrolyte, using a separation voltage of 21 kV. The off-line CE method was verified by the determination of enzymatic kinetic parameters and inhibitory mechanisms of two known inhibitors. A partial filling on-line CE method combined with rapid polarity switching was used for rapid screening of IDO1 inhibitors. The whole reaction and separation process was completed within 5 min. The on-line CE screening results showed that six of 18 natural products had inhibitory effect on IDO1, namely Carthamus tinctorius, Schisandra chinensis, Raisin, Coffee, Hawthorn and Radix angelicae sinensis. The results of on-line CE experiments were consistent with the off-line results, which proved the practicability and effectiveness of the method for inhibitors screening.
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http://dx.doi.org/10.1016/j.chroma.2021.462305DOI Listing
August 2021

Recent Advances in C.A. Meyer as a Herb for Anti-Fatigue: An Effects and Mechanisms Review.

Foods 2021 May 10;10(5). Epub 2021 May 10.

State Key Laboratory of Food Nutrition and Safety, College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China.

As an ancient Chinese herbal medicine, C.A. Meyer () has been used both as food and medicine for nutrient supplements and treatment of human diseases in China for years. Fatigue, as a complex and multi-cause symptom, harms life from all sides. Millions worldwide suffer from fatigue, mainly caused by physical labor, mental stress, and chronic diseases. Multiple medicines, especially , were used for many patients or sub-healthy people who suffer from fatigue as a treatment or healthcare product. This review covers the extract and major components of with the function of anti-fatigue and summarizes the anti-fatigue effect of for different types of fatigue in animal models and clinical studies. In addition, the anti-fatigue mechanism of associated with enhancing energy metabolism, antioxidant and anti-inflammatory activity is discussed.
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http://dx.doi.org/10.3390/foods10051030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151278PMC
May 2021

Regulatory effect of non-starch polysaccharides from purple sweet potato on intestinal microbiota of mice with antibiotic-associated diarrhea.

Food Funct 2021 Jun;12(12):5563-5575

"State Key Laboratory of Food Nutrition and Safety", Key Laboratory of Food Nutrition and Safety, Ministry of Education, College of Food Engineering and Biotechnology, Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin Economy Technological Development Area, Tianjin, 300457, People's Republic of China.

Antibiotic treatment causes antibiotic-associated diarrhea (AAD), which is usually accompanied by disorders of the intestinal flora, aggravating the patient's condition. Recently, more attention has been devoted to the ability of plant polysaccharides to improve the body's flora and enhance immunity. However, reports on whether purple sweet potato polysaccharides (PSPPs) can improve AAD are scarce. This study aimed to extract a non-starch polysaccharide from purple sweet potato and analyze its structure and ability to regulate the intestinal flora of mice with AAD. The diarrhea model was established via intragastric administration of lincomycin and different concentrations of PSPPs (0.1 g kg-1, 0.2 g kg-1, and 0.4 g kg-1) to Balb/C mice. The results showed that PSPP was a pyran polysaccharide with 1 → 2, 1 → 2, 6, 1 → 4, 1 → 4, 6 glycosidic bonds in an α-configuration. In vivo experiments showed that PSPP could relieve diarrhea and improve the structural damage in the ileum caused by lincomycin hydrochloride. In addition, treatment with PSPPs decreased the levels of IL-1β, IL-6 and TNF-α but increased the level of IL-10 in the intestines of mice (p < 0.01). The results of 16S rRNA sequencing showed that PSPPs changed the composition and diversity of the intestinal flora of mice with AAD. In addition, PSPP treatment increased the content of short-chain fatty acids (p < 0.01). These results revealed that PSPPs regulated the intestinal flora, balanced fatty acid metabolism, and relieved the symptoms of diarrhea to a certain extent in mice.
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http://dx.doi.org/10.1039/d0fo03465gDOI Listing
June 2021

The Efficacy of Combined Cisplatin and Nanoparticle Albumin-Bound Paclitaxel in a Stage IV Pancreatic Squamous Cell Carcinoma Patient With a Somatic Mutation: A Case Report.

Front Oncol 2021 29;11:585983. Epub 2021 Apr 29.

Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.

Pancreatic squamous cell carcinoma (SCC) is a rare primary pancreatic malignancy with a poor prognosis. The median overall survival (OS) for metastatic setting is only 4 months and the optimal management remains poorly defined. In the present study, we report a 52-year-old female patient with stage IV primary SCC of the pancreas harboring a deleteous somatic mutation. After 10 cycles of chemotherapy of cisplatin combined with nanoparticle albumin-bound paclitaxel, metastatic lesions in the liver and lymph nodes achieved radiographic complete responses and pancreatic lesion shrank from 5.7 to 1.5 cm in diameter. The patient subsequently underwent a posterior radical antegrade modular pancreatosplenectomy with R0 resection and residual liver lesions were also resected. After 3 months, a tumor relapsed in the liver. She was then treated with olaparib combined with pembrolizumab and achieved stable disease on the liver lesion. The patient eventually died from cerebral hemorrhage with a long OS of 21 months. Our case demonstrated a favorable clinical activity and survival advantage of the combined cisplatin and nanoparticle albumin-bound paclitaxel, which might serve as a therapeutic option for the patient with -mutant pancreatic SCC.
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http://dx.doi.org/10.3389/fonc.2021.585983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116796PMC
April 2021

High expression of TARP correlates with inferior FLT3 mutations in non-adolescents and young adults with acute myeloid leukaemia.

Hematology 2021 Dec;26(1):380-387

Department of Hematology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, People's Republic of China.

Objectives: Acute myeloid leukaemia (AML) is a haematopoietic malignancy with a dismal outcome. Consequently, risk stratification based on more effective prognostic biomarkers is crucial to make accurate therapy decisions. T cell receptor gamma alternative reading frame protein (TARP) has been reported in prostate and breast cancers, but its correlation with AML remains unclear.

Methods: Differential expression of TARP mRNA in different AML subtypes was analysed using the UALCAN online platform. Its relationship with baseline clinical attributes, survival and efficacy were analysed based on three GSE1159, GSE425 and GSE6891 microarray datasets downloaded from Gene Expression Omnibus (GEO) and Oncomine databases. Quantitative real-time PCR was performed to determine mRNA levels of TARP in bone marrow mononuclear cells (BMMCs) isolated from AML patients.

Results: TARP was significantly overexpressed in AML patients. In AML, relatively low TARP expression was associated with the fusion gene. The proportion of FLT3 mutations was significantly higher in non-adolescent and young adult (non-AYA, >39 years of age) AML patients who had high TARP levels but not in AYA (15-39 years) patients. High expression of TARP was related to poor outcome by univariate analysis but not by multivariate analysis and unsatisfactory therapeutic effects, which could be overcome by haematopoietic stem cell transplantation (HSCT).

Conclusion: Our findings suggest that TARP might be a potential prognostic marker of AML and serve as a promising immunotherapeutic target.
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http://dx.doi.org/10.1080/16078454.2021.1917915DOI Listing
December 2021

-inositol improves growth performance and regulates lipid metabolism of juvenile Chinese mitten crab () fed different percentage of lipid.

Br J Nutr 2021 Apr 29:1-13. Epub 2021 Apr 29.

Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai200241, People's Republic of China.

This study evaluated the effects of dietary myo-inositol (MI) on growth performance, antioxidant status and lipid metabolism of juvenile Chinese mitten crab (Eriocheir sinensis) fed different percentage of lipid. Crabs (4·58 (sem 0·05) g) were fed four diets including a normal lipid diet (N, containing 7 % lipid and 0 mg/kg MI), N with MI supplementation (N + MI, containing 7 % lipid and 1600 mg/kg MI), a high lipid diet (H, containing 13 % lipid and 0 mg/kg MI) and H with MI supplementation (H + MI, containing 13 % lipid and 1600 mg/kg MI) for 8 weeks. The H + MI group showed higher weight gain and specific growth rate than those in the H group. The dietary MI could improve the lipid accumulations in the whole body, hepatopancreas and muscle as a result of feeding on the high dietary lipid (13 %) in crabs. Besides, the crabs fed the H + MI diets increased the activities of antioxidant enzymes but reduced the malondialdehyde content in hepatopancreas compared with those fed the H diets. Moreover, dietary MI enhanced the expression of genes involved in lipid oxidation and exportation, yet reduced lipid absorption and synthesis genes expression in the hepatopancreas of crabs fed the H diet, which might be related to the activation of inositol 1,4,5-trisphosphate receptor (IP3R)/calmodulin-dependent protein kinase kinase-β (CaMKKβ)/adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway. This study demonstrates that MI could increase lipid utilisation and reduce lipid deposition in the hepatopancreas of E. sinensis fed a high lipid diet through IP3R/CaMKKβ/AMPK activation. This work provides new insights into the function of MI in the diet of crustaceans.
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http://dx.doi.org/10.1017/S0007114521001409DOI Listing
April 2021

The BCMA-Targeted Fourth-Generation CAR-T Cells Secreting IL-7 and CCL19 for Therapy of Refractory/Recurrent Multiple Myeloma.

Front Immunol 2021 5;12:609421. Epub 2021 Mar 5.

Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.

Chimeric antigen receptor (CAR) technology has revolutionized cancer treatment, particularly in malignant hematological tumors. Currently, the BCMA-targeted second-generation CAR-T cells have showed impressive efficacy in the treatment of refractory/relapsed multiple myeloma (R/R MM), but up to 50% relapse remains to be addressed urgently. Here we constructed the BCMA-targeted fourth-generation CAR-T cells expressing IL-7 and CCL19 (i.e., BCMA-7 × 19 CAR-T cells), and demonstrated that BCMA-7 × 19 CAR-T cells exhibited superior expansion, differentiation, migration and cytotoxicity. Furthermore, we have been carrying out the first-in-human clinical trial for therapy of R/R MM by use of BCMA-7 × 19 CAR-T cells (ClinicalTrials.gov Identifier: NCT03778346), which preliminarily showed promising safety and efficacy in first two enrolled patients. The two patients achieved a CR and VGPR with Grade 1 cytokine release syndrome only 1 month after one dose of CAR-T cell infusion, and the responses lasted more than 12-month. Taken together, BCMA-7 × 19 CAR-T cells were safe and effective against refractory/relapsed multiple myeloma and thus warranted further clinical study.
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http://dx.doi.org/10.3389/fimmu.2021.609421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985831PMC
July 2021

Long noncoding RNA (lncRNA) induces chemoresistance of gastric cancer via autophagy activation.

Autophagy 2021 Mar 25:1-19. Epub 2021 Mar 25.

Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Chemotherapy is currently the main treatment for unresectable or advanced postoperative gastric cancers. However, its efficacy is negatively affected by the occurrence of chemoresistance, which severely affects patient prognosis. Recently, dysregulation in autophagy has been suggested as a potential mechanism for chemoresistence, and long noncoding RNA (lncRNA) also shows its regulatory role in cancer drug resistance. Using RNA sequencing, we found that lncRNA was highly expressed in drug-resistant gastric cancer cells. In-vitro and in-vivo experiments showed that activated autophagy and induced drug resistance in gastric cancer cells by targeting ATG14. Bioinformatics and experimental results showed that regulated the expression of ATG14 through direct binding to enhance stabilization of mRNA and via blocking the degradation of mRNA through competitively binding with microRNA (miRNA) . Therefore, increased the expression of ATG14, contributing to activation of autophagy and chemoresistance. Furthermore, it was confirmed that and ATG14 were highly expressed in gastric cancer patients resistant to chemotherapy, and this was closely associated with patient prognosis. In conclusion, is involved in the regulation of autophagy and chemoresistance in gastric cancer cells by targeting ATG14. It may be a suitable new target for enhancing chemosensitivity and improving prognosis. 3-MA: 3-methyladenine; 5-Fu: 5-fluorouracil; ATG: autophagy related; C-CASP3: cleaved caspase 3; C-CASP7: cleaved caspase 7; C-PARP: cleaved PARP; CQ: chloroquine; CR: complete response; DIG: digoxigenin; ESR1: estrogen receptor 1; FBS: fetal bovine serum; FISH: fluorescence in situ hybridization; IHC: immunohistochemistry; ISH: in situ hybridization; lncRNA: long noncoding RNA; miRNA: microRNA; MUT: mutant; NC: negative control; OXA: oxaliplatin; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TEM: transmission electron microscopy; WT: wild type.
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http://dx.doi.org/10.1080/15548627.2021.1901204DOI Listing
March 2021

Ligand-induced structural changes analysis of ribose-binding protein as studied by molecular dynamics simulations.

Technol Health Care 2021 ;29(S1):103-114

Shandong Provincial Key Laboratory of Biophysics (Dezhou University), Dezhou, Shandong 253023, China.

Background: The ribose-binding protein (RBP) from Escherichia coli is one of the representative structures of periplasmic binding proteins. Binding of ribose at the cleft between two domains causes a conformational change corresponding to a closure of two domains around the ligand. The RBP has been crystallized in the open and closed conformations.

Objective: With the complex trajectory as a control, our goal was to study the conformation changes induced by the detachment of the ligand, and the results have been revealed from two computational tools, MD simulations and elastic network models.

Methods: Molecular dynamics (MD) simulations were performed to study the conformation changes of RBP starting from the open-apo, closed-holo and closed-apo conformations.

Results: The evolution of the domain opening angle θ clearly indicates large structural changes. The simulations indicate that the closed states in the absence of ribose are inclined to transition to the open states and that ribose-free RBP exists in a wide range of conformations. The first three dominant principal motions derived from the closed-apo trajectories, consisting of rotating, bending and twisting motions, account for the major rearrangement of the domains from the closed to the open conformation.

Conclusions: The motions showed a strong one-to-one correspondence with the slowest modes from our previous study of RBP with the anisotropic network model (ANM). The results obtained for RBP contribute to the generalization of robustness for protein domain motion studies using either the ANM or PCA for trajectories obtained from MD.
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http://dx.doi.org/10.3233/THC-218011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150535PMC
August 2021

Two Haplotypes of Detected by ND4 Mitochondrial Marker in Three Regions of Ecuador.

Insects 2021 Feb 27;12(3). Epub 2021 Feb 27.

Instituto Nacional de Investigación en Salud Pública, Gestión de Investigación, Desarrollo e Innovación, Quito 170136, Ecuador.

, also known as the yellow fever mosquito, is the main vector of several arboviruses. In Ecuador, dengue and chikungunya are the most prevalent mosquito-borne diseases. Hence, there is a need to understand the population dynamics and genetic structure of the vector in tropical areas for a better approach towards effective vector control programs. This study aimed to assess the genetic diversity of , through the analyses of the mitochondrial gene ND4, using a combination of phylogenetic and population genetic structure from 17 sites in Ecuador. Results showed two haplotypes in the Ecuadorian populations of . Haplotype 1 was closely related to reported from America, Asia, and West Africa. Haplotype 2 was only related to samples from America. The sampled vectors from the diverse localities showed low nucleotide diversity (π = 0-0.01685) and genetic differentiation (FST = 0.152). AMOVA analyses indicated that most of the variation (85-91%) occurred within populations, suggesting that geographical barriers have little effect on the genetic structure of Ecuadorian populations of . These results agree with the one main population (K = 1) detected by Structure. Vector genetic identity may be a key factor in the planning of vector control strategies.
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http://dx.doi.org/10.3390/insects12030200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996963PMC
February 2021

YF-H-2015005, a CXCR4 Antagonist, for the Mobilization of Hematopoietic Stem Cells in Non-Hodgkin Lymphoma Patients: A Randomized, Controlled, Phase 3 Clinical Trial.

Front Med (Lausanne) 2021 2;8:609116. Epub 2021 Feb 2.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China.

YF-H-2015005, a novel CXCR4 antagonist, has been proven to increase the quantities of circulating hematopoietic stem cells (HSCs), which results in an adequate collection of HSCs in non-Hodgkin lymphoma (NHL) patients. This was a multicenter, double-blind, randomized (1:1), placebo-controlled phase III clinical trial. All patients received granulocyte colony-stimulating factor (G-CSF) for up to 8 consecutive days. YF-H-2015005 or placebo was administrated on the evening of day 4 and continued daily for up to 4 days. Apheresis was conducted 9-10 h after each dose of YF-H-2015005 or placebo. The primary endpoint was the proportion of NHL patients procuring ≥5 × 10/kg CD34 HSCs within ≤4 apheresis sessions. In total, 101 patients with NHL were enrolled. The proportions of patients achieving primary endpoint were 57 and 12% in YF-H-2015005 and placebo groups, respectively ( < 0.001). Moreover, a higher proportion of YF-H-2015005-treated patients reached a minimum target collection of ≥2 × 10/kg CD34 HSCs in ≤4 apheresis days compared to placebo-treated patients (86 vs. 38%, < 0.001). Furthermore, the median time to collect ≥2 or 5 × 10/kg CD34+ HSCs were 1 and 3 days in YF-H-2015005-treated patients, but 4 days and not reached in placebo-treated patients, respectively. No severe treatment emergent adverse events were observed in both YF-H-2015005 treatment and placebo groups. YF-H-2015005 plus G-CSF regimen was a tolerable combination with high efficacy, which might be used to rapidly mobilize and collect HSCs in NHL patients.
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http://dx.doi.org/10.3389/fmed.2021.609116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884449PMC
February 2021

Successful treatment of two relapsed patients with t(11;19)(q23;p13) acute myeloid leukemia by CLAE chemotherapy sequential with allogeneic hematopoietic stem cell transplantation: Case reports.

Oncol Lett 2021 Mar 6;21(3):178. Epub 2021 Jan 6.

Department of Hematology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China.

The prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) is poor, with a 3-year overall survival rate of 10%. Patients with translocation (t)(11;19)(q23;p13) have a higher risk of relapse and there is no optimal regimen for these patients. The present study treated two young patients with t(11;19)(q23;p13) AML, who relapsed after one or two cycles of consolidation, with a salvage treatment consisting of sequential cladribine, cytarabine and etoposide (CLAE) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Both neutrophil and platelet engraftments were achieved within 15 days, and no severe transplant-related complications and graft-versus-host diseases were observed. Following allo-HSCT, both patients achieved complete hematologic and cytogenetic remission. Decitabine was used for the prophylaxis of relapse. The two patients remained alive and disease-free for 100 days following allo-HSCT. The results presented here suggest that CLAE regimen sequential with allo-HSCT may be effective in treating patients with R/R AML, with t(11;19)(q23;p13). However, further studies and a larger sample size are required to validate the effectiveness of this treatment regimen.
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http://dx.doi.org/10.3892/ol.2021.12439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816337PMC
March 2021

Effect of blood transfusion during cesarean section on postpartum hemorrhage in a tertiary hospital over a 4-year period.

Medicine (Baltimore) 2021 Jan;100(3):e23885

Department of Anesthesiology, Qilu Hospital of Shangdong University, 107 Wenhua Xi Road, Jinan, Shandong, China.

Abstract: Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and death worldwide. The history of cesarean section and the occurrence of placenta previa were significantly associated with the increase in blood transfusion. Therefore, to prevent PPH, it is important to understand the effect of blood transfusion during cesarean section on postpartum hemorrhage. The purpose of this study is to determine the cause of blood transfusion during cesarean section, especially large amounts of blood transfusion, and to take measures to reduce the blood demand caused by PPH with limited blood supply.This study was a retrospective study of patients who underwent blood transfusion during cesarean section in Qilu Hospital of Shandong University (China) from January 2013 to December 2016. Red blood cell infusion ≥10 U during cesarean section was defined as massive blood transfusion. The study collected the demographics of pregnant women, obstetric characteristics and reasons for blood transfusions, as well as blood components and blood transfusion results. Multivariate regression analysis was performed for evaluating the risk factors of PPN.From 2013 to 2016, a total of 587 patients received blood transfusions during cesarean section. The proportion of women receiving blood transfusion during cesarean section increased (from 3.21% to 7.40%, P < .001). The history of cesarean section (P = .005) and the occurrence of placenta previa were positively correlated with the increase in blood transfusion (P = .016). There were 72 cases of massive blood transfusion, accounting for 12.27% of blood transfusion patients. Among mass blood transfusions, 93.1% of cases had prior cesarean delivery, and placenta previa accounted for 95.8%. 19.4% of patients receiving massive blood transfusions underwent hysterectomy. There was no significant difference in maternal BMI and gestational age between the mass blood transfusion group and the non-mass blood transfusion group.From 2013 to 2016, the demand for blood transfusion, especially the demand for massive blood transfusion, increased. Repeated cesarean section and placental previa combined with uterine scar are positively correlated with increased blood transfusion. Reducing the initial cesarean section should help reduce the massive blood transfusion caused by placenta previa with a history of cesarean section.
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http://dx.doi.org/10.1097/MD.0000000000023885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837845PMC
January 2021

Distributive characteristics of the CYP2C9 and AGTR1 genetic polymorphisms in Han Chinese hypertensive patients: a retrospective study.

BMC Cardiovasc Disord 2021 02 4;21(1):73. Epub 2021 Feb 4.

Clinical Laboratory, Zhongda Hospital, School of Medicine, Southeast University, Dingjiaqiao Road 87, Nanjing, 210009, China.

Background: There is an individual variation in response to antihypertensive effect of the angiotensin II receptor antagonist. This study aimed to determine the allele and genotype frequencies of CYP2C9 and AGTR1 genetic polymorphisms and explore the potential role of these polymorphisms in guiding the selection of angiotensinIIreceptor antagonist in Han Chinese hypertensive patients.

Methods: Totally 2419 Han Chinese hypertensive patients and 126 normotensive controls were recruited in this study. Venous blood samples were collected from each patient, and the genetic polymorphisms of CYP2C9 and AGTR1 were assessed using a gene chip platform. The allele and genotype frequency of each gene and the combined genotypes in this study were analyzed respectively.

Results: The gene chip analysis identified an allelic frequency of 96.51% for CYP2C9*1 and 3.49% for CYP2C9*3 in the cohort of Han Chinese hypertensive patients. Statistical analysis showed that the frequency of wild-type homozygous for CYP2C9*1/*1 was 93.30%, while the frequency of heterozygous for *1/*3 or mutant homozygous for *3/*3 was 6.41% or 0.29%. Meanwhile, we detected allelic frequencies of 95.06% and 4.94% for the A and C allele of AGTR1, respectively. While the genotype frequency of wild-type homozygous for AA was 90.41%, the frequency of heterozygous for AC or mutant homozygous for CC was 9.30% or 0.29%. Notably, we observed that 84.66% (2048/2419) of the subjects exhibited a combined genotype of CYP2C9 and AGTR1 as *1/*1 + AA, while the combined genotypes *3/*3 + AC or *3/*3 + CC were not detected in hypertension patients. Besides, no significant association was found between normotensive controls and hypertensive patients, or among the three grades of hypertensive patients.

Conclusions: These data revealed the polymorphisms characteristics of CYP2C9 and AGTR1 in Han Chinese hypertensive patients, providing valuable information for genotype-based antihypertension therapy in prospective clinical studies in the future.
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http://dx.doi.org/10.1186/s12872-021-01895-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863246PMC
February 2021

Arabidopsis N-methyladenosine reader CPSF30-L recognizes FUE signals to control polyadenylation site choice in liquid-like nuclear bodies.

Mol Plant 2021 04 27;14(4):571-587. Epub 2021 Jan 27.

Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. Electronic address:

The biological functions of the epitranscriptomic modification N-methyladenosine (mA) in plants are not fully understood. CPSF30-L is a predominant isoform of the polyadenylation factor CPSF30 and consists of CPSF30-S and an mA-binding YTH domain. Little is known about the biological roles of CPSF30-L and the molecular mechanism underlying its mA-binding function in alternative polyadenylation. Here, we characterized CPSF30-L as an Arabidopsis mA reader whose mA-binding function is required for the floral transition and abscisic acid (ABA) response. We found that the mA-binding activity of CPSF30-L enhances the formation of liquid-like nuclear bodies, where CPSF30-L mainly recognizes mA-modified far-upstream elements to control polyadenylation site choice. Deficiency of CPSF30-L lengthens the 3' untranslated region of three phenotypes-related transcripts, thereby accelerating their mRNA degradation and leading to late flowering and ABA hypersensitivity. Collectively, this study uncovers a new molecular mechanism for mA-driven phase separation and polyadenylation in plants.
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http://dx.doi.org/10.1016/j.molp.2021.01.014DOI Listing
April 2021

KDM6A promotes imatinib resistance through YY1-mediated transcriptional upregulation of TRKA independently of its demethylase activity in chronic myelogenous leukemia.

Theranostics 2021 1;11(6):2691-2705. Epub 2021 Jan 1.

Institute of Medicinal Biotechnology, Jiangsu College of Nursing, Huai'an, Jiangsu, 223300, China.

Despite landmark therapy of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs), drug resistance remains problematic. Cancer pathogenesis involves epigenetic dysregulation and in particular, histone lysine demethylases (KDMs) have been implicated in TKI resistance. We sought to identify KDMs with altered expression in CML and define their contribution to imatinib resistance. Bioinformatics screening compared KDM expression in CML versus normal bone marrow with shRNA knockdown and flow cytometry used to measure effects on imatinib-induced apoptosis in K562 cells. Transcriptomic analyses were performed against KDM6A CRISPR knockout/shRNA knockdown K562 cells along with gene rescue experiments using wildtype and mutant demethylase-dead KDM6A constructs. Co-immunoprecipitation, luciferase reporter and ChIP were employed to elucidate mechanisms of KDM6A-dependent resistance. Amongst five KDMs upregulated in CML, only KDM6A depletion sensitized CML cells to imatinib-induced apoptosis. Re-introduction of demethylase-dead KDM6A as well as wild-type KDM6A restored imatinib resistance. RNA-seq identified NTRK1 gene downregulation after depletion of KDM6A. Moreover, NTRK1 expression positively correlated with KDM6A in a subset of clinical CML samples and KDM6A knockdown in fresh CML isolates decreased NTRK1 encoded protein (TRKA) expression. Mechanistically, KDM6A was recruited to the NTRK1 promoter by the transcription factor YY1 with subsequent TRKA upregulation activating down-stream survival pathways to invoke imatinib resistance. Contrary to its reported role as a tumor suppressor and independent of its demethylase function, KDM6A promotes imatinib-resistance in CML cells. The identification of the KDM6A/YY1/TRKA axis as a novel imatinib-resistance mechanism represents an unexplored avenue to overcome TKI resistance in CML.
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http://dx.doi.org/10.7150/thno.50571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806474PMC
July 2021

A new application of monosialotetrahexosylganglioside in pharmaceutics: preparation of freeze-thaw-resistant coenzyme Q10 emulsions.

Eur J Pharm Sci 2021 Apr 9;159:105701. Epub 2021 Jan 9.

College of Pharmacy, Shenyang Pharmaceutical University, NO. 103 Wenhua Road Shenhe District, Shenyang 110016, Liaoning Province, PR China. Electronic address:

Research on intravenous emulsions has been ongoing for several decades, and their unique advantages bring many opportunities for insoluble drugs. However, emulsions cannot withstand freezing in practical applications because their quality is severely affected. In this study, we used coenzyme Q10 as a model drug to prepare emulsions. Monosialotetrahexosylganglioside (GM1) was used to modify the emulsion to solve the freeze-thaw intolerance problem. The particle size, sterilization and freeze-thaw stability were affected by the oil content, phospholipid content, drug loading and homogenization conditions, which showed significant effects on the preparation properties. Emulsions prepared with a high oil content (30%, W/V) withstood three freeze-thaw cycles when the GM1 content was 0.2%-1.0% (W/V). In addition, pharmacokinetic studies indicated that emulsions modified with high-density GM1 had a long circulation time. Compared with the coenzyme Q10 solution, the emulsions showed different degrees of heart, liver, spleen and brain targeting. The relative uptake rate of the 0.2% GM1-modified emulsion in the heart was 37.06, while that of the 1.0% GM1-modified emulsion in the brain was 17.43. These results strongly suggest that coenzyme Q10 emulsions coated with GM1 can tolerate freeze-thaw cycles and are excellent for treatment of cardiac and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.ejps.2021.105701DOI Listing
April 2021

Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction.

Science 2021 01;371(6525):194-200

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA.

Medically important flaviviruses cause diverse disease pathologies and collectively are responsible for a major global disease burden. A contributing factor to pathogenesis is secreted flavivirus nonstructural protein 1 (NS1). Despite demonstrated protection by NS1-specific antibodies against lethal flavivirus challenge, the structural and mechanistic basis remains unknown. Here, we present three crystal structures of full-length dengue virus NS1 complexed with a flavivirus-cross-reactive, NS1-specific monoclonal antibody, 2B7, at resolutions between 2.89 and 3.96 angstroms. These structures reveal a protective mechanism by which two domains of NS1 are antagonized simultaneously. The NS1 wing domain mediates cell binding, whereas the β-ladder triggers downstream events, both of which are required for dengue, Zika, and West Nile virus NS1-mediated endothelial dysfunction. These observations provide a mechanistic explanation for 2B7 protection against NS1-induced pathology and demonstrate the potential of one antibody to treat infections by multiple flaviviruses.
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http://dx.doi.org/10.1126/science.abc0476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000976PMC
January 2021
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