Publications by authors named "Wenjing Li"

474 Publications

Preclinical evaluation of a novel anti-mesothelin immunotoxin based on a single domain antibody as the targeting ligand.

Int J Pharm 2021 Apr 26:120647. Epub 2021 Apr 26.

State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, P. R. China. Electronic address:

Pancreatic cancer, as one of the most aggressive and lethal malignancies in the world, is lack of effective treatment. Constructing immunotoxin molecules to target the mesothelin (MSLN) receptor is a potential therapeutic strategy for pancreatic cancer and other related malignant tumors, with some molecules being tested in clinical trials. However, currently, there are still some limitations in its applications, such as the difficulty of the preparation of drug molecules, the limited effectiveness of drugs, and the inadequacy of drug safety and immunogenicity. In this study, we constructed a novel type of anti-MSLN immunotoxin, A1-PE24X7, in which a single domain antibody (sdAb) molecule was used as the target ligand and an improved PE24X7 toxin with reduced off-target toxicity and immunogenicity was used as the effector. Unlike conventional immunotoxins, the designed A1-PE24X7 could be easily expressed in the E. coli system in the form of a soluble protein with a good yield (15 - 20 mg/L), avoiding the complex process of denaturation and refolding of inclusion bodies, and it can be conveniently stored in PBS solution for more than 7 days at 4 °C, showing high storage stability. Cell-based experiments showed that A1-PE24X7 entered MSLN-expressing tumor cells in a receptor-mediated manner and killed these cells with an EC in the low nanomolar range (0.13 nM against NCI-N87 cells and 0.79 nM against AsPC-1 cells) and it showed ideal selectivity for the MSLN receptor (>100 nM against receptor negative PC3 cells). In animal-based experiments, A1-PE24X7 had tumor enrichment ability in relation to MSLN-positive tumors and showed strong tumor killing and inhibition in mouse models of pancreatic cancer and gastric cancer. Five injections of 3.0 mg/kg A1-PE24X7 significantly reduced the tumor volume of gastric NCI-N87 cancer and also significantly inhibited the growth of pancreatic AsPC-1 cancer. In addition, the maximum tolerable dosage (MSD) of A1-PE24X7 to mice was higher than 15 mg/kg, showing that A1-PE24X7 has a relatively broad therapeutic window. These preclinical results indicate that this strategy has good potential for application to the treatment of pancreatic cancer and other tumors with high MSLN expression.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120647DOI Listing
April 2021

Long Noncoding RNA SNHG1 Knockdown Ameliorates Apoptosis, Oxidative Stress and Inflammation in Models of Parkinson's Disease by Inhibiting the miR-125b-5p/MAPK1 Axis.

Neuropsychiatr Dis Treat 2021 22;17:1153-1163. Epub 2021 Apr 22.

Department of Neurology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi City, Hubei Province, People's Republic of China.

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disease. Long noncoding RNA small molecule RNA host gene 1 (SNHG1) has been reported to play critical roles in Parkinson's disease (PD) progression. The study aimed to further elucidate the mechanism of SNHG1 in PD pathogenesis.

Methods: The levels of SNHG1, miR-125b-5p and mitogen-activated protein kinase 1 (MAPK1) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Cell viability and apoptosis were evaluated by Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. The activity of Caspase-3 or Caspase-9 was measured using a Caspase-3 or Caspase-9 Assay Kit. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, lactic dehydrogenase (LDH) activity, reactive oxygen species (ROS) generation and superoxide dismutase (SOD) activity were gauged by enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter assay was performed to identify the relationship between miR-125b-5p and SNHG1 or MAPK1. The MPTP-induced PD mouse was used as an in vivo model of PD and MPP-treated SK-N-SH and MN9D cells were used as in vitro models of PD.

Results: SNHG1 and MAPK1 were significantly up-regulated while miR-125b-5p was down-regulated in the MPTP-induced PD mouse model and MPP-induced PD cell models. SNHG1 silence or miR-125b-5p overexpression protected against MPP-evoked apoptosis, oxidative stress and inflammation in SK-N-SH and MN9D cells. Moreover, SNHG1 acted as a molecular sponge of miR-125b-5p, and the protective impact of SNHG1 silence on MPP-evoked cell damage was reversed by miR-125b-5p inhibition. Furthermore, MAPK1 was a functional target of miR-125b-5p and its overexpression attenuated the effects of miR-125b-5p restoration in MPP-triggered cell injury. In addition, the behavioral changes in MPTP-induced PD mouse in vivo model were relieved by SNHG1 silence.

Conclusion: SNHG1 knockdown exerted neuroprotective effects in MPP-evoked cytotoxicity through regulating the miR-125b-5p/MAPK1 axis both in human and mouse PD cell models, highlighting a possible target for PD therapy.
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http://dx.doi.org/10.2147/NDT.S286778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075359PMC
April 2021

The MdMYB16/MdMYB1-miR7125-MdCCR module regulates the homeostasis between anthocyanin and lignin biosynthesis during light induction in apple.

New Phytol 2021 Apr 28. Epub 2021 Apr 28.

Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, Beijing University of Agriculture, Beijing, 102206, China.

Light induces anthocyanin accumulation and hence decides the coloration of apple fruit. It also plays a key role in regulating the biosynthesis of other secondary metabolites. However, the crosstalk between anthocyanin and lignin metabolism during light induction, which affects the edible quality and visual quality of apple fruit, respectively, have rarely been characterized. In this study, we identified and functionally elucidated the roles of miR7125 and its target, cinnamoyl-coenzyme A reductase gene (CCR), in regulating the homeostasis between anthocyanin and lignin biosynthesis during light induction. Overexpressing miR7125 or inhibiting CCR transiently in apple fruit promoted anthocyanin biosynthesis but reduced lignin production under light-induced conditions. Consistently, opposite results were observed under the background of repressed miR7125 or overexpressed CCR. We found that the repressor MdMYB16 and the activator MdMYB1 bound to the miR7125 promoter. Transient repression of MdMYB16 upregulated miR7125 expression significantly, accompanied by decreased levels of MdCCR transcript, resulting in a reduction in the lignin biosynthesis and an increase in anthocyanin accumulation. However, transient overexpression of MdMYB16 produced the opposite effects to MdMYB16-RNAi. The results reveal a novel mechanism by which the MdMYB16/MdMYB1-miR7125-MdCCR module collaboratively regulates homeostasis between anthocyanin and lignin biosynthesis under light induction in apple.
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http://dx.doi.org/10.1111/nph.17431DOI Listing
April 2021

High-Efficiency, Low-Hysteresis Planar Perovskite Solar Cells by Inserting the NaBr Interlayer.

ACS Appl Mater Interfaces 2021 Apr 26. Epub 2021 Apr 26.

Fujian Key Laboratory of Photoelectric Functional Materials, Huaqiao University, Xiamen 361021, P. R. China.

With great research potential, the perovskite solar cells (PSCs) have been well developed in recent years, but there are still some urgent issues like efficiency and hysteresis defects that severely limit their commercialization. Interface modification is a significant measure to reduce defects and promote performance. In the article, an easy and effective strategy of modifying the electron transport layer (ETL) with NaBr is proposed to improve efficiency and reduce hysteresis. The charge carrier dynamics can be greatly optimized by diffusing NaBr on the ETL. The efficiency of the NaBr coated device can achieve 21.16%, which is extremely higher than the control one and shows low hysteresis behavior with a hysteresis index reduced from 0.135 to 0.025. The results indicate that the NaBr modification provides a novel strategy for preparing PSCs with high efficiency and low hysteresis.
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http://dx.doi.org/10.1021/acsami.1c04806DOI Listing
April 2021

Domestication Shapes the Community Structure and Functional Metagenomic Content of the Yak Fecal Microbiota.

Front Microbiol 2021 31;12:594075. Epub 2021 Mar 31.

Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, China.

Domestication is a key factor of genetic variation; however, the mechanism by which domestication alters gut microbiota is poorly understood. Here, to explore the variation in the structure, function, rapidly evolved genes (REGs), and enzyme profiles of cellulase and hemicellulose in fecal microbiota, we studied the fecal microbiota in wild, half-blood, and domestic yaks based on 16S rDNA sequencing, shotgun-metagenomic sequencing, and the measurement of short-chain-fatty-acids (SCFAs) concentration. Results indicated that wild and half-blood yaks harbored an increased abundance of the phylum and reduced abundance of the genus , which are both associated with efficient energy harvesting. The gut microbial diversity decreased in domestic yaks. The results of the shotgun-metagenomic sequencing showed that the wild yak harbored an increased abundance of microbial pathways that play crucial roles in digestion and growth of the host, whereas the domestic yak harbored an increased abundance of methane-metabolism-related pathways. Wild yaks had enriched amounts of REGs in energy and carbohydrate metabolism pathways, and possessed a significantly increased abundance of cellulases and endohemicellulases in the glycoside hydrolase family compared to domestic yaks. The concentrations of acetic, propionic, n-butyric, i-butyric, n-valeric, and i-valeric acid were highest in wild yaks. Our study displayed the domestic effect on the phenotype of composition, function in gut microbiota, and SCFAs associated with gut microbiota, which had a closely association with the growth performance of the livestock. These findings may enlighten the researchers to construct more links between economic characteristics and gut microbiota, and develop new commercial strains in livestock based on the biotechnology of gut microbiota.
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http://dx.doi.org/10.3389/fmicb.2021.594075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059439PMC
March 2021

Safety of house dust mite subcutaneous immunotherapy in preschool children with respiratory allergic diseases.

Ital J Pediatr 2021 Apr 23;47(1):101. Epub 2021 Apr 23.

Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, 430030, Hubei, China.

Background: Allergen immunotherapy (AIT) is the only causal therapy for IgE-mediated allergy. There is less evidence about the safety and efficacy of AIT especially subcutaneous immunotherapy (SCIT) in children under 5 years old. We aimed to investigate the side effects and associated risk factors of house dust mite (HDM) SCIT in preschool children with respiratory allergic diseases.

Methods: The preschool children who had HDM-related allergic rhinitis with/without asthma were enrolled and undergone standardized HDM SCIT in our department from June 2013 to December 2019. Local reactions (LRs) and systemic reactions (SRs) were recorded and categorized according to World Allergy Organization recommendations. Demographic data and other therapeutic-related parameters were also recorded to investigate potential risk factors for these side effects.

Results: A total of 91 children (60 boys, 65.93%; 31 girls, 34.07%; mean age 4.13 years old) were included in the study. Among the 91 patients, 3109 SCIT injections were recorded, 62/91 (68.13%) experienced 186 immediate LRs, 4 /91(4.40%) experienced 6 delayed LRs, 11/91 (12.09%) children experienced 44 immediate SRs, 21/44 (47.73%) were grade 1 SRs, 21/44 (47.73%) were grade 2, 2/44 (4.55%) were grade 3, no grade 4 or 5 SRs occurred. Furthermore, 1/91 (1.10%) experienced 1 delayed SRs, manifested by urticaria 2 days later after allergen injection. 9/91 (9.89%) experienced 2 or more times SRs. Multivariable logistic regression analysis showed BMI (OR 1.506; 95%CI 1.091 to 2.079; p < 0.05) and sIgE against HDM (OR 1.497; 95%CI 1.082 to 2.071; p < 0.05) were risk factors for LRs. No variable was found to correlate with SRs (all p > 0.05).

Conclusions: HDM subcutaneous immunotherapy is considered to be safe in preschool children with respiratory allergic diseases. Higher BMI and HDM sIgE level in children are risk factors for developing LRs. The incidence of SRs and the rate of severe SRs are low in preschool children.
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http://dx.doi.org/10.1186/s13052-021-01046-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063484PMC
April 2021

Insulating and Robust Ceramic Nanorod Aerogels with High-Temperature Resistance over 1400 °C.

ACS Appl Mater Interfaces 2021 Apr 20. Epub 2021 Apr 20.

Aerospace Institute of Advanced Material & Processing Technology, Beijing 100074, P. R. China.

Ceramic aerogels, which present a unique combination of low thermal conductivity and excellent high-temperature stability, are attractive for thermal insulation under extreme conditions. However, most ceramic aerogels are constructed by oxide ceramic nanoparticles and thus are usually plagued by their brittleness and structural collapse at elevated temperatures (less than 1000 °C). Despite great progress achieved in this regard recently, it still remains a big challenge to design and fabricate intriguing ceramic aerogels with enhanced mechanical strength and remarkable thermal stability at ultrahigh temperature up to 1400 °C. To this end, we herein report a facile and scalable strategy to manufacture ceramic nanorod aerogels (CNRAs) with hierarchically macroporous and mesoporous structures by the controllable assembly of AlO nanorods and SiO nanoparticles. Subsequently, the high-temperature annealing treatment of CNRAs significantly maximizes mechanical strength and promotes thermal tolerance. The obtained CNRAs demonstrate the integrated properties of super-strong heat resistance (up to 1400 °C), low thermal conductivity (0.026 W/m·K at 25 °C and 0.089 W/m·K at 1200 °C), high mechanical robustness (compressive strength 1.5 MPa), and low density (0.146 g/cm). We envision that this novel nanorod-assembled ceramic aerogels offer considerable advantages than most of the state-of-the-art ceramic aerogels for thermal superinsulation upon exposure to extremely harsh environments.
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http://dx.doi.org/10.1021/acsami.1c02501DOI Listing
April 2021

The fate of flavonoids after oral administration: a comprehensive overview of its bioavailability.

Crit Rev Food Sci Nutr 2021 Apr 13:1-18. Epub 2021 Apr 13.

Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.

Despite advancements in synthetic chemistry, nature remains the primary source of drug discovery, and this never-ending task of finding novel and active drug molecules will continue. Flavonoids have been shown to possess highly significant therapeutic activities such as anti-inflammatory, anti-oxidant, anti-viral, anti-diabetic, anti-cancer, anti-aging, neuroprotective, and cardioprotective, etc., However, it has been found that orally administered flavonoids have a critical absorption disorder and, therefore, have low bioavailability and show fluctuating pharmacokinetic and pharmacodynamic responses. A detailed investigation is required to assess and analyze the variation in the bioavailability of flavonoids due to interactions with the intestinal barrier. This review will emphasize on the bioavailability and the pharmacological applications of flavonoids, key factors affecting their bioavailability, and strategies for enhancing bioavailability, which may lead to deeper understanding of the extent of flavonoids as a treatment and/or prevention for different diseases in clinics.
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http://dx.doi.org/10.1080/10408398.2021.1898333DOI Listing
April 2021

Effect of Spray Drying Conditions on Physical Properties of Saponin (PNS) Powder and the Intra-Batch Dissolution Variability of PNS Hydrophilic Matrix Tablet.

Drug Des Devel Ther 2021 30;15:1425-1440. Epub 2021 Mar 30.

Department of Chinese Medicine Informatics, Beijing University of Chinese Medicine, Beijing, People's Republic of China.

Purpose: Understanding raw material variability and its impact on product quality are crucial for developing robust pharmaceutical processes. This work aimed to study the effects of spray drying conditions on properties of the spray dried saponin (PNS) powders as well as the subsequent intra-batch dissolution variability of PNS hydrophilic matrix tablets.

Methods: The Plackett-Burman design was applied to screen the critical process parameters (CPPs). Then, the Box-Behnken design was used to investigate the relationship between the CPPs and the physiochemical properties of spray dried PNS powders. The PNS hydrophilic matrix tablets containing 57% spray dried PNS powders were directly compressed. The partial least squares (PLS) regression was used to uncover the hidden multivariate relationships among the CPPs, intermediate powder properties, and tablet quality attributes.

Results: The identified CPPs were the feed concentration, the inlet air temperature, and the atomization pressure. It was found that the CPPs exerted little impact on chemical properties of spray dried PNS powders, but had significant impact on physical properties, such as particle size, specific surface area, bulk density, hygroscopicity, and inter-particle porosity, etc. Latent variable modeling results revealed that the high inlet air temperature of spray drying process could produce PNS powders with low moisture content and high hygroscopicity, which were beneficial to reduce the intra-batch dissolution variability of PNS hydrophilic matrix tablets. Finally, a design space of the spray drying process was built in order to ensure the dissolution consistency.

Conclusion: Our research provided a reference for improving the spray drying conditions in order to ensure the dissolution consistency of the PNS hydrophilic matrix tablet.
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http://dx.doi.org/10.2147/DDDT.S295825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019609PMC
March 2021

A responsive pure DNA hydrogel for label-free detection of lead ion.

Anal Chim Acta 2021 May 13;1157:338400. Epub 2021 Mar 13.

Institute of Materials, China Academy of Engineering Physics, Mianyang, 621907, China.

It is of great significance to develop facile and economical strategies for on-site detection and treatment of toxic metal ions. Stimulus-responsive DNA hydrogel materials have been increasingly used for convenient detection of metal ions due to their advantages such as simplicity, portability, and ease of storage. However, these methods still require encapsulation of signal tags by labeling or embedding. In this paper, a one-step preparation of Pb-responsive pure DNA hydrogel material was designed to realize a new label-free strategy for Pb biosensing. The Pb-dependent DNAzyme strand and substrate strand were introduced to fabricate the DNA hydrogel. The presence of Pb in the sample activates the enzyme strand in the hydrogel skeleton and triggers the cleavage of the substrate, thereby destroy the hydrogel structure. DNA fragments released by the collapsed hydrogel were readily measured as signal output for quantifying Pb concentrations with a minimum detection limit of 7.7 nM. We successfully eliminated the need for embedding or labeling of signal molecules by using the DNA molecules that construct hydrogels as the signal output. And the newly developed method for label-free detection of Pb based on pure DNA hydrogel is simple, easy readout, and cost-effective. By adjusting the DNAzyme and substrate sequences, label-free analysis of other metal ions can also be achieved. We expect that our strategy can be applied to the field detection of toxic metal ions.
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http://dx.doi.org/10.1016/j.aca.2021.338400DOI Listing
May 2021

Clinical and genetic characteristics of hypophosphatasia in Chinese children.

Orphanet J Rare Dis 2021 Apr 7;16(1):159. Epub 2021 Apr 7.

Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.

Background: Hypophosphatasia (HPP) is a rare inherited disorder, which is caused by loss-of-function mutations in the ALPL gene. HPP is a heterogeneous disease that has a wide spectrum of phenotypes. Few studies were carried out in the Chinese population with HPP, especially in children.

Methods: The clinical and genetic characteristics of 10 Chinese children with HPP who were referred to the Beijing Children's Hospital were described. Previously reported HPP cases of children in China were also reviewed.

Results: A total of 33 cases were identified, which included 2 perinatal lethal HPP, 10 infantile HPP, 10 childhood HPP, and 11 odonto HPP. The male-to-female ratio was 24:9. The average age at onset was 0.69 years (ranged from 2 h after birth to 14 years), while the average age at clinical diagnosis was 3.87 years (ranged from 2 h after birth to 19 years). Serum alkaline phosphatase (ALP) levels were significantly decreased in patients with perinatal lethal/infantile HPP when compared with those with the mild forms of HPP childhood/odonto HPP (P < 0.01). Although serum phosphate levels were not different (P > 0.05), serum calcium levels were elevated, and serum intact parathyroid hormone levels were decreased in patients with perinatal lethal/infantile HPP in comparison with those with the childhood/odonto HPP (P all < 0.01). Genetic analyses identified 40 mutations in 31 HPP cases, including 28 missense mutations, 9 frameshift mutations, 2 splice junction alterations, and 1 regulatory mutation. Of which, 5 novel mutations were identified in our present study: 2 frameshift mutations (p.Arg138GlyfsTer27, p.Leu511Profs*272); 2 missense mutations (p.Ala176Val, p.Phe268Leu), and 1 splice junction alteration (c.297+5G>A). Compound heterozygous mutations accounted for 80.6% of all variants. No mutational "hot-spot" was found. Most mutations of ALPL were located in exons 5, 7, 10, and 3. Notably, subjects that carrying single heterozygous mutations showed milder phenotypes of HPP, while subjects with nonsense mutations were associated with a severer phenotype.

Conclusions: HPP is a rare disease with often delayed diagnosis, and the incidence of HPP in China may be seriously underestimated. The present study expands the phenotypic and genotypic spectrum and the understanding of HPP in Chinese children. These findings will be useful for clinical assessment and shorten the diagnosis time for pediatric HPP in China.
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http://dx.doi.org/10.1186/s13023-021-01798-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028151PMC
April 2021

Field Cage Assessment of Feeding Damage by on Soybeans in China.

Insects 2021 Mar 17;12(3). Epub 2021 Mar 17.

College of Plant Protection, Jilin Agricultural University, Changchun 130118, China.

The bean bug, , is a major pest of soybeans. In order to assess the critical stages of soybean damage by , we tested the damage to soybeans at different growth stages (R, R, and R) caused by five densities of (1, 2, 3, 4, and 5) through a field cage experiment. The results show that the R stage was the most sensitive stage in terms of suffering injury damage, followed by the R stage and then the R stage. The number of stay green leaves was 7.04 per plant, the abortive pod rate of the soybeans was 56.36%, and the abortive seed rate of the soybeans was 46.69%. The dry weight of the soybeans was 14.20 g at the R stage; these values of R were significantly higher than at the R and R stages. However, the dry weight of soybean seed was 4.27 g and the nutrient transfer rate was 27.01% in the R stage; these values were significantly lower than in the R and R stages. The number of stay green leaves, abortive pod rates, and abortive seed rates were all increased significantly with increasing pest density at each stage of soybean growth. However, the nutrient transfer rate was significantly decreased with the increase in the pest density. Soybean nutrition factors changed after they suffered injury; the lipid content of the soybean seed decreased and the lipid content of the soybean plant increased compared to controls, when tested with a density of five in the R stage. These results will be beneficial to the future management of in soybean fields.
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http://dx.doi.org/10.3390/insects12030255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002668PMC
March 2021

Optical biopsy of laryngeal lesions using femtosecond multiphoton microscopy.

Biomed Opt Express 2021 Mar 8;12(3):1308-1319. Epub 2021 Feb 8.

Femtosecond Research Center (Guangzhou), A616 80 Lanyue Road, Guangzhou 510663, China.

Laryngeal squamous cell carcinoma (LSCC) is one of the most prevalent malignancy of the upper aerodigestive tract. Detection of early lesions could improve the survival rate significantly. In this study, we demonstrated that femtosecond multiphoton microscopy (MPM) is an effective tool to visualize the microscopic features within fixed laryngeal tissues, without sectioning, staining, or labeling. Accurate detection of lesions and determination of the tumor grading can be achieved, with excellent consistency with conventional histological examination. These results suggest that MPM may represent a powerful tool for in-vivo or fast ex-vivo diagnosis of laryngeal lesions at the point of care.
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http://dx.doi.org/10.1364/BOE.414931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984806PMC
March 2021

Transplantation of human induced pluripotent stem cell-derived neural crest cells for corneal endothelial regeneration.

Stem Cell Res Ther 2021 Mar 29;12(1):214. Epub 2021 Mar 29.

Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, 271016, China.

Background: The corneal endothelium maintains corneal hydration through the barrier and pump function, while its dysfunction may cause corneal edema and vision reduction. Considering its development from neural crest cells (NCCs), here we investigated the efficacy of the human induced pluripotent stem cell (hiPSC)-derived NCCs for corneal endothelial regeneration in rabbits.

Methods: Directed differentiation of hiPSC-derived NCCs was achieved using the chemically defined medium containing GSK-3 inhibitor and TGF-β inhibitor. The differentiated cells were characterized by immunofluorescence staining, FACS analysis, and in vitro multi-lineage differentiation capacity. For in vivo functional evaluation, 1.0 × 10 hiPSC-derived NCCs or NIH-3 T3 fibroblasts (as control) combined with 100 μM Y-27632 were intracamerally injected into the anterior chamber of rabbits following removal of corneal endothelium. Rabbit corneal thickness and phenotype changes of the transplanted cells were examined at 7 and 14 days with handy pachymeter, dual-immunofluorescence staining, and quantitative RT-PCR.

Results: The hiPSC-derived NCCs were differentiated homogenously through 7 days of induction and exhibited multi-lineage differentiation capacity into peripheral neurons, mesenchymal stem cells, and corneal keratocytes. After 7 days of intracameral injection in rabbit, the hiPSC-derived NCCs led to a gradual recovery of normal corneal thickness and clarity, when comparing to control rabbit with fibroblasts injection. However, the recovery efficacy after 14 days deteriorated and caused the reappearance of corneal edema. Mechanistically, the transplanted cells exhibited the impaired maturation, cellular senescence, and endothelial-mesenchymal transition (EnMT) after the early stage of the in vivo directional differentiation.

Conclusions: Transplantation of the hiPSC-derived NCCs rapidly restored rabbit corneal thickness and clarity. However, the long-term recovery efficacy was impaired by the improper maturation, senescence, and EnMT of the transplanted cells.
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http://dx.doi.org/10.1186/s13287-021-02267-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008577PMC
March 2021

Place attachment, environmental cognition and organic fertilizer adoption of farmers: evidence from rural China.

Environ Sci Pollut Res Int 2021 Mar 29. Epub 2021 Mar 29.

College of Economics & Management, Huazhong Agricultural University, Wuhan, 430070, Hubei, People's Republic of China.

For preventing the excessive consumption of agricultural resources, it is of vital importance to promote agricultural pro-environmental behavior of farmers. Despite the proven importance of psychological factors in encouraging farmers' adoption of organic fertilizer, the evidence is scarce. To fill this gap, this study aims to explore how place attachment and environmental cognition affect farmers' organic fertilizer adoption with a community sample of 944 rural farmers collected in Hubei province. Specifically, we firstly distinguish two dimensions of place attachment, namely, natural attachment and civic attachment, and then we explore the influence of those dimensions and environmental cognition on farmers' adoption of organic fertilizer. The results reveal that both place attachment and environmental cognition positively affect farmers' organic fertilizer adoption. Furthermore, the roles of place attachment vary across different groups divided by farmers' environmental cognition degree and age. Therefore, to promote green agricultural practices, policy-makers should enhance various farmers' place attachment and environmental cognition by strengthening infrastructure construction, organizing collective activities, and conducting animation propaganda.
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http://dx.doi.org/10.1007/s11356-021-13509-1DOI Listing
March 2021

Serum Levels of S100A11 and MMP-9 in Patients with Epithelial Ovarian Cancer and Their Clinical Significance.

Biomed Res Int 2021 3;2021:7341247. Epub 2021 Mar 3.

Department of Gynecology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China.

Objective: To investigate the serum levels of calgizzarin (S100A11) and matrix metalloproteinase-9 (MMP9) in patients with epithelial ovarian cancer (EOC) and determine their clinical significance.

Methods: Serum levels of S100A11 and MMP9 were detected in patients with EOC, patients with benign ovarian tumor, and healthy women. The correlation between the two markers and clinicopathological characteristics of ovarian cancer was analysed.

Results: The serum levels of S100A11 and MMP-9 in patients with EOC were higher than those in patients with benign ovarian tumor and in healthy women, and the expression levels of S100A11 and MMP-9 were positively correlated. S100A11 and MMP-9 were correlated with tumor staging, postoperative residual foci, ascites volume, serum CA125 level, chemotherapy response, and lymph node metastasis, while S100A11 and MMP-9 were not associated with the bilevel classification, histological type, age, and degree of differentiation.

Conclusion: S100A11 and MMP-9 were both highly expressed in the serum of patients with EOC and were associated with cancer development, invasion, and metastasis. Therefore, they can be used as an important reference maker in the diagnosis and treatment of ovarian cancer.
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http://dx.doi.org/10.1155/2021/7341247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952149PMC
March 2021

in Qinghai-Tibet plateau: population structure and confirmation of additional endemic areas.

Parasitology 2021 Mar 24:1-8. Epub 2021 Mar 24.

State Key Laboratory of Veterinary Etiological Biology/National Professional Laboratory for Animal Echinococcosis/Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, CAAS, Lanzhou730046, Gansu Province, People's Republic of China.

Echinococcus shiquicus is currently limited to the Qinghai–Tibet plateau, a large mountainous region in China. Although the zoonotic potential remains unknown, progress is being made on the distribution and intermediate host range. In this study, we report E. shiquicus within Gansu and Qinghai provinces in regions located not only around the central areas but also the southeast edge of the plateau and describe their genetic relationship with previous isolates from the plateau. From 1879 plateau pikas examined, 2.39% (95% CI 1.79–3.18) were infected with E. shiquicus. The highest prevalence of 10.26% (4.06–23.58) was recorded in Makehe town, Qinghai province. Overall the prevalence was marginally higher in Qinghai (2.5%, CI 1.82–3.43) than in Gansu (2%, CI 1.02–3.89). The cox1 and nad1 genes demonstrated high and low haplotype and nucleotide diversities, respectively. The median-joining network constructed by the cox1–nad1 gene sequences demonstrated a star-like configuration with a median vector (unsampled haplotype) occupying the centre of the network. No peculiar distinction or common haplotype was observed in isolates originating from the different provinces. The presence of E. shiquicus in regions of the southeast and northeast edges of the Qinghai–Tibet plateau and high genetic variation warrants more investigation into the haplotype distribution and genetic polymorphism by exploring more informative DNA regions of the mitochondrial genome to provide epidemiologically useful insight into the population structure of E. shiquicus across the plateau and its axis.
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http://dx.doi.org/10.1017/S0031182021000512DOI Listing
March 2021

Randomized controlled trial of PosiFlow regulator with infusion clamp for reducing intravenous catheter plugging.

Ann Palliat Med 2021 Mar 15;10(3):3135-3141. Epub 2021 Mar 15.

Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China.

Background: Intravenous (IV) catheter insertion may cause adverse reactions. It is necessary to investigate optimal methods for reducing blood return and extending the usage time of IV catheter by existing technologies. We investigated the efficacy of the PosiFlow regulator with an infusion clip for preventing IV catheter plugging due to venous blood return.

Methods: From January 2017 to August 2017, 960 patients requiring IV catheterization were recruited and by using the block randomization method randomly allocated to 4 groups (n=240 in each group): a control group receiving IV catheter with infusion clip; experimental group A receiving IV catheter without infusion clip; experimental group B receiving an IV catheter with the PosiFlow regulator; and experimental group C receiving an IV catheter with a PosiFlow regulator and infusion clip. The rates of catheter plugging and blood return were compared among groups.

Results: In different reasons for needle pulling, The rates of catheter plugging and blood return in experimental group C (Received IV catheterization with an infusion clip and PosiFlow regulato) were the lowest among all groups (P<0.05). In different puncture sites, forearm puncture further reduced IV catheter plugging in all groups compared to other puncture sites.

Conclusions: Catheter plugging and blood return can be significantly reduced by combining the PosiFlow regulator and an infusion clip, resulting in reduced medical costs and patient distress from catheter reinsertion.
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http://dx.doi.org/10.21037/apm-21-145DOI Listing
March 2021

Diagnostic significance of serum PP4R1 and its predictive value for the development of chronic complications in patients with type 2 diabetes mellitus.

Diabetol Metab Syndr 2021 Mar 9;13(1):27. Epub 2021 Mar 9.

Nephrology and Urology Centre, University-Town Hospital of Chongqing Medical University, No. 55, University-Town Middle Road, Chongqing, 401551, China.

Background: Protein phosphatase 4 regulatory subunit 1 (PP4R1) is one of the regulatory subunits of PP4. It has been determined to be involved in the regulation of TNF-α-induced hepatic insulin resistance and gluconeogenesis. Considering the important role of PP4R1 in hepatic insulin resistance, the current study explored the expression and diagnostic value of PP4R1 in type 2 diabetes mellitus (T2DM) patients and further investigated its predictive value for the development of chronic complications.

Method: Hundred and five patients with T2DM and 97 healthy controls were collected. qRT-PCR was used for the measurement of serum PP4R1 mRNA level in both T2DM and control groups. The diagnostic value of PP4R1 in T2DM patients was evaluated using receiver operating characteristic (ROC) curve. Kaplan-Meier methods and Cox regression analysis were used to evaluate the predictive value of PP4R1 for the development of chronic complications in T2DM patients.

Results: PP4R1 was determined to be elevated in the serum of T2DM patients compared with healthy controls. Serum PP4R1 had the potential to distinguish T2DM patients from healthy controls with a sensitivity of 81.9% and specificity of 82.5%. Patients with high PP4R1 expression experienced more chronic complications events. The multivariate Cox analysis results suggested that serum PP4R1 expression was an independent factor for the occurrence of chronic complications for T2DM patients.  CONCLUSION: PP4R1 is elevated in the serum of T2DM patients, had the potential to distinguish T2DM patients from healthy controls. PP4R1 serves as a promising biomarker for predicting the risk of future chronic complications in T2DM patients.
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http://dx.doi.org/10.1186/s13098-021-00642-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945353PMC
March 2021

An effective computational-screening strategy for simultaneously improving both catalytic activity and thermostability of α-l-rhamnosidase.

Biotechnol Bioeng 2021 Mar 20. Epub 2021 Mar 20.

College of Food and Biological Engineering, Jimei University, Xiamen, China.

Catalytic efficiency and thermostability are the two most important characteristics of enzymes. However, it is always tough to improve both catalytic efficiency and thermostability of enzymes simultaneously. In the present study, a computational strategy with double-screening steps was proposed to simultaneously improve both catalysis efficiency and thermostability of enzymes; and a fungal α-l-rhamnosidase was used to validate the strategy. As the result, by molecular docking and sequence alignment analysis within the binding pocket, seven mutant candidates were predicted with better catalytic efficiency. By energy variety analysis, A355N, S356Y, and D525N among the seven mutant candidates were predicted with better thermostability. The expression and characterization results showed the mutant D525N had significant improvements in both enzyme activity and thermostability. Molecular dynamics simulations indicated that the mutations located within the 5 Å range of the catalytic domain, which could improve root mean squared deviation, electrostatic, Van der Waal interaction, and polar salvation values, and formed water bridge between the substrate and the enzyme. The study indicated that the computational strategy based on the binding energy, conservation degree and mutation energy analyses was effective to develop enzymes with better catalysis and thermostability, providing practical approach for developing industrial enzymes.
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http://dx.doi.org/10.1002/bit.27758DOI Listing
March 2021

An analytical study of drug utilization, disease progression, and adverse events among 165 COVID-19 patients.

Ann Transl Med 2021 Feb;9(4):306

Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China.

Background: The coronavirus disease 2019 (COVID-19) epidemic has lasted for nearly 4 months by this study was conducted. We aimed to describe drug utilization, disease progression, and adverse drug events of COVID-19.

Methods: A retrospective, single-center case series study enrolled 165 consecutive hospitalized COVID-19 patients who were followed up until March 25, 2020, from a designated hospital in Wuhan. Patients were grouped by a baseline degree of severity: non-severe and severe. An analytical study of drug utilization, disease progression, and adverse events (AEs) of COVID-19 was conducted.

Results: Of the 165 COVID-19 cases, antivirals, antibacterials, glucocorticoids, and traditional Chinese medicine (TCM) were administered to 92.7%, 98.8%, 68.5%, and 55.2% of patients, respectively. The total kinds of drugs administered to the severe subgroup [26, interquartile range (IQR) 18-39] were 11 more than the non-severe subgroup (15, IQR 10-24), regardless of comorbidities. The 2 most common combinations of medications in the 165 cases were 'antiviral therapy + glucocorticoids + TCM' (81, 49.1%) and 'antiviral therapy + glucocorticoids' (23, 13.9%). Compared with non-severe cases, severe cases received more glucocorticoids (88.5% . 66.2%, P=0.02), but less TCM (50.0% . 63.3%, P=0.20), and suffered a higher percentage of death (34.6% . 7.2%, P=0.001). At the end of the follow-up, 130 (78.8%) patients had been discharged, and 24 (14.5%) died. There were 13 patients (7.9%) who had elevated liver enzymes, and 49 patients (29.7%) presented with worsening kidney function during the follow-up.

Conclusions: Of the 165 COVID-19 patients, the fatality rate remained high (14.5%). Drug utilization for COVID-19 was diverse and generally complied with the existing guidelines. Combination regimens containing antiviral drugs might be beneficial to assist COVID-19 recovery. Additionally, liver and kidney AEs should not be ignored.
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http://dx.doi.org/10.21037/atm-20-4960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944318PMC
February 2021

Batch fermentation kinetics of acetoin produced by HB-32.

Prep Biochem Biotechnol 2021 Mar 9:1-8. Epub 2021 Mar 9.

Key Laboratory of Food and Fermentation Engineering of Shandong Province, Shandong Food Ferment Industry Research & Design Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, P. R. China.

Objectives: The aim of this work was to study the changes of bacterial cell growth, acetion formation and glucose consumption with fermentation time during batch cultivation.

Results: A mathematical model of cell growth, product synthesis, and substrate consumption changes with time during the batch cultivation of acetion was established. By analyzing the fitting curve of the kinetic model, it is found that the calculated value of the model fits well with the experimental value, and the fitting model R2 is greater than 0.98.

Conclusions: The kinetic model established in this experiment can better reflect the batch cultivation process of acetion.
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http://dx.doi.org/10.1080/10826068.2021.1885047DOI Listing
March 2021

MetAP2 inhibition modifies hemoglobin S to delay polymerization and improves blood flow in sickle cell disease.

Blood Adv 2021 Mar;5(5):1388-1402

Department of Rare Blood Disorders, Sanofi, Waltham, MA.

Sickle cell disease (SCD) is associated with hemolysis, vascular inflammation, and organ damage. Affected patients experience chronic painful vaso-occlusive events requiring hospitalization. Hypoxia-induced polymerization of sickle hemoglobin S (HbS) contributes to sickling of red blood cells (RBCs) and disease pathophysiology. Dilution of HbS with nonsickling hemoglobin or hemoglobin with increased oxygen affinity, such as fetal hemoglobin or HbS bound to aromatic aldehydes, is clinically beneficial in decreasing polymerization. We investigated a novel alternate approach to modify HbS and decrease polymerization by inhibiting methionine aminopeptidase 2 (MetAP2), which cleaves the initiator methionine (iMet) from Val1 of α-globin and βS-globin. Kinetic studies with MetAP2 show that βS-globin is a fivefold better substrate than α-globin. Knockdown of MetAP2 in human umbilical cord blood-derived erythroid progenitor 2 cells shows more extensive modification of α-globin than β-globin, consistent with kinetic data. Treatment of human erythroid cells in vitro or Townes SCD mice in vivo with selective MetAP2 inhibitors extensively modifies both globins with N-terminal iMet and acetylated iMet. HbS modification by MetAP2 inhibition increases oxygen affinity, as measured by decreased oxygen tension at which hemoglobin is 50% saturated. Acetyl-iMet modification on βS-globin delays HbS polymerization under hypoxia. MetAP2 inhibitor-treated Townes mice reach 50% total HbS modification, significantly increasing the affinity of RBCs for oxygen, increasing whole blood single-cell RBC oxygen saturation, and decreasing fractional flow velocity losses in blood rheology under decreased oxygen pressures. Crystal structures of modified HbS variants show stabilization of the nonpolymerizing high O2-affinity R2 state, explaining modified HbS antisickling activity. Further study of MetAP2 inhibition as a potential therapeutic target for SCD is warranted.
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http://dx.doi.org/10.1182/bloodadvances.2020003670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948285PMC
March 2021

Quality markers based on phytochemical analysis and anti-inflammatory screening: An integrated strategy for the quality control of Dalbergia odorifera by UHPLC-Q-Orbitrap HRMS.

Phytomedicine 2021 Apr 12;84:153511. Epub 2021 Feb 12.

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China. Electronic address:

Background: Quality control, key for the clinical application of traditional Chinese medicines (TCMs), should be connected to the authentication and efficacy of TCMs. The heartwood of Dalbergia odorifera has been widely used to treat inflammation-related diseases. However, in the Chinese pharmacopeia, only the total volatile oil, which does not sufficiently reflect the clinical efficacy, is used as a quality control indicator.

Purpose: Establishing a "phytochemical-specificity-effectiveness-Q-marker" analytical strategy to improve the quality control of D. odorifera.

Methods: Combined with biosynthetic pathway analysis, phytochemical compositions identified by UHPLC-Q-Orbitrap HRMS were used to build substantial phytochemical groups and further discover specific Q-markers. Then, lipopolysaccharide-stimulated RAW 264.7 cells were used to screen effective anti-inflammatory ingredients. Finally, a UHPLC-HRMS method was developed and validated to quantify the selected Q-markers in D. odorifera samples.

Results: Along the constructed biosynthetic pathways, 93 phytochemical components were identified in D. odorifera, including 7 chalcones, 13 flavanones, 21 isoflavones, 21 isoflavanones, 3 flavonols, 19 neoflavones, etc. Among them, 31 compounds representing these 6 categories were further evaluated for their anti-inflammatory activities. It revealed that the extract of D. odorifera and nine flavonoids in the noncytotoxic range could alleviated lipopolysaccharide-stimulated inflammation in RAW 264.7 cells by decreasing the production of proinflammatory mediators such as nitric oxide and interleukin-6. Notably, neoflavones, as species-specific components, exhibited superior anti-inflammatory activities among the representative compounds. Finally, 12 Q-markers (butin, liquiritigenin, eriodictyol, melanettin, naringenin, butein, genistein, 4'-hydroxy-4-methoxydalbergione, isoliquiritigenin, 2,4-dihydroxy-5-methoxybenzophenone, medicarpin, and pinocembrin), which reflect specificity and effectiveness, were successfully quantified in 10 batches of samples from different origins. The origins and consistency of D. odorifera could be efficiently discriminated by hierarchical cluster analysis (HCA).

Conclusion: The analysis strategy that combines phytochemical analysis with anti-inflammatory screening clarified the therapeutic material basis and discovered Q-markers, which possibly offers a more comprehensive quality assessment of D. odorifera.
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http://dx.doi.org/10.1016/j.phymed.2021.153511DOI Listing
April 2021

Quality markers based on phytochemical analysis and anti-inflammatory screening: An integrated strategy for the quality control of Dalbergia odorifera by UHPLC-Q-Orbitrap HRMS.

Phytomedicine 2021 Apr 12;84:153511. Epub 2021 Feb 12.

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China. Electronic address:

Background: Quality control, key for the clinical application of traditional Chinese medicines (TCMs), should be connected to the authentication and efficacy of TCMs. The heartwood of Dalbergia odorifera has been widely used to treat inflammation-related diseases. However, in the Chinese pharmacopeia, only the total volatile oil, which does not sufficiently reflect the clinical efficacy, is used as a quality control indicator.

Purpose: Establishing a "phytochemical-specificity-effectiveness-Q-marker" analytical strategy to improve the quality control of D. odorifera.

Methods: Combined with biosynthetic pathway analysis, phytochemical compositions identified by UHPLC-Q-Orbitrap HRMS were used to build substantial phytochemical groups and further discover specific Q-markers. Then, lipopolysaccharide-stimulated RAW 264.7 cells were used to screen effective anti-inflammatory ingredients. Finally, a UHPLC-HRMS method was developed and validated to quantify the selected Q-markers in D. odorifera samples.

Results: Along the constructed biosynthetic pathways, 93 phytochemical components were identified in D. odorifera, including 7 chalcones, 13 flavanones, 21 isoflavones, 21 isoflavanones, 3 flavonols, 19 neoflavones, etc. Among them, 31 compounds representing these 6 categories were further evaluated for their anti-inflammatory activities. It revealed that the extract of D. odorifera and nine flavonoids in the noncytotoxic range could alleviated lipopolysaccharide-stimulated inflammation in RAW 264.7 cells by decreasing the production of proinflammatory mediators such as nitric oxide and interleukin-6. Notably, neoflavones, as species-specific components, exhibited superior anti-inflammatory activities among the representative compounds. Finally, 12 Q-markers (butin, liquiritigenin, eriodictyol, melanettin, naringenin, butein, genistein, 4'-hydroxy-4-methoxydalbergione, isoliquiritigenin, 2,4-dihydroxy-5-methoxybenzophenone, medicarpin, and pinocembrin), which reflect specificity and effectiveness, were successfully quantified in 10 batches of samples from different origins. The origins and consistency of D. odorifera could be efficiently discriminated by hierarchical cluster analysis (HCA).

Conclusion: The analysis strategy that combines phytochemical analysis with anti-inflammatory screening clarified the therapeutic material basis and discovered Q-markers, which possibly offers a more comprehensive quality assessment of D. odorifera.
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http://dx.doi.org/10.1016/j.phymed.2021.153511DOI Listing
April 2021

Anxiety and depression in allergic rhinitis patients during COVID-19 pandemic in Wuhan, China.

Asian Pac J Allergy Immunol 2021 Feb 21. Epub 2021 Feb 21.

Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong Univerity of Science and Technology, Wuhan, China.

Background: During COVID-19 pandemic, many allergic rhinitis (AR) patients stopped their treatment including pharmacotherapy and allergen immunotherapy.

Objective: This study aimed to investigate the anxiety and depression and general effect of COVID-19 pandemic on AR patients' psychological status in Wuhan, China.

Methods: In October 2019, 222 outpatients suffering from AR in our department and 133 healthy controls were enrolled. All participants were asked to finish the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) questionnaire. The demographic characteristics and the severity of AR symptoms were recorded. In April 2020, the AR patients and healthy controls were re-contacted to finish the questionnaires by telephone or online. The SAS and SDS scores in AR patients and healthy controls and the correlation with other variables were analyzed.

Results: For AR patients, the SAS and SDS scores were significantly higher than healthy controls. Meanwhile, the rates of anxiety and depression were 24.8% and 19.4% respectively. The education level and symptoms severity were correlated with SAS and SDS scores. Ninety-eight AR patients and 56 healthy controls finished the questionnaires after COVID-19 pandemic. The AR patients' SAS and SDS scores were lower than before COVID-19 pandemic and were correlated with AR symptom scores. The scores of healthy controls were not different with before COVID-19 pandemic.

Conclusions: The occurrence of anxiety and depression is common in AR patients. Severity of symptoms and low education level are the risk factors causing anxiety and depression. COVID-19 pandemic has no significant negative impact on the AR patients' psychological status.
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http://dx.doi.org/10.12932/AP-140820-0941DOI Listing
February 2021

P22 virus-like particles as an effective antigen delivery nanoplatform for cancer immunotherapy.

Biomaterials 2021 Apr 18;271:120726. Epub 2021 Feb 18.

State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin, 300071, PR China. Electronic address:

As a new strategy for cancer immunotherapy, therapeutic cancer vaccines have been greatly improved in recent years. However, addressing the needs to quickly and efficiently elicit a high-intensity immune response against neoantigen peptides, especially to induce an effective cytotoxic lymphocyte (CTL) reaction, remain challenges in this field. In this study, virus-like particles (VLPs) derived from the phage P22 were adopted to load peptide antigens on the surface, to test whether VLP technology can be used as a platform for efficient peptide antigen delivery by therapeutic cancer vaccines. The B and T epitopes (OVA peptide and OVA peptide) of ovalbumin (OVA) were used here as model antigens and fused individually at the C terminus of the coat protein (CP), which allowed display on the surface of P22 particles to form two types of vaccine particles (VLP-OVA and VLP-OVA). Subsequent experiments showed that VLP-OVA induced an antibody titer against the peptide antigen as high as 5.0 × 10 and that VLP-OVA induced highly effective cross-presentation and then strongly activated a T epitope-specific CTL response. Mouse tumor model experiments showed that VLP-OVA could significantly inhibit tumor growth by increasing the proportions of CD4 T cells, CD8 T cells and effector memory T cells (T cells) and lowering the proportion of myeloid-derived suppressor cells (MDSCs) among tumor-infiltrating lymphocytes and splenocytes. Compared with other chemically synthesized nanomaterials, VLPs have obvious advantages as vaccine carriers due to their clear chemical composition, fixed spatial structure, excellent biocompatibility, and relatively high potential for clinical translation. Therefore, this platform may lay a solid foundation for the design and preparation of personalized therapeutic vaccines based on neoantigen peptides.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120726DOI Listing
April 2021

A synergetic effect of BARD1 mutations on tumorigenesis.

Nat Commun 2021 02 23;12(1):1243. Epub 2021 Feb 23.

Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.

To date, a large number of mutations have been screened from breast and ovarian cancer patients. However, most of them are classified into benign or unidentified alterations due to their undetectable phenotypes. Whether and how they could cause tumors remains unknown, and this significantly limits diagnosis and therapy. Here, in a study of a family with hereditary breast and ovarian cancer, we find that two BARD1 mutations, P24S and R378S, simultaneously exist in cis in surviving cancer patients. Neither of the single mutations causes a functional change, but together they synergetically impair the DNA damage response and lead to tumors in vitro and in vivo. Thus, our report not only demonstrates that BARD1 defects account for tumorigenesis but also uncovers the potential risk of synergetic effects between the large number of cis mutations in individual genes in the human genome.
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http://dx.doi.org/10.1038/s41467-021-21519-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902612PMC
February 2021

Multiple roles of FGF10 in the regulation of corneal endothelial wound healing.

Exp Eye Res 2021 Apr 20;205:108517. Epub 2021 Feb 20.

State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China; Shandong Eye Hospital, Shandong Eye Institute, Shandong First Medical University &Shandong Academy of Medical Sciences, China. Electronic address:

Corneal endothelial dysfunction usually induces corneal haze and oedema, which seriously affect visual function. The main therapeutic strategy for this condition is corneal transplantation, but the use of this strategy is limited by the shortage of healthy donor corneas. Compared with corneal transplantation, drug intervention is less invasive and more accessible; thus, finding an effective pharmaceutical alternative for cornea transplantation is critical for the treatment of corneal endothelial dysfunction. In this study, we established a rabbit scratch model to investigate the effect of fibroblast growth factor 10 (FGF10) on corneal endothelial wound healing. Results showed that FGF10 injection accelerated the recovery of corneal transparency and increased the protein expression levels of ZO1, Na/K-ATPase and AQP-1. Moreover, FGF10 significantly inhibited the expression levels of endothelial-to-mesenchymal transition proteins and reduced the expression levels of the proinflammatory factors IL-1β and TNF-α in the anterior chamber aqueous humour. FGF10 also enhanced the Na/K-ATPase activity by enhancing mitochondrial function as a result of its direct interaction with its conjugate receptor. Thus, FGF10 could be a new pharmaceutical preparation as treatment for corneal endothelial dysfunction.
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http://dx.doi.org/10.1016/j.exer.2021.108517DOI Listing
April 2021

Association Between Furosemide Exposure and Clinical Outcomes in a Retrospective Cohort of Critically Ill Children.

Front Pediatr 2020 25;8:589124. Epub 2021 Jan 25.

Department of Nephrology and Immunology, Children's Hospital of Soochow University, Suzhou, China.

Furosemide is commonly prescribed in critically ill patients to increase the urine output and prevent fluid overload (FO) and acute kidney injury (AKI), but not supported by conclusive evidence. There remain conflicting findings on whether furosemide associates with AKI and adverse outcomes. Information on the impact of furosemide on adverse outcomes in a general population of pediatric intensive care unit (PICU) is limited. The aim of the cohort study was to investigate the associations of furosemide with AKI and clinical outcomes in critically ill children. We retrospectively reviewed a cohort of 456 critically ill children consecutively admitted to PICU from January to December 2016. The exposure of interest was the use of furosemide in the first week after admission. FO was defined as ≥5% of daily fluid accumulation, and mean FO was considered significant when mean daily fluid accumulation during the first week was ≥5%. The primary outcomes were AKI in the first week after admission and mortality during PICU stay. AKI diagnosis was based on Kidney Disease: Improving Global Outcomes criteria with both serum creatinine and urine output. Furosemide exposure occurred in 43.4% of all patients ( = 456) and 49.3% of those who developed FO ( = 150) in the first week after admission. Patients who were exposed to furosemide had significantly less degree of mean daily fluid accumulation than those who were not (1.10 [-0.33 to 2.61%] vs. 2.00 [0.54-3.70%], < 0.001). There was no difference in the occurrence of AKI between patients who did and did not receive furosemide (22 of 198 [11.1%] vs. 36 of 258 [14.0%], = 0.397). The mortality rate was 15.4% (70 of 456), and death occurred more frequently among patients who received furosemide than among those who did not (21.7 vs. 10.5%, = 0.002). Furosemide exposure was associated with increased odds for mortality in a multivariate logistic regression model adjusted for body weight, gender, illness severity assessed by PRISM III score, the presence of mean FO, and AKI stage [adjusted odds ratio (AOR) 1.95; 95%CI, 1.08-3.52; = 0.026]. Exposure to furosemide might be associated with increased risk for mortality, but not AKI, in critically ill children.
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http://dx.doi.org/10.3389/fped.2020.589124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874070PMC
January 2021