Publications by authors named "Qin He"

402 Publications

Shield and sword nano-soldiers ameliorate rheumatoid arthritis by multi-stage manipulation of neutrophils.

J Control Release 2021 May 6. Epub 2021 May 6.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China. Electronic address:

Rheumatoid arthritis (RA) is characterized by the outbreak of inflammation. Neutrophils, the main culprit of the outbreak of inflammation, are the first inflammatory cells to be recruited to inflamed joints and facilitate the recruitment of themselves by stimulating the release of chemokines. Here, based on neutrophils, a novel anti-inflammatory "shield and sword soldiers" strategy is established with LMWH-TOS nanoparticles (LT NPs). The hydrophilic fragment low molecular weight heparin (LMWH) acts as a shield which block the transvascular movement of neutrophils through inhibiting the adhesion cascade by binding to P-selectin on inflamed endothelium. Synergistically, MMP-9, which is secreted by the recruited neutrophils and degrade the main component of articular cartilage, is reduced by the hydrophobic fragment d-α-tocopheryl succinate (TOS), functioning as a sword. In collagen-induced arthritis (CIA) mouse model, LT NPs show significant targeting effect, and exhibit prominent therapeutic efficacy after enveloping the first-line anti-RA drug methotrexate. Our work proves that the multi-stage manipulation of neutrophils is feasible and effective, providing a new concept for RA treatment.
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http://dx.doi.org/10.1016/j.jconrel.2021.05.008DOI Listing
May 2021

A pH-Responsive Supramolecular Drug Delivery System Constructed by Cationic Pillar[5]arene for Enhancing Antitumor Activity.

Front Chem 2021 12;9:661143. Epub 2021 Apr 12.

Guangxi Institute of Chinese Traditional Medical & Pharmaceutical Science and Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, Nanning, China.

Drug delivery systems have good biocompatibiliy and low side effects for cancer treatment, but overcoming high efficiency of drug-loading and the drug-targeting controlled release still remains challenging. In this work, supramolecular vesicles, with pH-triggering effect, have been successfully constructed for drug delivery, which are fabricated by the complexation between a cationic pillar[5]arene (DAWP5) and a sodium dodecyl sulfonate (SDS) in aqueous solution. Drug-loading and releasing results demonstrated that anticancer drug doxorubicin (DOX) could be loaded efficiently by such cationic vesicles in neutral condition, and the drug release could be controlled in the simulated weak acid environment of tumor cells. Moreover, the vesicles had low cytotoxicity to normal human cell (L02), while the DOX-loaded vesicles could significantly enhance the cytotoxicity of free DOX for normal cell L02 and four tested tumor cells (Hela, HepG2, MGC-803 and T24). Especially for HepG2, after 24 h incubation time, IC of DOX-loaded vesicles was only 0.79 μM, about 23% of that of DOX (3.43 μM). These results suggested that such novel vesicles have promising potential to construct nano-drug delivery systems for various biomedical applications.
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http://dx.doi.org/10.3389/fchem.2021.661143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072374PMC
April 2021

Homeobox B5 promotes metastasis and poor prognosis in Hepatocellular Carcinoma, via FGFR4 and CXCL1 upregulation.

Theranostics 2021 31;11(12):5759-5777. Epub 2021 Mar 31.

Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.

Since metastasis remains the main reason for HCC-associated death, a better understanding of molecular mechanism underlying HCC metastasis is urgently needed. Here, we elucidated the role of Homeobox B5 (HOXB5), a member of the HOX transcriptional factor family, in promoting HCC metastasis. The expression of HOXB5 and its functional targets fibroblast growth factor receptor 4 (FGFR4) and C-X-C motif chemokine ligand 1 (CXCL1) were detected by immunohistochemistry. Luciferase reporter and chromatin immunoprecipitation assays were performed to measure the transcriptional regulation of target genes by HOXB5. The effects of FGFR4 and CXCL1 on HOXB5-mediated metastasis were analyzed by an orthotopic metastasis model. Elevated expression of HOXB5 had a positive correlation with poor tumour differentiation, higher TNM stage, and indicated unfavorable prognosis. Overexpression of HOXB5 promoted HCC metastasis through transactivating FGFR4 and CXCL1 expression, whereas knockdown of FGFR4 and CXCL1 decreased HOXB5-enhanced HCC metastasis. Moreover, HOXB5 overexpression in HCC cells promoted myeloid derived suppressor cells (MDSCs) infiltration through CXCL1/CXCR2 axis. Either depletion of MDSCs by anti-Gr1 or blocking CXCL1-CXCR2 axis by CXCR2 inhibitor impaired HOXB5-mediated HCC metastasis. In addition, fibroblast growth factor 19 (FGF19) contributed to the HOXB5 upregulation through PI3K/AKT/HIF1α pathway. Overexpression of FGF15 (an analog of FGF19 in mouse) promoted HCC metastasis, whereas knockdown of HOXB5 significantly inhibited FGF15-enhanced HCC metastasis in immunocompetent mice. HOXB5 expression was positively associated with CXCL1 expression and intratumoral MDSCs accumulation in human HCC tissues. Patients who co-expressed HOXB5/CXCL1 or HOXB5/CD11b exhibited the worst prognosis. Furthermore, the combination of FGFR4 inhibitor BLU-554 and CXCR2 inhibitor SB265610 dramatically decreased HOXB5-mediated HCC metastasis. HOXB5 was a potential prognostic biomarker in HCC patients and targeting this loop may provide a promising treatment strategy for the inhibition of HOXB5-mediated HCC metastasis.
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http://dx.doi.org/10.7150/thno.57659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058721PMC
March 2021

Rapid pH-responsive self-disintegrating nanoassemblies balance tumor accumulation and penetration for enhanced anti-breast cancer therapy.

Acta Biomater 2021 Apr 18. Epub 2021 Apr 18.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China. Electronic address:

The dilemma of tumor accumulation and deep penetration has always been a barrier in antitumor therapy. Stimuli-responsive size changeable drug delivery systems provide possible solutions. Nevertheless, the low size-shrinkage efficiency limited the antitumor effects. In this study, an instant pH-responsive size shrinkable nanoassemblies named self-aggregated DOX@HA-CD (SA-DOX@HA-CD) was formulated using small-sized hyaluronic acid modified carbon dots (HA-CD) as monomers, which could self-aggregate into raspberry-like structure via hydrophobicity force in neutral pH and rapidly disassemble into shotgun-like DOX-loaded CD monomer in simulated tumor microenvironment (pH 6.5), owing to the transformation in electrical charge and hydrophobicity/hydrophilicity of this system. The transmission electron microscopy showed that the clustered SA-DOX@HA-CD had a diameter of ∼ 150 nm, and thoroughly disassembled into ∼30 nm nanoparticles in response to acidic environment. The disassemble efficiency was approximately 100%. Attributed to this property, SA-DOX@HA-CD led to enhanced cellular internalization and accumulation in 4T1 cells in simulated tumor microenvironment, as well as deep tumor penetration in 3D tumor spheroid model. Besides, the imine bond between DOX and HA-CD endowed DOX with pH-responsive release profile in the acidic lysosome environment. Furthermore, in the orthotopic 4T1 tumor-bearing mouse model, SA-DOX@HA-CD demonstrated higher tumor accumulation than non-aggregated DOX-HA-CD. Meanwhile, in response to the acid tumor microenvironment, the dissociated DOX-HA achieved deep tumor penetration, which consequently resulted in 2.5-fold higher antitumor efficiency. The formulation of self-aggregated SA-DOX@HA-CD provides a simple and effective alternative to prepare pH-responsive size-shrinkable nanodrug delivery systems. Statement of Significance: The heterogeneity of tumor vasculature and the high tumor interstitial pressure lead to the barriers in tumor accumulation and deep penetration, which calls for opposite properties (e.g. size) of drug delivery systems. To address this dilemma, various size changeable nanoparticles have been developed utilizing special features of tumor microenvironment, such as pH, enzyme and reactive oxygen species. Nevertheless, the current strategies face the problems of incomplete hydrolysis of chemical bonds or insufficient enzyme degradation, which result in only partial size shrinkage, hindering the tumor deep penetration effects. Here we developed a self-assembled nanocluster, which could respond to acidic pH rapidly and thoroughly disassemble into small nanodots due to the alteration of hydrophobicity/hydrophilicity/charge, leading to approximately 100% dissociation. This strategy provides a new concept for design of size changeable drug delivery systems.
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http://dx.doi.org/10.1016/j.actbio.2021.04.022DOI Listing
April 2021

Tryptophan 2, 3‑dioxygenase promotes proliferation, migration and invasion of ovarian cancer cells.

Mol Med Rep 2021 Jun 13;23(6). Epub 2021 Apr 13.

Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China.

Tryptophan 2,3‑dioxygenase (TDO2) is a key rate‑limiting enzyme in the kynurenine pathway and promotes tumor growth and escape from immune surveillance in different types of cancer. The present study aimed to investigate whether TDO2 serves a role in the development of ovarian cancer. Reverse transcription‑quantitative PCR and western blotting were used to detect the expression of TDO2 in different cell lines. The effects of TDO2 overexpression, TDO2 knockdown and TDO2 inhibitor on ovarian cancer cell proliferation, migration and invasion were determined by MTS, colony formation and Transwell assays. The expression of TDO2 in ovarian cancer tissues, normal ovarian tissues and fallopian tube tissues were analyzed using the gene expression data from The Cancer Genome Atlas and Genotype‑Tissue Expression project. Immune cell infiltration in cancer tissues was evaluated using the single sample gene set enrichment analysis algorithm. The present study found that RasV12‑mediated oncogenic transformation was accompanied by the upregulation of TDO2. In addition, it was demonstrated that TDO2 was upregulated in ovarian cancer tissues compared with normal ovarian tissues. TDO2 overexpression promoted proliferation, migration and invasion of ovarian cancer cells, whereas TDO2 knockdown repressed these phenotypes. Treatment with LM10, a TDO2 inhibitor, also repressed the proliferation, migration and invasion of ovarian cancer cells. The present study indicated that TDO2 can be used as a new target for the treatment of ovarian cancer.
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http://dx.doi.org/10.3892/mmr.2021.12084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060793PMC
June 2021

pH-Triggered Copper-Free Click Reaction-Mediated Micelle Aggregation for Enhanced Tumor Retention and Elevated Immuno-Chemotherapy against Melanoma.

ACS Appl Mater Interfaces 2021 Apr 9;13(15):18033-18046. Epub 2021 Apr 9.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.

Natural killer (NK) cell-based immunotherapy presents a promising antitumor strategy and holds potential for combination with chemotherapy. However, the suppressed NK cell activity and poor tumor retention of therapeutics hinder the efficacy. To activate NK cell-based immuno-chemotherapy and enhance the tumor retention, we proposed a pH-responsive self-aggregated nanoparticle for the codelivery of chemotherapeutic doxorubicin (DOX) and the transforming growth factor-β (TGF-β)/Smad3 signaling pathway inhibitor SIS3. Polycaprolactone-poly(ethylene glycol) (PCL-PEG) micelles modified with dibenzylcyclooctyne (DBCO) or azido (N) and coated with acid-cleavable PEG were established. This nanoplatform, namely, M-DN@DOX/SIS3, could remain well dispersed in the neutral systemic circulation, while quickly respond to the acidic tumor microenvironment and intracellular lysosomes, triggering copper-free click reaction-mediated aggregation, leading to the increased tumor accumulation and reduced cellular efflux. In addition, the combination of DOX with SIS3 facilitated by the aggregation strategy resulted in potent inhibition of melanoma tumor growth and significantly increased NK cells, NK cell cytokines, and antitumor T cells in the tumor. Taken together, our study offered a new concept of applying copper-free click chemistry to achieve nanoparticle aggregation and enhance tumor retention, as well as a promising new combined tumor treatment approach of chemotherapy and immunotherapy.
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http://dx.doi.org/10.1021/acsami.1c02567DOI Listing
April 2021

Seaweed polysaccharide mitigates intestinal barrier dysfunction induced by enterotoxigenic Escherichia coli through NF-κB pathway suppression in porcine intestinal epithelial cells.

J Anim Physiol Anim Nutr (Berl) 2021 Apr 5. Epub 2021 Apr 5.

Jiangxi Province Key Laboratory of Animal Nutrition, Jiangxi Province Key Innovation Center of Integration in Production and Education for High-quality and Safe Livestock and Poultry, Jiangxi Agricultural University, Nanchang, China.

This study aimed to investigate the protective effects and underlying mechanism of seaweed polysaccharide (SWP) on intestinal epithelial barrier dysfunction induced by E. coli in an IPEC-J2 model. A preliminary study was done to screen optimum SWP concentrations by cell viability, cytotoxicity, apoptosis and proliferation evaluation. The regular study was conducted to evaluate the protective effects of SWP against E. coli challenge via the analysis of transepithelial electrical resistance (TEER), tight junction proteins, NF-κB signalling pathway, proinflammatory cytokines and the E. coli adhesion and invasion. Our results show that 4 h E. coli challenge down-regulated tight junction proteins expression, decreased TEER, activated NF-κB signalling pathway and increased proinflammatory response, which indicates that the E. coli infection model was well-established. Pre-treatment with 240 μg/ml SWP for 24 h alleviated the 4 h E. coli -induced intestinal epithelial barrier dysfunction, as evidenced by the up-regulated expression of Occludin, Claudin-1 and ZO-1 at both mRNA and protein level and the increased TEER of IPEC-J2 cells. Pre-incubation with 240 μg/ml SWP for 24 h inhibited the activation of the NF-κB signalling pathway by 4 h E. coli challenge, including the decreased mRNA expression of TLR-4, MyD88, IκBα, p-65, as well as the reduced ratio of protein expression of p-p65/p65. Also, pre-treatment with 240 μg/ml SWP for 24 h decreased proinflammatory response (IL-6 and TNF-α) induced by 4 h E. coli challenge and decreased the E. coli adhesion and invasion. In conclusion, SWP mitigated intestinal barrier dysfunction caused by E. coli through NF-κB pathway in IPEC-J2 cells and 240 μg/ml SWP exhibited better effect. Our results also provide a fundamental basis for SWP in reducing post-weaning diarrhoea of weaned piglets, especially under E. coli -infected or in-feed antibiotic-free conditions.
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http://dx.doi.org/10.1111/jpn.13540DOI Listing
April 2021

Dietary seaweed-derived polysaccharides improve growth performance of weaned pigs through maintaining intestinal barrier function and modulating gut microbial populations.

J Anim Sci Biotechnol 2021 Mar 10;12(1):28. Epub 2021 Mar 10.

Jiangxi Province Key Laboratory of Animal Nutrition, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, Jiangxi, China.

Background: Seaweed-derived polysaccharides (SDP) represent an attractive source of prebiotic nutraceuticals for the food and animal husbandry industry. However, the mechanism by which SDP from Enteromorpha mediates pig growth are not fully understood. This study aimed to investigate how SDP supplementation influences the growth performance and intestinal health in weaned pigs.

Results: In Exp. 1, 240 weaned pigs were randomly assigned to four dietary treatments and fed with a basal diet or a basal diet containing 200, 400 or 800 mg/kg SDP, respectively, in a 21-day trial. Pigs on the 400 or 800 mg/kg SDP-supplemented group had greater ADG and lower F/G ratio than those on the control group (P<0.05). In Exp. 2, 20 male weaned pigs were randomly assigned to two treatments and fed with a basal diet (CON group) or a basal diet supplemented with 400 mg/kg SDP (the optimum does from Exp. 1), in a 21-day trial. Pigs fed the SDP diet had greater ADG, the concentrations of serum IL-6 and TNF-α and the activities of glutathione peroxidase, superoxide dismutase and catalase (P<0.05), and lower F/G, diarrhea rate, as well as serum D-lactate concentrations and diamine oxidase activity (P<0.05). Moreover, dietary SDP supplementation enhanced secretory immunoglobulin A content, villus height and villous height: crypt depth ratio in small intestine, as well as the lactase and maltase activities in jejunum mucosa (P<0.05). SDP supplementation elevated the mRNA levels of inflammatory response-related genes (IL-6, TNF-α, TLR4, TLR6 and MyD88), and the mRNA and protein levels of ZO-1, claudin-1 and occludin in jejunum mucosa (P<0.05). Importantly, SDP not only increased the Lactobacillus population but also reduced the Escherichia coli population in cecum (P<0.05). Furthermore, SDP increased acetic acid and butyric acid concentrations in cecum (P<0.05).

Conclusions: These results not only suggest a beneficial effect of SDP on growth performance and intestinal barrier functions, but also offer potential mechanisms behind SDP-facilitated intestinal health in weaned pigs.
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http://dx.doi.org/10.1186/s40104-021-00552-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945339PMC
March 2021

Melatonin prevents diabetes-associated cognitive dysfunction from microglia-mediated neuroinflammation by activating autophagy via TLR4/Akt/mTOR pathway.

FASEB J 2021 Apr;35(4):e21485

Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China.

Cognitive dysfunction often occurs in diabetes mellitus patients. This study aimed to investigate the efficacy of melatonin (MLT) in improving diabetes-associated cognitive decline and the underlying mechanism involved. Type 2 diabetic mice and palmitic acid (PA)-stimulated BV-2 cells were treated by MLT, and the potential mechanisms among MLT, cognition, and autophagy were explored. The results showed that type 2 diabetic mice showed obvious learning and memory impairments in the Morris water maze test compared with normal controls, which could be ameliorated by MLT treatment. Meanwhile, MLT administration significantly improved neuroinflammation and regulated microglial apoptosis. Furthermore, autophagy inhibitor 3-methyladenine (3-MA) increased the microglial inflammation and apoptosis, indicating that the treatment effect of MLT was mediated by autophagy. Lastly, MLT treatment significantly decreased the levels of toll-like receptors 4 (TLR4), phosphorylated-protein kinase B (Akt), and phosphorylated-mechanistic target of rapamycin (mTOR), indicating that blocking TLR4/Akt/mTOR pathway might be an underlying basis for the anti-inflammatory and anti-apoptosis effects of MLT. Collectively, our study suggested that MLT could improve learning and memory in type 2 diabetic mice by activating autophagy via the TLR4/Akt/mTOR pathway, thereby inhibiting neuroinflammation and microglial apoptosis.
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http://dx.doi.org/10.1096/fj.202002247RRDOI Listing
April 2021

Ralstonia solanacearum type III effector RipV2 encoding a novel E3 ubiquitin ligase (NEL) is required for full virulence by suppressing plant PAMP-triggered immunity.

Biochem Biophys Res Commun 2021 Apr 7;550:120-126. Epub 2021 Mar 7.

Key Laboratory of Horticultural Plant Biology, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, PR China; Key Laboratory of Potato Biology and Biotechnology, Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, 430070, PR China. Electronic address:

Ralstonia solanacearum causes bacterial wilt disease in a broad range of plants, primarily through type Ⅲ secreted effectors. However, the R. solanacearum effectors promoting susceptibility in host plants remain limited. In this study, we determined that the R. solanacearum effector RipV2 functions as a novel E3 ubiquitin ligase (NEL). RipV2 was observed to be locali in the plasma membrane after translocatio into plant cells. Transient expression of RipV2 in Nicotiana benthamiana could induce cell death and suppress the flg22-induced pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) responses, mediating such effects as attenuation of the expression of several PTI-related genes and ROS bursts. Furthermore, we demonstrated that the conserved catalytic residue is highly important for RipV2. Transient expression of the E3 ubiquitin ligase catalytic mutant RipV2 C403A alleviated the PTI suppression ability and cell death induction, indicating that RipV2 requires its E3 ubiquitin ligase activity for its role in plant-microbe interactions. More importantly, mutation of RipV2 in R. solanacearum reduces the virulence of R. solanacearum on potato. In conclusion, we identified a NEL effector that is required for full virulence of R. solanacearum by suppressing plant PTI.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.082DOI Listing
April 2021

Optimized protocol for high-titer lentivirus production and transduction of primary fibroblasts.

J Basic Microbiol 2021 May 8;61(5):430-442. Epub 2021 Mar 8.

Department of Ophthalmology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

The lentivirus-short hairpin RNA (shRNA) system is a widely used tool for RNA interference. Multiple factors may affect the RNA interference efficiency during lentivirus production and transduction procedures. Thus, an optimized protocol is required to achieve high-titer lentivirus and efficient gene delivery. In the present study, lentivirus was produced by transfecting lentiviral transfer and packaging plasmids into HEK 293T cells. The factors affecting lentiviral titer were assessed, including lentiviral plasmid ratio, lentiviral transfer plasmid type, serum type for cell culture, transfection reagent-plasmid mixture incubation time, and the inoculation density of 293T cells for transfection. The high-titer lentivirus was achieved when plasmids were transfected at a molar ratio of 1:1:1:2, and the transfection reagent-plasmid mixture was replaced 6-8 h after transfection. The pLVX-shRNA2 lentiviral transfer plasmid was associated with the highest lentiviral titer, while both pLVX-shRNA2 and psi-LVRU6GP plasmids were associated with efficient RNA interference in target cells. The serum type for 293T cell culture affected the lentiviral titer significantly, while the inoculation density of 293T cells showed no influence on transfection efficiency or lentiviral titer. Moreover, the human primary fibroblasts infected with lentivirus, using the centrifugation method, achieved higher transduction efficiency than those infected with the non-centrifugation method. In conclusion, this study helped optimize lentiviral production and transduction procedures for more efficient gene delivery.
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http://dx.doi.org/10.1002/jobm.202100008DOI Listing
May 2021

Effect of corneal incision features on anterior and posterior corneal astigmatism and higher-order aberrations after cataract surgery.

Acta Ophthalmol 2021 Mar 4. Epub 2021 Mar 4.

The Department of Ophthalmology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Purpose: To evaluate the influence of 2.2 mm clear corneal incision (CCI) features in surgically induced astigmatism (SIA) and higher-order aberrations (HOAs) after cataract surgery.

Methods: Right eyes of 92 subjects receiving 2.2 mm incision cataract surgery were involved. A total of 38 eyes were categorized as the intact incision group, and 54 eyes were the defective incision group. Pre- and postoperative (1 month and 6 months) corneal astigmatism and HOAs on anterior and posterior corneal surfaces, corneal volume, and corneal thickness (CT) were measured using Pentacam. The CCI features including incision length (IL), incision angles, distance from incision to central cornea (Dis-En/Ex), and CT at incision site were quantified using AS-OCT.

Results: The defective incision group showed shorter IL and larger incision angles [false discovery rate (FDR) - p < 0.05]. Changes in CT at incision site were more pronounced for the defective incision group (FDR - p < 0.05). Some SIA parameters were related to the certain specific CCI features, especially IL (FDR - p < 0.05). Both groups exhibited significant increased 6 mm posterior corneal tHOAs at 1 month (Bonferroni corrected - p < 0.01) and the defective incision group showed increased 6 mm posterior tHOAs at 6 months (Bonferroni corrected - p = 0.023). There were characteristic correlations between Zernike terms and CCI features including IL, CT, Dis-En/Ex, and incision angles at 1 month, especially over 6 mm zone.

Conclusion: The CCI deformities can affect corneal recovery and induce more HOAs at 1 month postoperatively. Such effects became minor, but could persist until 6 months. The IL combined with Angle-En/Ex was important factor influencing CCI integrity and corneal optical quality.
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http://dx.doi.org/10.1111/aos.14778DOI Listing
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

OsPRR37 Alternatively Promotes Heading Date Through Suppressing the Expression of Ghd7 in the Japonica Variety Zhonghua 11 under Natural Long-Day Conditions.

Rice (N Y) 2021 Feb 25;14(1):20. Epub 2021 Feb 25.

National Key Laboratory of Crop Genetic Improvement and National Center of Plant Gene Research (Wuhan), Huazhong Agricultural University, Wuhan, 430070, China.

Heading date is an important agronomic trait of rice (Oryza sativa L.) and is regulated by numerous genes, some of which exhibit functional divergence in a genetic background-dependent manner. Here, we identified a late heading date 7 (lhd7) mutant that flowered later than wild-type Zhonghua 11 (ZH11) under natural long-day (NLD) conditions. Map-based cloning facilitated by the MutMap strategy revealed that LHD7 was on the same locus as OsPRR37 but exhibited a novel function as a promoter of heading date. A single-nucleotide mutation of G-to-A in the coding region caused a substitution of aspartic acid for glycine at site 159 within the pseudo-receiver (PR) domain of OsPRR37. Transcriptional analysis revealed that OsPRR37 suppressed Ghd7 expression in both ZH11 background under NLD conditions and the Zhenshan 97 background under natural short-day conditions. Consistently, the expression of Ehd1, Hd3a and RFT1 was enhanced by OsPRR37 in the ZH11 background. Genetic analysis indicated that the promotion of heading date and reduction in grain yield by OsPRR37 were partially dependent on Ghd7. Further investigation showed that the alternative function of OsPRR37 required an intact Ghd7-related regulatory pathway involving not only its upstream regulators OsGI and PhyB but also its interacting partner Hd1. Our study revealed the distinct role of OsPRR37 in the ZH11 background, which provides a more comprehensive understanding of OsPRR37 function and enriches the theoretical bases for improvement of rice heading date in the future.
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http://dx.doi.org/10.1186/s12284-021-00464-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907330PMC
February 2021

Utilization of Endoscopy Scissors for Retrieval of Esophageal Embedded Foreign Body.

Am J Gastroenterol 2021 Feb 18. Epub 2021 Feb 18.

Department of Gastroenterology, The First People's Hospital of Chongqing Liangjiang New Area, Chongqing, China.

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http://dx.doi.org/10.14309/ajg.0000000000001211DOI Listing
February 2021

Mesenchymal stem cell-conditioned medium improved mitochondrial function and alleviated inflammation and apoptosis in non-alcoholic fatty liver disease by regulating SIRT1.

Biochem Biophys Res Commun 2021 03 9;546:74-82. Epub 2021 Feb 9.

Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China. Electronic address:

Non-alcoholic fatty liver disease (NAFLD), an emerging risk factor for diabetes, is now recognized as the most common liver disease worldwide. Mesenchymal stem cells (MSCs), a promising tool in regenerative medicine, release abundant molecules into the conditioned medium (CM). Increasing evidence showed that MSC-CM is beneficial for diabetes-associated NAFLD. However, the mechanism of how MSC-CM improves NAFLD remains uncertain. In this study, to determine the effects of MSC-CM on NAFLD, streptozotocin (STZ) and high-fat diet (HFD) induced T2DM mice model and palmitic acid (PA)-stimulated L-O2 cells were used and treated with MSC-CM. Our results demonstrated that MSC-CM improved insulin resistance in diabetic mice, amended the pathological structure of the liver, enhanced the liver's total antioxidant capacity and mitochondrial function, reduced inflammation and cell apoptosis. We further verified that SIRT1 played a key role in mediating the protective effect of MSC-CM. These findings provide novel evidence that MSC-CM has the potential to treat T2DM patients with NAFLD clinically.
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http://dx.doi.org/10.1016/j.bbrc.2021.01.098DOI Listing
March 2021

HIV drug resistance and HIV transmission risk factors among newly diagnosed individuals in Southwest China.

BMC Infect Dis 2021 Feb 8;21(1):160. Epub 2021 Feb 8.

Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, 530028, Guangxi, China.

Background: The widespread use of antiretroviral therapy (ART) has resulted in the development of transmitted drug resistance (TDR), which reduces ART efficacy. We explored TDR prevalence and its associated risk factors in newly diagnosed individuals in Guangxi.

Methods: We enrolled 1324 participants who were newly diagnosed with HIV-1 and had not received ART at voluntary counselling and testing centres (VCT) in Guangxi, China, who had not received ART. Phylogenetic relationship, transmission cluster, and genotypic drug resistance analyses were performed using HIV-1 pol sequences. We analysed the association of demographic and virological factors with TDR.

Results: In total, 1151 sequences were sequenced successfully, of which 83 (7.21%) showed evidence of TDR. Multivariate logistic regression analysis revealed that there was significant difference between the prevalence of TDR and unmarried status (adjusted odds ratio (aOR) = 2.41, 95% CI: 1.23-4.71), and CRF08_BC subtype (aOR = 2.03, 95% CI: 1.13-3.64). Most cases of TDR were related to resistance to non-nucleoside reverse transcriptase inhibitors (4.87%) and V179E was the most common mutation detected. We identified a total of 119 HIV transmission clusters (n = 585, 50.8%), of which 18 (15.1%) clusters showed evidence of TDR (36, 41.86%). Three clusters were identified that included drug-resistant individuals having a transmission relationship with each other. The following parameters were associated with TDR transmission risk: Unmarried status, educational level of junior high school or below, and CRF08_BC subtype may be a risk of the transmission of TDR.

Conclusions: Our findings indicated that moderate TDR prevalence and highlighted the importance of continuous TDR monitoring and designing of strategies for TDR mitigation.
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http://dx.doi.org/10.1186/s12879-021-05854-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871613PMC
February 2021

FOXC1 promotes HCC proliferation and metastasis by Upregulating DNMT3B to induce DNA Hypermethylation of CTH promoter.

J Exp Clin Cancer Res 2021 Feb 1;40(1):50. Epub 2021 Feb 1.

Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.

Background: Forkhead box C1 (FOXC1), as a member of the FOX family, is important for promote HCC invasion and metastasis. FOX family protein lays a pivotal role in metabolism. ROS is involved in tumor progression and is associated with the expression of lots of transcription factors. We next explored the mechanism underlying FOXC1 modulating the metabolism and ROS hemostasis in HCC.

Methods: We used amino acids arrays to verify which metabolism is involved in FOXC1-induced HCC. The kits were used to detect the ROS levels in HCC cells with over-expression or down-expression of FOXC1. After identified the downstream target genes and candidate pathway which regulated by FOXC1 during HCC progression in vitro and in vivo, we used western blot, immunohistochemistry, bisulfite genomic sequencing, methylation-specific PCR, chromatin immunoprecipitation analysis and luciferase reporter assays to explore the relationship of FOXC1 and downstream genes. Moreover, the correlation between FOXC1 and target genes and the correlation between target genes and the recurrence and overall survival were analyzed in two independent human HCC cohorts.

Results: Here, we reported that FOXC1 could inhibit the cysteine metabolism and increase reactive oxygen species (ROS) levels by regulating cysteine metabolism-related genes, cystathionine γ-lyase (CTH). Overexpression of CTH significantly suppressed FOXC1-induced HCC proliferation, invasion and metastasis, while the reduction in cell proliferation, invasion and metastasis caused by the inhibition of FOXC1 could be reversed by knockdown of CTH. Meanwhile, FOXC1 upregulated de novo DNA methylase 3B (DNMT3B) expression to induce DNA hypermethylation of CTH promoter, which resulted in low expression of CTH in HCC cells. Moreover, low levels of ROS induced by N-acetylcysteine (NAC) which is an antioxidant inhibited the cell proliferation, migration, and invasion abilities mediated by FOXC1 overexpression, whereas high levels of ROS induced by L-Buthionine-sulfoximine (BSO) rescued the suppression results mediated by FOXC1 knockdown. Our study demonstrated that the overexpression of FOXC1 that was induced by the ROS dependent on the extracellular regulated protein kinases 1 and 2 (ERK1/2)- phospho-ETS Transcription Factor 1 (p-ELK1) pathway. In human HCC tissues, FOXC1 expression was positively correlated with oxidative damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), p-ELK1 and DNMT3B expression, but negatively correlated with CTH expression. HCC patients with positive co-expression of 8-OHdG/FOXC1 or p-ELK1/FOXC1 or FOXC1/DNMT3B had the worst prognosis, whereas HCC patients who had positive FOXC1 and negative CTH expression exhibited the worst prognosis.

Conclusion: In a word, we clarify that the positive feedback loop of ROS-FOXC1-cysteine metabolism-ROS is important for promoting liver cancer proliferation and metastasis, and this pathway may provide a prospective clinical treatment approach for HCC.
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http://dx.doi.org/10.1186/s13046-021-01829-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852227PMC
February 2021

Alteration of lipid metabolism, autophagy, apoptosis and immune response in the liver of common carp (Cyprinus carpio) after long-term exposure to bisphenol A.

Ecotoxicol Environ Saf 2021 Mar 25;211:111923. Epub 2021 Jan 25.

Wuxi Fisheries College, Nanjing Agricultural University, Wuxi 214081, China; Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China. Electronic address:

Bisphenol A (BPA), as a phenolic compound, is harmful to human health, and its residue in the aquatic environment also threatens the health of aquatic animals. In this research, the toxicity effects of BPA on liver tissues were evaluated in common carp (Cyprinus carpio) after long-term exposure. Fish were exposed to five concentrations of BPA (0, 0.01, 0.1, 0.5 and 2 mg/L) for 30 days. The blood and liver tissues were gathered to analyze biochemical indices and genes transcription levels. The data related to lipid metabolism showed that BPA exposure increased serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) levels, upregulated the expressions of fatp1, pparγ, fas, atgl, hsl, pparα, cpt1b, acox-1, and downregulated the expression of dgat1 in liver. Antioxidative parameters displayed a reduced antioxidant ability and increased lipid peroxidation after BPA exposure. Meanwhile, the upregulations of nrf2, ho-1, cyp1a and cyp1b genes revealed an adaptive response mechanism against oxidative stress-induced adverse effects. After 30 days of exposure, BPA induced apoptosis and endoplasmic reticulum stress (ERS) via upregulating the expression levels of apoptosis and ERS-related genes and increasing Ca concentration in liver. Moreover, the downregulation of mtor and the upregulation of atg3, atg7, tfeb, uvrag and mcoln1 indicated that BPA could influence the normal process of autophagy. Furthermore, BPA exposure activated toll like receptors (TLRs) pathway to mediate the inflammatory response. Our results demonstrated that BPA exposure disturbed lipid metabolism, and induced oxidative stress, ERS, apoptosis, autophagy and inflammatory response in the liver of common carp. These findings contributed to the understanding of hepatotoxicity mechanism induced by BPA in fish.
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http://dx.doi.org/10.1016/j.ecoenv.2021.111923DOI Listing
March 2021

Patterns and risk of HIV-1 transmission network among men who have sex with men in Guangxi, China.

Sci Rep 2021 Jan 12;11(1):513. Epub 2021 Jan 12.

Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, No. 18 Jinzhou Road, Nanning, 530028, Guangxi, China.

The prevalence of HIV-1 in Guangxi is very high, and the rate of HIV-1 infection among men who have sex with men (MSM) has been increasing. Therefore, it is necessary to explore the patterns and risk factors of HIV transmission in Guangxi. For this purpose, individuals diagnosed with HIV-1 during 2013-2018 in Guangxi were recruited. Phylogenetic relationship, transmission clusters, and genotypic drug resistance analyses were performed based on HIV-1 pol sequences. Related factors were analysed to assess for their association with HIV-1 transmission. CRF07_BC (50.4%) and CRF01_AE (33.4%) were found to be the predominant subtypes. The analysed 1633 sequences (50.15%, Guangxi; 49.85%, other provinces) were segregated into 80 clusters (size per cluster, 2-704). We found that 75.3% of the individuals were in three clusters (size ˃ 100), and 73.8% were high-risk spreaders (links ≥ 4). Infection time, marital status, and subtype were significantly associated with HIV-1 transmission. Additionally, 80.2% of recent infections were linked to long-term infections, and 46.2% were linked to other provinces. A low level of transmitted drug resistance was detected (4.8%). Our findings indicated superclusters and high-risk HIV-1 spreaders among the MSM in Guangxi. Effective strategies blocking the route of transmission should be developed.
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http://dx.doi.org/10.1038/s41598-020-79951-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803972PMC
January 2021

Meta-Analysis of CTLA-4 +49 Gene Polymorphism and Susceptibility to Graves' Disease.

Crit Rev Eukaryot Gene Expr 2020 ;30(5):377-390

Key Laboratory of Fertility Preservation and Maintenance (NXMU), Ministry of Education, Ningxia Medical University, Yinchuan, Ningxia, China.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) plays an important role in the initiation and development of Graves' disease (GD), especially CTLA-4 +49A/G polymorphism and genetic susceptibility to GD. However, the current conclusions are consistent. Therefore, this study adopted meta-analysis method to assess the exact correlation between this polymorphism and GD risk.

Methods: Literature searches were performed in PubMed, Embase, Web of Science, China National Knowledge Infrastructure, China Wanfang, and other databases for data on the correlation between polymorphisms of CTLA-4 +49A/G and GD risk. The end date for publications was May 2020. Stata 15.0 software was used for data analysis.

Results: A total of 33 papers were included, covering 8,555 cases and 9,533 controls. The results showed that the CTLA-4 +49 allele G compared to allele A, odds ratio (OR) = 1.62, 95% CI [1.56, 2.09]. In the dominant, recessive, homozygous, and heterozygous genetic models, comparing the GD group and the control group, the combined OR was 1.81, 95% CI [1.56, 2.09]; 1.91, 95% CI [1.66, 2.21]; 2.75, 95% CI, [2.21, 3.41]; and 1.49, 95% CI [1.29, 1.71], respectively. When it was analyzed by dividing genetic models into subgroups according to ethnicity and published year, the data the of genetic model in each subgroup were also statistically significant.

Conclusion: The CTLA-4 +49A/G polymorphism was strongly associated with genetic susceptibility to GD. Allele G, genotypes GG, GG + GA, and GA are correlated with an increase in the risk of GD.
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http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2020034872DOI Listing
January 2020

All Roads Lead to Susceptibility: The Many Modes of Action of Fungal and Oomycete Intracellular Effectors.

Plant Commun 2020 Jul 24;1(4):100050. Epub 2020 Apr 24.

Division of Plant Sciences, School of Life Sciences, University of Dundee (at JHI), Invergowrie, Dundee DD2 5DA, UK.

The ability to secrete effector proteins that can enter plant cells and manipulate host processes is a key determinant of what makes a successful plant pathogen. Here, we review intracellular effectors from filamentous (fungal and oomycete) phytopathogens and the host proteins and processes that are targeted to promote disease. We cover contrasting virulence strategies and effector modes of action. Filamentous pathogen effectors alter the fates of host proteins that they target, changing their stability, their activity, their location, and the protein partners with which they interact. Some effectors inhibit target activity, whereas others enhance or utilize it, and some target multiple host proteins. We discuss the emerging topic of effectors that target negative regulators of immunity or other plant proteins with activities that support susceptibility. We also highlight the commonly targeted host proteins that are manipulated by effectors from multiple pathogens, including those representing different kingdoms of life.
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http://dx.doi.org/10.1016/j.xplc.2020.100050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748000PMC
July 2020

Conserved Imprinted Genes between Intra-Subspecies and Inter-Subspecies Are Involved in Energy Metabolism and Seed Development in Rice.

Int J Mol Sci 2020 Dec 17;21(24). Epub 2020 Dec 17.

National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan 430070, China.

Genomic imprinting is an epigenetic phenomenon in which a subset of genes express dependent on the origin of their parents. In plants, it is unclear whether imprinted genes are conserved between subspecies in rice. Here we identified imprinted genes from embryo and endosperm 5-7 days after pollination from three pairs of reciprocal hybrids, including inter-subspecies, intra-subspecies, and intra-subspecies reciprocal hybrids. A total of 914 imprinted genes, including 546 in inter-subspecies hybrids, 211 in intra-subspecies hybrids, and 286 in intra-subspecies hybrids. In general, the number of maternally expressed genes (MEGs) is more than paternally expressed genes (PEGs). Moreover, imprinted genes tend to be in mini clusters. The number of shared genes by R9N (reciprocal crosses between 9311 and Nipponbare) and R9Z (reciprocal crosses between 9311 and Zhenshan 97), R9N and RZN (reciprocal crosses between Zhonghua11 and Nipponbare), R9Z and RZN was 72, 46, and 16. These genes frequently involved in energy metabolism and seed development. Five imprinted genes (, , , , and ) are commonly detected in all three pairs of reciprocal hybrids and were validated by RT-PCR sequencing. Gene editing of two imprinted genes revealed that both genes conferred grain filling. Moreover, 15 and 27 imprinted genes with diverse functions in rice were shared with Arabidopsis and maize, respectively. This study provided valuable resources for identification of imprinting genes in rice or even in cereals.
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http://dx.doi.org/10.3390/ijms21249618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765902PMC
December 2020

Maternal Methyl-Donor Micronutrient Supplementation During Pregnancy Promotes Skeletal Muscle Differentiation and Maturity in Newborn and Weaning Pigs.

Front Nutr 2020 30;7:609022. Epub 2020 Nov 30.

Key Laboratory of Animal Nutrition in Jiangxi Province, Jiangxi Agricultural University, Nanchang, China.

Adequate maternal methyl-donor micronutrient (MET) intake is an important determinant of the organ development and metabolic renovation of offspring. The mechanism involved in skeletal myogenesis and the effect of MET supplementation during pregnancy on the maternal body remain unclear. Thus, this study aimed to investigate the potential effect of methyl donor micronutrients (MET) on skeletal muscle development and metabolism in offspring using pig models. Forty-three Duroc × Erhualian gilts were assigned to two dietary groups during gestation: control diet (CON) and CON diet supplemented with MET (folic acid, methionine, choline, vitamin B6, and vitamin B12). The results showed that maternal MET exposure during pregnancy significantly increased the concentrations of protein, triiodothyronine (T3), and thyroxine (T4) in colostrum and methyl metabolites, including S-adenosylmethionine (SAM), S-adenosyl-L-homocysteine (SAH), 5-methyl-tetrahydrofolate (5-MTHF), and betaine, in the maternal and offspring umbilical vein serum. A similar pattern was demonstrated in the body weight gain and myofiber diameters in offspring. In addition, maternal MET supplementation significantly increased the concentration of offspring serum insulin-like growth factor 1 (IGF-1), T3, and T4; upregulated the mRNA expression of IGF-1 and IGF-1 receptor (IGF-1r) and the phosphorylation level of protein kinases in offspring longissimus dorsi muscle; and upregulated the expression of myogenic genes and fast myosin heavy chain (fast MyHC) in offspring skeletal muscle. Supplementing sows with higher levels of MET during gestation may promote skeletal muscle differentiation and maturity and improve the skeletal muscle mass of the piglets.
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http://dx.doi.org/10.3389/fnut.2020.609022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734050PMC
November 2020

microRNA-491-5p protects against atherosclerosis by targeting matrix metallopeptidase-9.

Open Med (Wars) 2020 2;15(1):492-500. Epub 2020 Jun 2.

Department of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26 Shengli Street, Jiang'an District, Wuhan 430030, Hubei Province, China.

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are critical processes that are involved in atherosclerosis. The aim of this study was to explore the role of microRNA-491-5p (miR-491-5p) in the progression of atherosclerosis by regulating the growth and migration of VSMCs. In this study, we showed that the expression of miR-491-5p was downregulated in the atherosclerotic plaque tissues and plasma samples of the patients with atherosclerosis. The bioinformatic analysis and dual-luciferase reporter assay identified that matrix metallopeptidase-9 (MMP-9) was a target gene of miR-491-5p. The results showed a significant upregulation of MMP-9 in the atherosclerotic plaque tissues and plasma samples. Subsequently, the results also showed that downregulation of miR-491-5p significantly promoted the proliferation and migration of VSMCs and inhibited the apoptosis in VSMCs. Furthermore, we detected the effects of miR-491-5p mimic on the growth and migration of VSMCs, and the results illustrated that miR-491-5p mimic could inhibit the proliferation and migration of VSMCs and promote the apoptosis of VSMCs. Notably, MMP-9 plasmid could reverse all the effects of miR-491-5p mimic on VSMCs. Collectively, our study provides the first evidence that miR-491-5p inhibited the growth and migration of VSMCs by targeting MMP-9, which might provide new biomarkers and potential therapeutic targets for atherosclerosis treatment.
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http://dx.doi.org/10.1515/med-2020-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706122PMC
June 2020

A "dual-guide" bioinspired drug delivery strategy of a macrophage-based carrier against postoperative triple-negative breast cancer recurrence.

J Control Release 2021 Jan 27;329:191-204. Epub 2020 Nov 27.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University, Chengdu 610064, PR China. Electronic address:

Recurrence after tumor resection is mainly caused by post-operative inflammation and residual cancer cells, which is a serious obstacle to breast cancer treatment. Traditional nanoparticles rely primarily on the enhanced permeability and retention (EPR) effect in well-vascularized tumors. In this study, a macrophage-based carrier is designed to enhance the efficiency of targeting to recurrent tumors through a "dual-guide" strategy. After tumor resection, a burst of inflammatory factors occurs in the resection wound, which can recruit monocytes/macrophages rapidly. Combined with the tropism of monocyte chemoattractant protein, a large number of macrophage-mediated carriers will be recruited to surgical recurrence sites. Octaarginine (RRRRRRRR, R8)-modified liposomes in macrophages contain two agents with different pharmacological mechanisms, paclitaxel (PTX) and resveratrol (Res), which have enhanced therapeutic effects. In vitro study demonstrated that macrophage-mediated carriers approach 4 T1 cells through an inflammatory gradient and reach recurrence tumors through a "dual-guide" strategy. Then, membrane fusion and inflammation-triggered release deliver the drug into the recurrent tumor cells. In vivo experiments show that macrophage-based carriers exhibit effective tumor-targeting ability, especially in post-operation situations. More importantly, macrophage-mediated liposomes encapsulated with PTX and Res inhibit tumor recurrence in both ectopic and orthotopic 4 T1 post-operative recurrence models.
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http://dx.doi.org/10.1016/j.jconrel.2020.11.039DOI Listing
January 2021

Immune, inflammatory, autophagic and DNA damage responses to long-term HO exposure in different tissues of common carp (Cyprinus carpio).

Sci Total Environ 2021 Feb 21;757:143831. Epub 2020 Nov 21.

Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China. Electronic address:

Hydrogen peroxide (HO) is a stable reactive oxygen species (ROS) in aquatic environment, and high concentration of ambient HO may directly or indirectly affect aquatic animal health. However, the response mechanism of fish to ambient HO has not been well studied yet. Therefore, the aim of the study was to investigate the immune, inflammatory, autophagic and DNA damage responses to long-term HO exposure in different tissues of common carp. The results showed that HO exposure induced a significant immune response, with alterations in the levels of immune parameters including AKP, ACP, LZM, C3, HSP90 and HSP70 in different tissues. The inflammatory response evoked by HO exposure was associated with the activations of TLRs and NF-κB (P65) in the majority of tested tissues. The autophagy process was significantly affected by HO exposure, evidenced by the upregulations of the autophagy-related genes in liver, gills, muscle, intestines, heart and spleen and the downregulations in kidney. Meanwhile, the mRNA level of atm, a primary transducer of DNA damage response, was upregulated in liver, gills, intestines and spleen, and the DNA damage was evidenced by increased 8-OHdG level in intestines after HO exposure. Moreover, cell cycle regulation-related genes, including cyclin A1, B and/or E1, highly expressed in all tested tissues except heart after HO exposure. Interestingly, IBR analysis exhibited that immune, inflammatory, autophagic and DNA damage responses to HO exposure were in a dose-dependent and tissue-specific manner. These data may contribute to understanding HO toxicity for fish and assessing potential risk of HO in aquatic environment.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143831DOI Listing
February 2021

Enhanced stability and efficacy of GEM-TOS prodrug by co-assembly with antimetastatic shell LMWH-TOS.

Acta Pharm Sin B 2020 Oct 26;10(10):1977-1988. Epub 2019 Jun 26.

Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610064, China.

Chemotherapy agents have been widely used for cancer treatment, while the insolubility, instability and toxicity seriously restrict their efficacy. Thus, prodrug strategy was devised. Since some prodrugs are still with poor solubility or stability, a synergy strategy is needed to enhance their efficacy. Gemcitabine (GEM) is a prescribed anticancer drug, however, the rapid clearance, growing resistance and serious side effects limit its clinical efficacy. Conjugating GEM with d--tocopherol succinate (TOS) is an effective solution, while the GEM-TOS (GT) is unstable in aqueous solution. d--Tocopherol polyethylene glycol succinate (TPGS) has been used to enhance the stability, but GT stabilized by TPGS (GTT) has limited effect on tumor metastases. Tumor metastases lead to high mortality in patients suffering from cancers. In order to further achieve antimetastatic effect, an amphiphilic polymer (LT) was synthesized by connecting low-molecular-weight heparin (LMWH) with TOS, and eventually obtained desired self-delivery micellar NPs (GLT) by co-assembly GT with LT. The GLT not only possessed excellent stability, but also inhibited the metastases by acting on different phases of the metastatic cascade. The hydrophobic TOS inhibited the secretion of matrix metalloproteinase-9 (MMP-9), the hydrophilic LMWH inhibited the interaction between tumor cells and platelets. As a result, GLT reduced tumor cells entering the blood and implanting at the distant organs, leading to a much more excellent inhibitory effect on the lung metastasis than GEM and GTT.
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http://dx.doi.org/10.1016/j.apsb.2019.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606181PMC
October 2020

Trifolium Flavonoids Overcome Gefitinib Resistance of Non-Small-Cell Lung Cancer Cell by Suppressing ERK and STAT3 Signaling Pathways.

Biomed Res Int 2020 22;2020:2491304. Epub 2020 Oct 22.

Jinhua Municipal Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, China.

Gefitinib is a tyrosine kinase inhibitor of EGFR (epidermal growth factor receptor) and represents the first-line treatment for EGFR mutation patients with NSCLC (non-small-cell lung cancer) therapeutics. However, NSCLC patients are inclined to develop acquired gefitinib drug resistance through nowadays, unarticulated mechanisms of chemoresistance. Here, we investigated the role of TF (Trifolium flavonoids) on sensitizing gefitinib resistance in NSCLC cells and revealed its potential mechanism of action. We demonstrated that TF exerted significantly potential chemosensitivity in gefitinib resistant NSCLC cells. MTT assay and cytological methods were used to analyze cell viability and apoptosis in NSCLC cell line PC-9R. Both TF and gefitinib suppressed PC-9R cell growth in a dose-dependent manner. Subtoxic concentrations of TF did significantly augment gefitinib-induced apoptosis in PC-9R cell line. The TF promoted chemosensitivity was major mediated by the PARP and caspases activation. Meanwhile, the TF promoted chemosensitivity also decreased the expression of Bcl-2 and Mcl-1. Finally, TF significantly reduced the phosphorylation levels of STAT3 and ERK. Altogether, the results of the present study indicated the potential mechanisms of chemosensitivity of TF in gefitinib-induced apoptosis of NSCLC by downregulating ERK and STAT3 signaling pathways and Bcl2 and Mcl-1 expression and a promising application of TF in therapy of NSCLC with gefitinib resistant.
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http://dx.doi.org/10.1155/2020/2491304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603574PMC
May 2021

Improved Herbicide Resistance of 4-Hydroxyphenylpyruvate Dioxygenase from sp. TPM-19 through Directed Evolution.

J Agric Food Chem 2020 Nov 26;68(44):12365-12374. Epub 2020 Oct 26.

Department of Microbiology, Key Laboratory of Agricultural Environmental Microbiology, Ministry of Agriculture, College of Life Sciences, Nanjing Agricultural University, Nanjing 210095 Jiangsu, P. R. China.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted extensive interest as a promising target for the genetic engineering of herbicide-resistant crops. However, naturally occurring HPPDs are generally very sensitive to HPPD inhibitors. In this study, random mutagenesis was performed to increase the HPPD inhibitors' resistance of sp. HPPD (HPPD). Two mutants, Q258M and Y333F, with improved resistance were obtained. Subsequently, a double-mutant (Q258M/Y333F) was generated through combined mutation. Q258M/Y333F exhibited the highest resistance to four HPPD inhibitors [topramezone, mesotrione, tembotrione, and diketonitrile (DKN)]. The enzyme fitness of Q258M/Y333F to topramezone, mesotrione, tembotrione, and DKN was increased by 4.0-, 4.1-, 4.2-, and 3.2-folds, respectively, in comparison with that of the wild-type. Molecular modeling and docking revealed that Q258M mutation leads to the decrease of enzyme-inhibitor-binding strength by breaking the hydrogen bond between the enzyme and the inhibitor, and Y333F mutation changes the conformational balance of the C-terminal helix H11, which hinders the binding of the inhibitor to the enzyme and thus would contribute to improved herbicide resistance. This study helps to further elucidate the structural basis for herbicide resistance and provides better genetic resources for the genetic engineering of herbicide-resistant crops.
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http://dx.doi.org/10.1021/acs.jafc.0c05785DOI Listing
November 2020