Publications by authors named "Xiao Ding"

287 Publications

TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy.

Nat Commun 2021 07 20;12(1):4404. Epub 2021 Jul 20.

Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany.

Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.
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http://dx.doi.org/10.1038/s41467-021-24601-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292318PMC
July 2021

Immunotherapies for Anti-N-M-methyl-D-aspartate Receptor Encephalitis: Multicenter Retrospective Pediatric Cohort Study in China.

Front Pediatr 2021 29;9:691599. Epub 2021 Jun 29.

Division of Pediatric Neurology, Pediatrics Department, Peking University First Hospital, Beijing, China.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been discovered for more than a decade, but the establishment of standardized immunotherapy protocol for pediatric patients still needs more clinical evidence. A multicenter, retrospective study was conducted on pediatric patients diagnosed with anti-NMDAR encephalitis between November 2011 and December 2018. The clinical records including clinical manifestations, immunotherapy strategies, and outcomes were collected and analyzed. A total of 386 patients were included in our study and the median onset age was 8.00 (IQR 4.83-10.90) years. All patients received first-line immunotherapy and the majority (341, 88.3%) used the standard combination of methylprednisolone pulses (MEP) and intravenous immunoglobulins (IVIG), but 211 patients did not show satisfactory improvement (mRS ≥ 3). Mainly three treatment strategies were applied after first-line immunotherapy: second-line immunotherapy, repetitive first-line immunotherapy, and maintaining oral prednisolone. For patients with mRS ≥ 4 after first-line immunotherapy, the incidence of poor outcome (mRS ≥ 3) in oral prednisolone group was higher than that in other treatment groups ( = 0.039). No difference in complete recovery rate (mRS = 0) was found between patients receiving second-line and repetitive first-line immunotherapy, or patients using long-term and short-term prednisolone. Out of 149 patients who received anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab) test, 27 (18.12%) were positive. Patients with concomitantly positive MOG-Ab showed milder conditions compared to patients with typical anti-NMDAR encephalitis and were more inclined to relapses. We also identified female, MOG-Ab positive, and not receiving second-line and/or repetitive first-line immunotherapy were risk factors for relapses. For patients with mRS ≥ 4 after first-line immunotherapy and patients with concomitantly positive MOG-Ab, second-line immunotherapy is recommended. When second-line immunotherapy is not applicable, repetitive first-line immunotherapy can be considered as an option. Both second-line and repetitive first-line immunotherapy are beneficial to reduce relapse rate. The duration of sequential oral prednisolone can be shortened after fully evaluating patients' conditions.
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http://dx.doi.org/10.3389/fped.2021.691599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276978PMC
June 2021

Ten new nortriterpenes from Euphorbia resinifera and their anti-tomato yellow leaf curl virus activities.

Fitoterapia 2021 Jul 9;153:104989. Epub 2021 Jul 9.

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China. Electronic address:

Ten new nortriterpenes, euphorbiumrins A-J (1-10), together with three known analogues (11-13) were isolated from the latex of Euphorbia resinifera. Their structures were established on the basis of extensive spectroscopic analyses (IR, UV, HRESIMS, 1D and 2D NMR). Their inhibitions on tomato yellow leaf curl virus (TYLCV) were evaluated and compound 5 exhibited significant anti-TYLCV activity with an inhibition rate of 71.7% at concentration of 40 μg/mL.
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http://dx.doi.org/10.1016/j.fitote.2021.104989DOI Listing
July 2021

Small molecule approaches to treat autoimmune and inflammatory diseases (Part III): Targeting cytokines and cytokine receptor complexes.

Bioorg Med Chem Lett 2021 Jun 30;48:128229. Epub 2021 Jun 30.

Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research and Early Development, Shanghai 201203, China. Electronic address:

Chronic and dysregulated cytokine signaling plays an important role in the pathogenic development of many autoimmune and inflammatory diseases. Despite intrinsic challenges in the disruption of interactions between cytokines and cytokine receptors, many first-in-class small-molecule inhibitors have been discovered over the past few years. The third part of the digest series presents recent progress in identifying such inhibitors and highlights the application of novel research tools in the fields of structural biology, computational analysis, screening methods, biophysical/biochemical assays and medicinal chemistry strategy.
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http://dx.doi.org/10.1016/j.bmcl.2021.128229DOI Listing
June 2021

Co-mutation modules capture the evolution and transmission patterns of SARS-CoV-2.

Brief Bioinform 2021 Jun 14. Epub 2021 Jun 14.

Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China.

The rapid spread and huge impact of the COVID-19 pandemic caused by the emerging SARS-CoV-2 have driven large efforts for sequencing and analyzing the viral genomes. Mutation analyses have revealed that the virus keeps mutating and shows a certain degree of genetic diversity, which could result in the alteration of its infectivity and pathogenicity. Therefore, appropriate delineation of SARS-CoV-2 genetic variants enables us to understand its evolution and transmission patterns. By focusing on the nucleotides that co-substituted, we first identified 42 co-mutation modules that consist of at least two co-substituted nucleotides during the SARS-CoV-2 evolution. Then based on these co-mutation modules, we classified the SARS-CoV-2 population into 43 groups and further identified the phylogenetic relationships among groups based on the number of inconsistent co-mutation modules, which were validated with phylogenetic trees. Intuitively, we tracked tempo-spatial patterns of the 43 groups, of which 11 groups were geographic-specific. Different epidemic periods showed specific co-circulating groups, where the dominant groups existed and had multiple sub-groups of parallel evolution. Our work enables us to capture the evolution and transmission patterns of SARS-CoV-2, which can contribute to guiding the prevention and control of the COVID-19 pandemic. An interactive website for grouping SARS-CoV-2 genomes and visualizing the spatio-temporal distribution of groups is available at https://www.jianglab.tech/cmm-grouping/.
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http://dx.doi.org/10.1093/bib/bbab222DOI Listing
June 2021

Multi-functional carboxymethyl chitin-based nanoparticles for modulation of tumor-associated macrophage polarity.

Carbohydr Polym 2021 Sep 24;267:118245. Epub 2021 May 24.

Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, Hubei 430081, China; State Key Laboratory of Separation Membranes and Membrane Process, School and Chemical Engineering & School of Environmental Science and Engineering, Tiangong University, Tianjin 300378, China; College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China. Electronic address:

Current challenge of using cytokines is its poor distribution and systemic side effects. To avoid this issue, we prepared the tumor-targeted and microenvironment-responsive nanocarriers (TRN), which were consisted of α-tocopheryl succinate (α-TOS) loaded mesoporous silica nanoparticles as cores, and surface-modified by thioketal-linkage, electrostatically coated with carboxymethyl chitin, and further anchored glucose-regulated protein 78-binding peptide as shells for encapsulating IL-12. TRN showed a size of 260 nm after encapsulated IL-12 and α-TOS with loading content of 0.0206% and 7.21%, respectively, and exhibited good biocompatibility to 4 T1 cells and macrophages. Moreover, IL-12/α-TOS loaded TRN displayed obvious anti-tumor efficacy on BALB/c nude mice bearing 4 T1 tumors, which was derived from promoted targeting to tumor tissue, endocytosed by macrophages and locally release IL-12 to subsequently repolarize tumor-associated macrophages into tumoricidal M1 phenotype with reduced side effects. The nanosystem exhibited as a promising strategy with functional conversion of macrophages in tumor microenvironment for anti-tumor therapy.
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http://dx.doi.org/10.1016/j.carbpol.2021.118245DOI Listing
September 2021

Comprehensive Proteomic Profiling of Aqueous Humor Proteins in Proliferative Diabetic Retinopathy.

Transl Vis Sci Technol 2021 05;10(6)

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province, China.

Purpose: Proliferative diabetic retinopathy (PDR) is a serious ocular disease that can lead to retinal microvascular complications in patients with diabetes mellitus. To date, no studies have explored PDR development by analyzing the aqueous humor (AH). Therefore we carried out tandem mass tag (TMT) proteomic quantification to compare AH protein profiles between PDR and non-PDR subjects.

Methods: We enrolled six PDR and six control (senile cataract) subjects. AH samples were collected during surgery and stored at -80°C. Proteins were extracted, trypsin-digested, and labeled with TMTs for mass spectrometric analysis.

Results: We found 191 proteins to be changed with |log2 (fold change)| ≥1 (P < 0.05 and identification with at least two peptides per protein). Of them, 111 were downregulated, whereas 80 were upregulated in the PDR group. Proteomic bioinformatic analysis indicated that PDR development was related to complement and coagulation cascades, platelet activation, extracellular matrix-receptor interaction, focal adhesion, protein digestion and absorption, human papillomavirus infection, PI3K-Akt signaling pathway, cholesterol metabolism, peroxisome proliferator-activated receptor signaling pathways, fat digestion and absorption, and vitamin digestion and absorption pathways.

Conclusions: Comprehensive proteomic profiling of the AH revealed 191 differentially expressed proteins between the two groups. Most of these proteins belong to secretory pathways, and therefore can be used as biomarkers in clinical testing and basic research.

Translational Relevance: Pathway analysis and a review of the literature enabled us to draw a novel biological map that will support further studies on the underlying mechanisms and therapeutic control of PDR development.
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http://dx.doi.org/10.1167/tvst.10.6.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107506PMC
May 2021

Targeting angiogenesis for fracture nonunion treatment in inflammatory disease.

Bone Res 2021 Jun 7;9(1):29. Epub 2021 Jun 7.

Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO, USA.

Atrophic fracture nonunion poses a significant clinical problem with limited therapeutic interventions. In this study, we developed a unique nonunion model with high clinical relevance using serum transfer-induced rheumatoid arthritis (RA). Arthritic mice displayed fracture nonunion with the absence of fracture callus, diminished angiogenesis and fibrotic scar tissue formation leading to the failure of biomechanical properties, representing the major manifestations of atrophic nonunion in the clinic. Mechanistically, we demonstrated that the angiogenesis defect observed in RA mice was due to the downregulation of SPP1 and CXCL12 in chondrocytes, as evidenced by the restoration of angiogenesis upon SPP1 and CXCL12 treatment in vitro. In this regard, we developed a biodegradable scaffold loaded with SPP1 and CXCL12, which displayed a beneficial effect on angiogenesis and fracture repair in mice despite the presence of inflammation. Hence, these findings strongly suggest that the sustained release of SPP1 and CXCL12 represents an effective therapeutic approach to treat impaired angiogenesis and fracture nonunion under inflammatory conditions.
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http://dx.doi.org/10.1038/s41413-021-00150-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184936PMC
June 2021

Fecal Microbiota Transplantation is a Promising Switch Therapy for Patients with Prior Failure of Infliximab in Crohn's Disease.

Front Pharmacol 2021 17;12:658087. Epub 2021 May 17.

Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.

How to handle patients with anti-tumor necrosis factor (anti-TNF) failure was a common challenge to clinicians in Crohn's disease (CD). The present study is dedicated to clarifying whether fecal microbiota transplantation (FMT) could be a switch therapy for patients with prior failure of infiiximab (IFX) in CD in a long-term observation. Thirty-six patients with CD who had prior failure of IFX were recruited from January 2013 to December 2019. The "one-hour FMT protocol" was followed in all patients. All patients received the first course of FMT through gastroscopy or mid-gut transendoscopic enteral tubing. After April 2014, the methodology of FMT was coined as washed microbiota transplantation (WMT), substituting for the manual methods, which is dependent on the automatic microbiota purification system and the washing process. The primary endpoint of this study was the clinical remission at one month and one year after FMT. The secondary endpoint was the safety of FMT in the short and long term, and clinical factors as predictors for long-term efficacy of FMT. Clinical factors as independent predictors of efficacy from FMT were isolated using univariable and multivariable logistic regression analysis. There was no significant difference in the rates of clinical response and remission between IFX treatment stage and FMT treatment stage (at one month, three months and six months after administration) ( > 0.05). Compared with those of 19 patients who achieved clinical remission at one month after FMT, the rates of clinical relapse were significantly higher in 18 patients who achieved clinical remission at one month after IFX [log-rank test = 0.0009 HR = 3.081 (95% CI 1.43-6.639)]. Multivariate analysis revealed that the gender of donor (95% CI: 0.001-0.72; = 0.031) was an independent predictor of efficacy at one year after FMT. No serious adverse events (AEs) associated with FMT were observed during and after FMT. The rate of AEs was significantly lower in group FMT than that in group IFX ( = 0.002). The present findings first time provided the evidence for clinicians to consider FMT into practice as an alternative switch therapy for patients with prior loss of response or intolerance to IFX in CD. https://clinicaltrials.gov, identifier NCT01793831.
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http://dx.doi.org/10.3389/fphar.2021.658087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166050PMC
May 2021

Angiopoietin-like protein 4 regulates breast muscle lipid metabolism in broilers.

Poult Sci 2021 Jul 26;100(7):101159. Epub 2021 Mar 26.

College of Animal Sciences and Technology, Shandong Agricultural University, Tai-an, Shandong, 271018, P. R. China.

The objective of this study was to determine the effects of angiopoietin-like protein 4 (ANGPTL4) on breast muscle lipid metabolism in broilers. In experiment 1, 36 thirty-five-day-old male Arbor Acres broilers were randomly allocated into 6 treatment groups with 6 birds in a completely randomized design. The broilers were subjected to intravenous injection of His-SUMO-ANGPTL4 at the dose of 0 (injection of normal saline [NS]), 20, 100, 500, 2,500, or 12,500 ng/kg BW, respectively. The results showed that broilers at 30 min after His-SUMO-ANGPTL4 at the level of 12,500 ng/kg BW intravenous injection had higher (P < 0.05) concentrations of triglyceride and non-esterified fatty acid in the serum, higher (P < 0.05) adipose triglyceride lipase and carnitine palmitoyltransferase 1 mRNA expression in the breast muscle, but lower (P < 0.05) lipoprotein lipase (LPL) mRNA expression in the breast muscle. In experiment 2, 18 thirty-five-day-old male Arbor Acres broilers were randomly allocated into 3 treatment groups with 6 birds in a completely randomized design. The broilers were subjected to intravenous injection of NS, His-SUMO, or His-SUMO-ANGPTL4 (12,500 ng/kg BW) in order to rule out the effect of His-SUMO tag. It's confirmed that ANGPTL4 could increase (P < 0.05) concentrations of triglyceride and non-esterified fatty acid in the serum, enhance (P < 0.05) adipose triglyceride lipase mRNA expression in the breast muscle, and decrease (P < 0.05) LPL mRNA expression in the breast muscle. In experiment 3 and 4, co-culture experiments of chicken primary myoblasts and NS, His-SUMO, or His-SUMO-ANGPTL4 (250 pg/mL, physiological dose) were set up to monitor the cytotoxicity of ANGPTL4 and the changes of lipid metabolism-related genes expression. It was found that cell viability was not affected but LPL mRNA expression in chicken primary myoblasts was highly reduced (P < 0.05) by ANGPTL4. In conclusion, ANGPTL4 could promote lipodieresis and inhibit LPL in the breast muscle of broilers.
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http://dx.doi.org/10.1016/j.psj.2021.101159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181176PMC
July 2021

Facile Fabrication of Polyaniline/Pristine Graphene-Bacterial Cellulose Composites as High-Performance Electrodes for Constructing Flexible All-Solid-State Supercapacitors.

ACS Omega 2021 May 23;6(17):11427-11435. Epub 2021 Apr 23.

School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China.

A novel structured composite of polyaniline/pristine graphene (PG)-bacterial cellulose (BC) as electrodes fabricated in a facile approach and the foldable all-solid-state supercapacitors with high performance were reported in this work. The shear mixed PG-BC substrate was fixed with in situ polymerized polyaniline as a solder, improving its charge carrier transfer rate and cycling stability, while hydrophilic BC greatly improved the ion diffusion rate of the electrolyte. The as-prepared composites possessed a high areal capacitance of 3.65 F/cm at 5 mA/cm, and the electrode was able to be bent into different shapes without fracture. The assembled all-solid-state supercapacitor was flexible and exhibited excellent areal capacitance of 1389 mF/cm, energy density of 9.80 mWh/cm, and 89.8% retention of its initial capacitance after 5000 cycles at a current density of 2 mA/cm. The composite is expected to have applications in making flexible supercapacitors applied in wearable devices.
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http://dx.doi.org/10.1021/acsomega.1c00442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153940PMC
May 2021

Washed microbiota transplantation in patients with respiratory spreading diseases: Practice recommendations.

Med Microecol 2021 Mar 10;7:100024. Epub 2020 Oct 10.

Department of Gastroenterology, National Clinical Research Center of Infectious Disease, The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518114, China.

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http://dx.doi.org/10.1016/j.medmic.2020.100024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547313PMC
March 2021

Progress and Challenge in Computational Identification of Influenza Virus Reassortment.

Virol Sin 2021 May 26. Epub 2021 May 26.

Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.

Genomic reassortment is an important evolutionary mechanism for influenza viruses. In this process, the novel viruses acquire new characteristics by the exchange of the intact gene segments among multiple influenza virus genomes, which may cause flu endemics and epidemics within or even across hosts. Due to the safety and ethical limitations of the experimental studies on influenza virus reassortment, numerous computational researches on the influenza virus reassortment have been done with the explosion of the influenza virus genomic data. A great amount of computational methods and bioinformatics databases were developed to facilitate the identification of influenza virus reassortments. In this review, we summarized the progress and challenge of the bioinformatics research on influenza virus reassortment, which can guide the researchers to investigate the influenza virus reassortment events reasonably and provide valuable insight to develop the related computational identification tools.
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http://dx.doi.org/10.1007/s12250-021-00392-wDOI Listing
May 2021

Linking young children's teaching to their reasoning of mental states: Evidence from Singapore.

J Exp Child Psychol 2021 Sep 14;209:105175. Epub 2021 May 14.

Department of Psychology, National University of Singapore, Singapore 117570, Singapore. Electronic address:

To fully participate in the human information-sharing ecosystem that allows for efficient knowledge dissemination and creation, children need to be able to teach others effectively. The current research is the first to investigate links between children's teaching abilities and their developing theory of mind abilities in a non-Western sample. In a sample of 4- to 6-year-old Singaporean children (N = 49), we examined relations between specific components of theory of mind abilities and teaching ability on a social cognitive task. We found that both false belief understanding and the ability to make mental state inferences in a teaching context were associated with effective teaching even after controlling for age and language ability. These findings provide a nuanced picture of the links between mental state reasoning and teaching ability. More broadly, they provide evidence that these links extend beyond Western cultures and generalize to social-cognitive teaching contexts.
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http://dx.doi.org/10.1016/j.jecp.2021.105175DOI Listing
September 2021

Absorption, metabolism and excretion of pictilisib, a potent pan-class I phosphatidylinositol-3-Kinase (PI3K) inhibitor, in rats, dogs, and humans.

Xenobiotica 2021 Jul 24;51(7):796-810. Epub 2021 May 24.

Clinical Pharmacology, Genentech Inc, South San Francisco, CA, USA.

The absorption, metabolism and excretion of pictilisib, a selective small molecule inhibitor of class 1 A phosphoinositide 3-kinase (PI3K), was characterized following a single oral administration of [C]pictilisib in rats, dogs and humans at the target doses of 30 mg/kg, 5 mg/kg and 60 mg, respectively.Pictilisib was rapidly absorbed with T less than 2 h across species. In systemic circulation, pictilisib represented the predominant total radioactivity greater than 86.6% in all species.Total pictilisib and related radioactivity was recovered from urine and faeces in rats, dogs, and human at 98%, 80% and 95%, respectively, with less than 2% excreted in urine and the rest excreted into faeces.In rat and dog, more than 40% of drug-related radioactivity was excreted into the bile suggesting biliary excretion was the major route of excretion. Unchanged pictilisib was a minor component in rat and dog bile. The major metabolite in bile was -glucuronide of oxidation on indazole moiety (M20, 21% of the dose) in rats and an oxidative piperazinyl ring-opened metabolite M7 (10.8% of the dose) in dogs.Oxidative glutathione (GSH) conjugates (M18, M19) were novel metabolites detected in rat bile, suggesting the potential generation of reactive intermediates from pictilisib. The structure of M18 was further confirmed by NMR to be a -hydroxylated and GSH conjugated metabolite on the moiety of the indazole ring.
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http://dx.doi.org/10.1080/00498254.2021.1923859DOI Listing
July 2021

Osteosarcoma Cell-Derived Exosomal miR-1307 Promotes Tumorgenesis via Targeting AGAP1.

Biomed Res Int 2021 25;2021:7358153. Epub 2021 Mar 25.

Department of Orthopaedics, The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, China.

The occurrence of osteosarcoma (OS) is associated with abnormal expression of many microRNAs (miRNAs). Exosomal miRNAs get much more attentions in intracellular communications. miR-1307 has been studied in many cancers, but its effects in OS have not been studied. We hypothesized that OS-derived exosomal miR-1307 regulates OS tumorigenesis. First, we found OS cell-derived exosomes (Exos) significantly promoted the proliferation, migration, and invasion of OS cells. Secondly, we found miR-1307 was highly expressed in OS cell-derived exosomes (OS-Exos), human OS tissues, and OS cell lines. Then, OS-Exos were extracted after OS cells were cultured and transfected with miR-1307 inhibitor, and the level of miR-1307 in OS-Exos was significantly reduced. When the level of miR-1307 in OS-Exos was significantly reduced, the effects of OS-Exos on migration, invasion, and proliferation of OS cells were also significantly weakened. Furthermore, using TargetScan, miRDB, and mirDIP databases, we identified that AGAP1 was a target gene of miR-1307. Overexpression of miR-1307 could inhibit the expression of AGAP1 gene. We also found AGAP1 was lower expressed in human OS tissues and OS cell lines. Luciferase gene indicated that miR-1307 directly bound the 3'-UTR of AGAP1. miR-1307 was negatively correlated with AGAP1 in clinical study. miR-1307 could significantly promote the proliferation, migration, and invasion of OS cells. In addition, upregulation of AGAP1 could significantly inhibit the role of miR-1307 in OS. In conclusion, our study suggests that OS cell-derived exosomal miR-1307 promotes the proliferation, migration, and invasion of OS cells via targeting AGAP1, and miR-1307-AGAP1 axis may play an important role in the future treatment of OS.
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http://dx.doi.org/10.1155/2021/7358153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016573PMC
May 2021

Herbicide Resistance: Another Hot Agronomic Trait for Plant Genome Editing.

Plants (Basel) 2021 Mar 24;10(4). Epub 2021 Mar 24.

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

Weeds have continually interrupted crop plants since their domestication, leading to a greater yield loss compared to diseases and pests that necessitated the practice of weed control measures. The control of weeds is crucial to ensuring the availability of sufficient food for a rapidly increasing human population. Chemical weed control (herbicides) along with integrated weed management (IWM) practices can be the most effective and reliable method of weed management programs. The application of herbicides for weed control practices calls for the urgency to develop herbicide-resistant (HR) crops. Recently, genome editing tools, especially CRISPR-Cas9, have brought innovation in genome editing technology that opens up new possibilities to provide sustainable farming in modern agricultural industry. To date, several non-genetically modified (GM) HR crops have been developed through genome editing that can present a leading role to combat weed problems along with increasing crop productivity to meet increasing food demand around the world. Here, we present the chemical method of weed control, approaches for herbicide resistance development, and possible advantages and limitations of genome editing in herbicide resistance. We also discuss how genome editing would be effective in combating intensive weed problems and what would be the impact of genome-edited HR crops in agriculture.
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http://dx.doi.org/10.3390/plants10040621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064318PMC
March 2021

Effect of 'hand and foot acupuncture with twelve needles' on hemiplegia patients with 'qi deficiency and blood stasis' syndrome in the convalescent stage of Ischaemic stroke: study protocol for a randomised controlled trial.

Trials 2021 Mar 18;22(1):215. Epub 2021 Mar 18.

Shunyi Hospital, Beijing Traditional Chinese Medicine Hospital, Beijing, 101300, China.

Background: Hemiplegia is a common sequela after stroke, and acupuncture is one of the most common physical therapies used to treat hemiplegia during the recovery stage after ischaemic stroke. 'Hand and foot acupuncture with twelve needles' is an acupuncture treatment performed after stroke. The principal objective of this study is to assess the efficacy and safety of 'hand and foot acupuncture with twelve needles' for hemiplegia in the convalescent stage of ischaemic stroke.

Methods: This is the protocol for a randomised, controlled clinical trial with two groups: a 'hand and foot acupuncture with twelve needles' group and a routine acupuncture group. A total of 208 participants will be randomly assigned to two different groups in a 1:1 ratio and will undergo conventional rehabilitation. Limb function will be evaluated by the simplified Fugl-Meyer assessment scale, Barthel Index, modified Ashworth scale and National Institute of Health stroke scale. The participants will be evaluated at baseline (on the day of enrolment) and followed up at 2 weeks, 1 month, 2 months and 3 months after enrolment.

Discussion: The results of this study will provide evidence on the effectiveness of 'hand and foot acupuncture with twelve needles' in the treatment of limb dysfunction that can be used for future evaluations.

Trial Registration: Chictr.org.cn ChiCTR1900021774 . Registered on 8 March 2019.
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http://dx.doi.org/10.1186/s13063-021-05128-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977321PMC
March 2021

Jatrophane Diterpenoids from the Seeds of Euphorbia peplus with Potential Bioactivities in Lysosomal-Autophagy Pathway.

Nat Prod Bioprospect 2021 Jun 14;11(3):357-364. Epub 2021 Mar 14.

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China.

Euphopepluanones F - K (1 - 4), four new jatrophane type diterpenoids were isolated from the seeds of Euphorbia peplus, along with eight known diterpenoids (5 - 12). Their structures were established on the basis of extensive spectroscopic analysis and X-ray crystallographic experiments. The new compounds 1 - 4 were assessed for their activities to induce lysosomal biogenesis through LysoTracker Red staining. Compound 2 significantly induced lysosomal biogenesis. In addition, compound 2 could increase the number of LC3 dots, indicating that it could activate the lysosomal-autophagy pathway.
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http://dx.doi.org/10.1007/s13659-021-00301-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140953PMC
June 2021

Importance of Community Impact as the Fourth Academic Mission: A Qualitative Study.

Popul Health Manag 2021 Mar 11. Epub 2021 Mar 11.

Department of Population Health, Dell Medical School, University of Texas at Austin, Austin, Texas, USA.

Most US medical schools have 3 primary missions: education, research, and clinical service. Recently there have been calls for a fourth primary mission focused on improving health in their surrounding communities. To date, few medical schools have done so. To identify factors supporting and challenges to establishing a sustainable community impact mission, the authors conducted semi-structured key informant interviews with the dean, associate deans, departments chairs, and institute and center directors at a new US medical school that established a fourth "community impact" mission at its conception. Interviewees believed that it was appropriate for a community-focused tax-supported medical school to embrace community impact as a fourth mission to enhance community health outside of its hospitals and clinics. Many also felt that community impact should be an overriding framework for activities in the 3 primary missions. Achieving community impact would require creating a "learning health community" via partnerships with community organizations and linking faculty effort and funding to specific and valid measures of community health improvement. Sustainable funding would require core school funds and a broad portfolio of extramural funding. Faculty promotions with community impact as a focus would need explicit, achievable, and unique milestones. Interviewees made specific suggestions on the support and structure needed to launch and sustain this fourth mission. Establishing a fourth mission of community impact can extend medical schools' influence beyond typical health care venues to enhance the health of their communities and their residents. Doing so requires rethinking organizational structures, support, and measures of success.
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http://dx.doi.org/10.1089/pop.2021.0004DOI Listing
March 2021

Opposing functions of β-arrestin 1 and 2 in Parkinson's disease via microglia inflammation and Nprl3.

Cell Death Differ 2021 Jun 8;28(6):1822-1836. Epub 2021 Mar 8.

Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 818 Tianyuan East Road, Nanjing, 211166, Jiangsu, China.

Although β-arrestins (ARRBs) regulate diverse physiological and pathophysiological processes, their functions and regulation in Parkinson's disease (PD) remain poorly defined. In this study, we show that the expression of β-arrestin 1 (ARRB1) and β-arrestin 2 (ARRB2) is reciprocally regulated in PD mouse models, particularly in microglia. ARRB1 ablation ameliorates, whereas ARRB2 knockout aggravates, the pathological features of PD, including dopaminergic neuron loss, neuroinflammation and microglia activation in vivo, and microglia-mediated neuron damage in vitro. We also demonstrate that ARRB1 and ARRB2 produce adverse effects on inflammation and activation of the inflammatory STAT1 and NF-κB pathways in primary cultures of microglia and macrophages and that two ARRBs competitively interact with the activated form of p65, a component of the NF-κB pathway. We further find that ARRB1 and ARRB2 differentially regulate the expression of nitrogen permease regulator-like 3 (Nprl3), a functionally poorly characterized protein, as revealed by RNA sequencing, and that in the gain- and loss-of-function studies, Nprl3 mediates the functions of both ARRBs in microglia inflammatory responses. Collectively, these data demonstrate that two closely related ARRBs exert opposite functions in microglia-mediated inflammation and the pathogenesis of PD which are mediated at least in part through Nprl3 and provide novel insights into the understanding of the functional divergence of ARRBs in PD.
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http://dx.doi.org/10.1038/s41418-020-00704-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184754PMC
June 2021

One year of SARS-CoV-2 evolution.

Cell Host Microbe 2021 04 24;29(4):503-507. Epub 2021 Feb 24.

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address:

Since the outbreak of SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, the viral genome has acquired numerous mutations with the potential to increase transmission. One year after its emergence, we now further analyze emergent SARS-CoV-2 genome sequences in an effort to understand the evolution of this virus.
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http://dx.doi.org/10.1016/j.chom.2021.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903908PMC
April 2021

New insights into the fine-scale history of western-eastern admixture of the northwestern Chinese population in the Hexi Corridor via genome-wide genetic legacy.

Mol Genet Genomics 2021 May 1;296(3):631-651. Epub 2021 Mar 1.

Belt and Road Research Center for Forensic Molecular Anthropology Gansu University of Political Science and Law, Lanzhou, 730000, China.

Trans-Eurasian cultural and genetic exchanges have significantly influenced the demographic dynamics of Eurasian populations. The Hexi Corridor, located along the southeastern edge of the Eurasian steppe, served as an important passage of the ancient Silk Road in Northwest China and intensified the transcontinental exchange and interaction between populations on the Central Plain and in Western Eurasia. Historical and archeological records indicate that the Western Eurasian cultural elements were largely brought into North China via this geographical corridor, but there is debate on the extent to which the spread of barley/wheat agriculture into North China and subsequent Bronze Age cultural and technological mixture/shifts were achieved by the movement of people or dissemination of ideas. Here, we presented higher-resolution genome-wide autosomal and uniparental Y/mtDNA SNP or STR data for 599 northwestern Han Chinese individuals and conducted 2 different comprehensive genetic studies among Neolithic-to-present-day Eurasians. Genetic studies based on lower-resolution STR markers via PCA, STRUCTURE, and phylogenetic trees showed that northwestern Han Chinese individuals had increased genetic homogeneity relative to northern Mongolic/Turkic/Tungusic speakers and Tibeto-Burman groups. The genomic signature constructed based on modern/ancient DNA further illustrated that the primary ancestry of the northwestern Han was derived from northern millet farmer ancestors, which was consistent with the hypothesis of Han origin in North China and more recent northwestward population expansion. This was subsequently confirmed via excess shared derived alleles in f/f statistical analyses and by more northern East Asian-related ancestry in the qpAdm/qpGraph models. Interestingly, we identified one western Eurasian admixture signature that was present in northwestern Han but absent from southern Han, with an admixture time dated to approximately 1000 CE (Tang and Song dynasties). Generally, we provided supporting evidence that historic Trans-Eurasian communication was primarily maintained through population movement, not simply cultural diffusion. The observed population dynamics in northwestern Han Chinese not only support the North China origin hypothesis but also reflect the multiple sources of the genetic diversity observed in this population.
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http://dx.doi.org/10.1007/s00438-021-01767-0DOI Listing
May 2021

Small molecule approaches to treat autoimmune and inflammatory diseases (Part I): Kinase inhibitors.

Bioorg Med Chem Lett 2021 04 18;38:127862. Epub 2021 Feb 18.

Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research and Early Development, Shanghai 201203, China. Electronic address:

Autoimmune and inflammatory diseases place a huge burden on the healthcare system. Small molecule (SM) therapeutics provide much needed complementary treatment options for these diseases. This digest series highlights the latest progress in the discovery and development of safe and efficacious SMs to treat autoimmune and inflammatory diseases with each part representing a class of SMs, namely: 1) protein kinases; 2) nucleic acid-sensing pathways; and 3) soluble ligands and receptors on cell surfaces. In this first part of the series, the focus is on kinase inhibitors that emerged between 2018 and 2020, and which exhibit increased target and tissue selectivity with the aim of increasing their therapeutic index.
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http://dx.doi.org/10.1016/j.bmcl.2021.127862DOI Listing
April 2021

Theory of mind, executive function, and lying in children: a meta-analysis.

Dev Sci 2021 Feb 5:e13096. Epub 2021 Feb 5.

Department of Psychology, Zhejiang Normal University, Jinhua, China.

Scientific research on how children learn to tell lies has existed for more than a century. Earlier studies mainly focused on moral, social, and situational factors contributing to the development of lying. Researchers have only begun to explore the cognitive correlations of children's lying in the last two decades. Cognitive theories suggest that theory of mind (ToM) and executive function (EF) should be closely related to the development of lying since lying is, in essence, ToM and EF in action. Yet, findings from empirical studies are mixed. To address this issue, the current meta-analysis reviewed all prior literature that examined the relations between children's lying and ToM and/or between children's lying and EF. In total, 47 papers consisting of 5099 participants between 2 and 19 years of age were included, which yielded 74 effect sizes for ToM and 94 effect sizes for EF. Statistically significant but relatively small effects were found between children's lying and ToM (r = .17) and between lying and EF (r = .13). Furthermore, EF's correlation with children's initial lies was significantly smaller than its correlation with children's ability to maintain lies. This comprehensive meta-analysis provides a clear picture of the associations between children's ToM/EF and their lying behavior and confirms that ToM and EF indeed play a positive role in children's lying and its development.
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http://dx.doi.org/10.1111/desc.13096DOI Listing
February 2021

Diterpenoids with an unprecedented ring system from and their activities in the lysosomal-autophagy pathway.

Org Biomol Chem 2021 02;19(7):1541-1545

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, P.R. China.

Three novel jatrophane diterpenes, cyclojatrophanes A-C (1-3), were isolated from the seeds of Euphorbia peplus. Compounds 1-3 featured an unprecedented 5/5/5/11 tetracyclic ring system incorporating ditetrahydropyran rings. Their structures including their absolute configurations were established by extensive spectroscopic analysis, X-ray crystallographic experiments and chemical transformations. In addition, these compounds could significantly activate the lysosomal-autophagy pathway.
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http://dx.doi.org/10.1039/d0ob02414gDOI Listing
February 2021

Discovery of highly potent and selective influenza virus neuraminidase inhibitors targeting 150-cavity.

Eur J Med Chem 2021 Feb 13;212:113097. Epub 2020 Dec 13.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address:

Encouraged by our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Herein, we report the design, synthesis and biological evaluation of a series of novel oseltamivir derivatives via the structural modifications at C-NH of oseltamivir targeting 150-cavity. Among them, compound 5c bearing 4-(3-methoxybenzyloxy)benzyl group exhibited the most potent activity, which was lower or modestly improved activities than oseltamivir carboxylate (OSC) against N1 (H1N1), N1 (H5N1) and N1 (H5N1-H274Y). Specifically, there was 30-fold loss of activity against the wild-type strain H1N1. However, 5c displayed 4.85-fold more potent activity than OSC against H5N1-H274Y NA. Also, 5c demonstrated low cytotoxicity in vitro and no acute toxicity in mice. Molecular docking studies provided insights into the high potency of 5c against N1 and N1-H274Y mutant NAs. Besides, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability of representative compounds were conducted to evaluate their drug-like properties.
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http://dx.doi.org/10.1016/j.ejmech.2020.113097DOI Listing
February 2021

Traditional Chinese medicine compound, Bu Sheng Hui Yang Fang, promotes the proliferation of lymphocytes in the immunosuppressed mice potentially by upregulating IL-4 signaling.

Biomed Pharmacother 2021 Feb 16;134:111107. Epub 2020 Dec 16.

Yunnan Blood Disease Clinical Medical Center, Yunnan Blood Disease Hospital, National Key Clinical Specialty of Hematology, Department of Hematology, The First People's Hospital of Yunnan Province, Kunming, China; Kunming University of Science and Technology, Kunming, China. Electronic address:

The immune system plays a pivotal role in defending against infection and cancer immunosurveillance during the onset and procession of malignant disease. Cancer patients are frequently immunocompromised and subject to refractory infection and relapse of leukemia, due to the cytotoxic agents and immunosuppressive glucocorticoids in the chemotherapy regimens. Bu Shen Hui Yang Fang (BSHY), a traditional Chinese compound, was widely used in China to enhance the immune system of leukemia patients combined with chemotherapy and effectively lowered their risk of infection, with specific mechanism unknown yet. Thus, we investigated the effects of BSHY on the immune system using immunosuppressive mouse models. By analyzing the immune system of immunosuppressed BALB/C mice induced by hydrocortisone, we found an increase of CD4 and CD8 lymphocytes in the spleens of mice after BSHY treatment. Furthermore, we found the enhanced immune system in BSHY treated group was due to increased proliferation and decreased apoptosis of lymphocytes. Cytokine array analysis revealed that interleukin 4 (IL-4) was reduced in the plasma of immunosuppressed mice but returned to a normal level after BSHY treatment. Moreover, we found IL-4 was an adverse prognostic factor in acute myeloid leukemia patients and part of them could be elevated by BSHY. Mechanistically, we found BSHY enhances the proliferation of lymphocytes in a Stat6-dependent manner. In summary, our current study demonstrates that BSHY enhances the proliferation of lymphocytes in the immunosuppressed mice via upregulating IL-4 signaling.
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http://dx.doi.org/10.1016/j.biopha.2020.111107DOI Listing
February 2021

The Prevalence and Causes of Visual Impairment in Type 2 Diabetes Mellitus in Northeast China.

J Ophthalmol 2020 29;2020:5969816. Epub 2020 Nov 29.

Fushun Eye Hospital, Fushun, Liaoning, China.

Purpose: To evaluate the prevalence and causes of visual impairment in a group of community people with type 2 diabetes mellitus (T2DM) in Northeast China.

Methods: Population-based cross-sectional survey. Patients diagnosed with T2DM residing in 15 communities in Fushun, Northeast China, were enrolled between July 2012 and May 2013. All participants underwent an extensive and standardized eye examination (visual acuity testing, slit-lamp, and fundus examination). Low vision was defined as presenting VA of better-seeing eye <20/60 and ≥20/400, and blindness was defined as VA <20/400, according to the World Health Organization (WHO) definitions. The primary causes of blindness and low vision were assessed by senior ophthalmologists.

Results: Visual acuity measurements were available for 1998 (89.8%) of 2224 subjects in the study. The prevalence of bilateral blindness and low vision defined was 0.90% and 10.81%. Uncorrected refractive error was the first leading cause of low vision (75.0%) and blindness (38.9%). After correcting the refractive error, the first leading cause of low vision was cataract (44.4%), followed by diabetic retinopathy (29.6%) and myopic maculopathy (18.5%), while the first leading cause of blindness was proliferative DR (45.4%), followed by cataract (36.4%) and myopic maculopathy (18.2%).

Conclusions: This study suggested a high prevalence of low vision and blindness in this study cohort. Uncorrected refractive error and cataract remain the leading cause of visual impairment, but the major challenge is the early diagnosis and intervention of diabetic retinopathy to reduce diabetes-related blindness.
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http://dx.doi.org/10.1155/2020/5969816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719542PMC
November 2020

Efficacy and feasibility of amniotic membrane for the treatment of burn wounds: A meta-analysis.

J Trauma Acute Care Surg 2021 04;90(4):744-755

From the Department of Plastic and Burn Surgery, Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, Luzhou, Sichuan, China.

Background: Burns cause a huge economic burden to society, and the wounds can be very difficult to manage. Clinical experience suggests that amniotic membrane (AM) is an economical and effective biological dressing for burns. However, few systematic reviews or meta-analyses have been published on such use. We aimed to evaluate the role of AM dressings in burn wounds.

Methods: A systematic search of the PubMed, Cochrane, Embase, and Web of Science databases was conducted in March 2020. The search was conducted to identify randomized control trials that compared selected features of AM with those of other dressings, such as silver sulfadiazine, polyurethane membrane, and honey. For skin-grafted wounds, we compared AM-covered skin grafts and traditional staple-fixed skin grafts. Outcomes of interest for the efficacy analysis included wound infection, pain, itching, scarring, and healing time. The number of adverse events in each treatment group, the rate of withdrawal because of adverse effects, the cost of treatment, and patient acceptability were assessed for the feasibility analysis.

Results: Eleven randomized controlled trials with 816 participants total were identified in our review. Amniotic membrane treatment was more effective than conventional methods, silver sulfadiazine, and polyurethane membrane in treating burn wounds, but AM appears to be less effective than honey. No reports of AM-related disease transmission or adverse reactions were described in the included articles.

Conclusion: Amniotic membrane has beneficial effects in treating burn wounds; however, the evidence needs to be strengthened by further robust randomized controlled trials.

Level Of Evidence: Systematic Review/Meta-analysis, level III.
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http://dx.doi.org/10.1097/TA.0000000000003050DOI Listing
April 2021
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