Publications by authors named "Yan Wu"

2,624 Publications

  • Page 1 of 1

O-GlcNAcylation promotes cerebellum development and medulloblastoma oncogenesis via SHH signaling.

Proc Natl Acad Sci U S A 2022 Aug 15;119(34):e2202821119. Epub 2022 Aug 15.

Department of Neurobiology, Beijing Institute of Basic Medical Sciences, 100850 Beijing, China.

Sonic hedgehog (Shh) signaling plays a critical role in regulating cerebellum development by maintaining the physiological proliferation of granule neuron precursors (GNPs), and its dysregulation leads to the oncogenesis of medulloblastoma. O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuitry. Here, we demonstrate that O-GlcNAc transferase (OGT) in GNPs mediate the cerebellum development, and the progression of the Shh subgroup of medulloblastoma. Specifically, OGT regulates the neurogenesis of GNPs by activating the Shh signaling pathway via O-GlcNAcylation at S355 of GLI family zinc finger 2 (Gli2), which in turn promotes its deacetylation and transcriptional activity via dissociation from p300, a histone acetyltransferases. Inhibition of OGT via genetic ablation or chemical inhibition improves survival in a medulloblastoma mouse model. These data uncover a critical role for O-GlcNAc signaling in cerebellar development, and pinpoint a potential therapeutic target for Shh-associated medulloblastoma.
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http://dx.doi.org/10.1073/pnas.2202821119DOI Listing
August 2022

A comprehensive analysis of miRNA/isomiRs profile of hydrosalpinx patients with interventional ultrasound sclerotherapy.

PLoS One 2022 15;17(8):e0268328. Epub 2022 Aug 15.

Reproductive Medicine Center, Hefei, Anhui, P.R. China.

Hydrosalpinx is a chronic inflammatory condition with high recurrence rate, and it is reported among female population having fallopian tubal factor infertility. Previously, we have reported that interventional ultrasound sclerotherapy improves endometrial receptivity and pregnancy rate with negligible adverse effects in patients suffering from hydrosalpinx. During present investigation, we have used next generation sequencing (NGS) to characterize the isomiR profiles from the endometrium of patients suffering from hydrosalpinx before and after interventional ultrasound sclerotherapy. Our results indicated that miRNA arm shift and switch remained unaffected when compared in patients before and after interventional ultrasound sclerotherapy. We observed that isomiRs with trimming at 3' and isomiRs with canonical sequences were lower in post-treatment than in pre-treatment group. Gene ontology (GO) annotation and KEGG pathway analysis revealed that the expression of mature mir-30 was significantly lower in the pre-treatment as compared to post treatment group while the expression of mir-30 isomiR was 4.26-fold higher in pre-treatment when compared with the post-treatment group. These different expression patterns of mir-30 mature miRNA and mir-30 isomiRs in two groups are affecting the physiological function of the endometrium. Our results suggested that differential isomiR distribution in hydrosalpinx patients before and after treatment plays an important role in hydrosalpinx incidence and can help in designing novel strategy for the treatment of hydrosalpinx in female population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0268328PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377599PMC
August 2022

Aaptamine - a dual acetyl - and butyrylcholinesterase inhibitor as potential anti-Alzheimer's disease agent.

Pharm Biol 2022 Dec;60(1):1502-1510

Medical Research Center, Binzhou Medical University Hospital, Binzhou, PR China.

Context: Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are promising therapeutic targets for AD.

Objective: To evaluate the inhibitory effects of aaptamine on two cholinesterases and investigate the therapeutic effect on AD in a zebrafish model.

Materials And Methods: Aaptamine was isolated from the sponge Brøndsted (Suberitidae). Enzyme inhibition, kinetic analysis, surface plasmon resonance (SPR) and molecular docking assays were used to determine its inhibitory effect on AChE and BuChE . Zebrafish were divided into six groups: control, model, 8 μM donepezil, 5 , 10  and 20 μM aaptamine. After three days of drug treatment, the behaviour assay was performed.

Results: The IC values of aaptamine towards AChE and BuChE were 16.0 and 4.6 μM. And aaptamine directly inhibited the two cholinesterases in the mixed inhibition type, with values of 6.96 ± 0.04 and 6.35 ± 0.02 μM, with values of 87.6 and 10.7 μM. Besides, aaptamine interacts with the crucial anionic sites of AChE and BuChE. studies indicated that the dyskinesia recovery rates of 5 , 10  and 20 μM aaptamine group were 34.8, 58.8 and 60.0%, respectively, and that of donepezil was 63.7%.

Discussion And Conclusions: Aaptamine showed great potential to exert its anti-AD effects by directly inhibiting the activities of AChE and BuChE. Therefore, this study identified a novel medicinal application of aaptamine and provided a new structural scaffold for the development of anti-AD drugs.
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http://dx.doi.org/10.1080/13880209.2022.2102657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380430PMC
December 2022

Enhanced hippocampal neurogenesis mediated by PGC-1α-activated OXPHOS after neonatal low-dose Propofol exposure.

Front Aging Neurosci 2022 27;14:925728. Epub 2022 Jul 27.

Department of Anesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Background: Developing brain is highly plastic and can be easily affected. Growing pediatric usage of anesthetics during painless procedures has raised concerns about the effect of low-dose anesthetics on neurodevelopment. It is urgent to ascertain the neuronal effect of low-dose Propofol, a widely used anesthetic in pediatrics, on developing brains.

Methods: The behavioral tests after neonatal exposure to low-dose/high-dose Propofol in mice were conducted to clarify the cognitive effect. The nascent cells undergoing proliferation and differentiation stage in the hippocampus and cultured neural stem cells (NSCs) were further identified. In addition, single-nuclei RNA sequencing (snRNA-seq), NSCs bulk RNA-seq, and metabolism trials were performed for pathway investigation. Furthermore, small interfering RNA and stereotactic adenovirus injection were, respectively, used in NSCs and hippocampal to confirm the underlying mechanism.

Results: Behavioral tests in mice showed enhanced spatial cognitive ability after being exposed to low-dose Propofol. Activated neurogenesis was observed both in hippocampal and cultured NSCs. Moreover, transcriptome analysis of snRNA-seq, bulk RNA-seq, and metabolism trials revealed a significantly enhanced oxidative phosphorylation (OXPHOS) level in NSCs. Furthermore, PGC-1α, a master regulator in mitochondria metabolism, was found upregulated after Propofol exposure both and . Importantly, downregulation of PGC-1α remarkably prevented the effects of low-dose Propofol in activating OXPHOS and neurogenesis.

Conclusions: Taken together, this study demonstrates a novel alteration of mitochondrial function in hippocampal neurogenesis after low-dose Propofol exposure, suggesting the safety, even potentially beneficial effect, of low-dose Propofol in pediatric use.
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http://dx.doi.org/10.3389/fnagi.2022.925728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9363786PMC
July 2022

FGF22 deletion causes hidden hearing loss by affecting the function of inner hair cell ribbon synapses.

Front Mol Neurosci 2022 28;15:922665. Epub 2022 Jul 28.

Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Ribbon synapses are important structures in transmitting auditory signals from the inner hair cells (IHCs) to their corresponding spiral ganglion neurons (SGNs). Over the last few decades, deafness has been primarily attributed to the deterioration of cochlear hair cells rather than ribbon synapses. Hearing dysfunction that cannot be detected by the hearing threshold is defined as hidden hearing loss (HHL). The relationship between ribbon synapses and FGF22 deletion remains unknown. In this study, we used a 6-week-old FGF22 knockout mice model ( ) and mainly focused on alteration in ribbon synapses by applying the auditory brainstem response (ABR) test, the immunofluorescence staining, the patch-clamp recording, and quantitative real-time PCR. In mice, we found the decreased amplitude of ABR wave I, the reduced vesicles of ribbon synapses, and the decreased efficiency of exocytosis, which was suggested by a decrease in the capacitance change. Quantitative real-time PCR revealed that led to dysfunction in ribbon synapses by downregulating SNAP-25 and Gipc3 and upregulating MEF2D expression, which was important for the maintenance of ribbon synapses' function. Our research concluded that FGF22 deletion caused HHL by affecting the function of IHC ribbon synapses and may offer a novel therapeutic target to meet an ever-growing demand for deafness treatment.
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http://dx.doi.org/10.3389/fnmol.2022.922665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366910PMC
July 2022

Three lines of defense: A multifunctional coating with anti-adhesion, bacteria-killing and anti-quorum sensing properties for preventing biofilm formation of Pseudomonas aeruginosa.

Acta Biomater 2022 Aug 9. Epub 2022 Aug 9.

State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China. Electronic address:

Surfaces of synthetic materials are highly susceptible to pathogenic bacteria colonization and further biofilm formation, leading to device failure in both biomedical and industrial applications. Complete elimination of the mature biofilms formed on the surfaces, however, remains a great challenge due to the complexity of chemical composition and physical structure. Therefore, prevention of biofilm formation becomes a preferred strategy for solving the biofilm-associated problems. Herein, a multifunctional coating showing three lines of defense to prevent biofilm formation of Pseudomonas aeruginosa is fabricated by a simple and versatile method. This coating is composed of multilayers of quaternized chitosan with bactericidal property and acylase with anti-quorum sensing property and a topmost layer of hyaluronic acid with anti-adhesion property. The substrate deposited with this coating could suppress initial adhesion of a majority of bacteria, and then kill the attached bacteria and interfere with their quorum sensing systems related to biofilm formation. The results of short-term antibacterial experiments show that our coating reduced 98 ± 2% of attached live bacteria. In long-term antibiofilm experiments, this "three lines of defense" design endows the coating with enhanced antibiofilm property against the biofilm formation for at least 3 days by reducing 98 ± 1% of bacterial proliferation and 71 ± 2% of biomass production. Benefiting from the natural building blocks with good biocompatibility and the versatile and environmentally friendly preparation method, this coating shows negligible cytotoxicity and broad applicability, providing great potential for a variety of biomedical applications. STATEMENT OF SIGNIFICANCE: Pathogenic biofilms formed on the surfaces of medical devices and materials pose an urgent problem, and it remains challenging to treat and eradicate the established biofilms. Herein, we developed an antibiofilm coating showing three lines of defense to prevent biofilm formation, which could be deposited on diverse substrates via a simple and versatile method. This coating was based on three natural materials with anti-adhesive, bactericidal, and anti-quorum sensing properties and showed different function in a self-adaptive way to target the sequential stages of biofilm formation by preventing initial bacterial adhesion, killing attached bacteria and interfering with their quorum sensing system to inhibit bacterial proliferation and biofilm maturation. This coating with improved antibiofilm performance might provide a simple and reliable solution to the problems associated with biofilm on surfaces.
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http://dx.doi.org/10.1016/j.actbio.2022.08.008DOI Listing
August 2022

Application of Elastin-like Polypeptide in Tumor Therapy.

Cancers (Basel) 2022 Jul 28;14(15). Epub 2022 Jul 28.

School of Life Sciences, Jiangsu University, Zhenjiang 212013, China.

Elastin-like polypeptides (ELPs) are stimulus-responsive artificially designed proteins synthesized from the core amino acid sequence of human tropoelastin. ELPs have good biocompatibility and biodegradability and do not systemically induce adverse immune responses, making them a suitable module for drug delivery. Design strategies can equip ELPs with the ability to respond to changes in temperature and pH or the capacity to self-assemble into nanoparticles. These unique tunable biophysicochemical properties make ELPs among the most widely studied biopolymers employed in protein purification, drug delivery, tissue engineering and even in tumor therapy. As a module for drug delivery and as a carrier to target tumor cells, the combination of ELPs with therapeutic drugs, antibodies and photo-oxidation molecules has been shown to result in improved pharmacokinetic properties (prolonged half-life, drug targeting, cell penetration and controlled release) while restricting the cytotoxicity of the drug to a confined infected site. In this review, we summarize the latest developments in the application methods of ELP employed in tumor therapy, with a focus on its conjugation with peptide drugs, antibodies and photosensitizers.
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http://dx.doi.org/10.3390/cancers14153683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9367306PMC
July 2022

Effect of Methionine Supplementation on Serum Metabolism and the Rumen Bacterial Community of Sika Deer ().

Animals (Basel) 2022 Jul 31;12(15). Epub 2022 Jul 31.

Jilin Key Laboratory for Molecular Biology of Special Economic Animals, Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun 130112, China.

Methionine is the first or second limiting amino acid for ruminants, such as sika deer, and has a variety of biological functions such as antioxidant activity, immune response, and protein synthesis. This study aimed to investigate the effects of methionine supplementation on antler growth, serum biochemistry, rumen fermentation, and the bacterial community of sika deer during the antler-growing period. Twelve 4-year-old male sika deer were randomly assigned to three dietary groups supplemented with 0 g/day ( = 4, CON), 4.0 g/day ( = 4, LMet), and 6.0 g/day ( = 4, HMet) methionine. No significant difference ( > 0.05) was found in the production performance between the three groups, but antler weight was higher in both the LMet and HMet groups than in the CON group. Methionine supplementation significantly increased the serum glutathione peroxidase activity ( < 0.05). The serum immunoglobulin G level was significantly higher in the HMet group than in the other two groups ( < 0.05). No significant effect was found on the apparent amino acid digestibility of the three groups, but cysteine and methionine digestibility were higher in the LMet group. The serum hydroxylysine level was significantly lower in the LMet and HMet groups, whereas the serum lysine level was significantly lower in the HMet group compared with the CON group ( < 0.05). The LMet group had the highest but a nonsignificant total volatile fatty acid content and significantly higher microbial protein content in the rumen than the CON group ( < 0.05). The phyla Bacteroidetes, Firmicutes, and Proteobacteria were dominant in the rumen of the sika deer. The principal coordinate analysis (PCoA) and analysis of similarities (ANOSIM) results showed a significant change in the bacterial composition of the three groups ( < 0.05). The relative abundance of and -RC9 was significantly higher in the LMet group compared with the CON group and CON and HMet groups, respectively. These results revealed that methionine supplementation improved the antioxidant activity and immune status, affecting amino acid metabolism and rumen microbial composition of the sika deer.
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http://dx.doi.org/10.3390/ani12151950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9367550PMC
July 2022

Impact of COVID-19 pandemic on the pregnancy outcomes of women undergoing assisted reproductive techniques (ARTs): a systematic review and meta-analysis.

J Zhejiang Univ Sci B 2022 Aug;23(8):655-665

Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.

The global outbreak of the coronavirus disease 2019 (COVID-19) led to the suspension of most treatments with assisted reproductive technique (ART). However, with the recent successful control of the pandemic in China, there is an urgent public need to resume full reproductive care. To determine whether the COVID-19 pandemic had any adverse effects on female fertility and the pregnancy outcomes of women undergoing ART, a systematic review and meta-analysis was conducted using the electronic Chinese and English databases. Dichotomous outcomes were summarized as prevalence, and odds ratios (ORs) and continuous outcomes as standardized mean difference (SMD) with 95% confidence interval (CI). The risk of bias and subgroup analyses were assessed using Stata/SE 15.1 and R 4.1.2. The results showed that compared with women treated by ART in the pre-COVID-19 time frame, women undergoing ART after the COVID-19 pandemic exhibited no significant difference in the clinical pregnancy rate (OR 1.07, 95% CI 0.97 to 1.19; =0.0%), miscarriage rate (OR 0.95, 95% CI 0.79 to 1.14; =38.4%), embryo cryopreservation rate (OR 2.90, 95% CI 0.17 to 48.13; =85.4%), and oocyte cryopreservation rate (OR 0.30, 95% CI 0.03 to 3.65; =81.6%). This review provided additional evidence for gynecologists to guide the management of women undergoing ART treatment during the COVID-19 pandemic timeframe.
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http://dx.doi.org/10.1631/jzus.B2200154DOI Listing
August 2022

Effect of Etomidate vs Propofol for Total Intravenous Anesthesia on Major Postoperative Complications in Older Patients: A Randomized Clinical Trial.

JAMA Surg 2022 Aug 10. Epub 2022 Aug 10.

Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.

Importance: Older patients may benefit from the hemodynamic stability of etomidate for general anesthesia. However, it remains uncertain whether the potential for adrenocortical suppression with etomidate may increase morbidity.

Objective: To test the primary hypothesis that etomidate vs propofol for anesthesia does not increase in-hospital morbidity after abdominal surgery in older patients.

Design, Setting, And Participants: This multicenter, parallel-group, noninferiority randomized clinical trial (Etomidate vs Propofol for In-hospital Complications [EPIC]) was conducted between August 15, 2017, and November 20, 2020, at 22 tertiary hospitals in China. Participants were aged 65 to 80 years and were scheduled for elective abdominal surgery. Patients and outcome assessors were blinded to group allocation. Data analysis followed a modified intention-to-treat principle.

Interventions: Patients were randomized 1:1 to receive either etomidate or propofol for general anesthesia by target-controlled infusion.

Main Outcomes And Measures: Primary outcome was a composite of major in-hospital postoperative complications (with a noninferiority margin of 3%). Secondary outcomes included intraoperative hemodynamic measurements; postoperative adrenocortical hormone levels; self-reported postoperative pain, nausea, and vomiting; and mortality at postoperative months 6 and 12.

Results: A total of 1944 participants were randomized, of whom 1917 (98.6%) completed the trial. Patients were randomized to the etomidate group (n = 967; mean [SD] age, 70.3 [4.0] years; 578 men [59.8%]) or propofol group (n = 950; mean [SD] age, 70.6 [4.2] years; 533 men [56.1%]). The primary end point occurred in 90 of 967 patients (9.3%) in the etomidate group and 83 of 950 patients (8.7%) in the propofol group, which met the noninferiority criterion (risk difference [RD], 0.6%; 95% CI, -1.6% to 2.7%; P = .66). In the etomidate group, mean (SD) cortisol levels were lower at the end of surgery (4.8 [2.7] μg/dL vs 6.1 [3.4] μg/dL; P < .001), and mean (SD) aldosterone levels were lower at the end of surgery (0.13 [0.05] ng/dL vs 0.15 [0.07] ng/dL; P = .02) and on postoperative day 1 (0.14 [0.04] ng/dL vs 0.16 [0.06] ng/dL; P = .001) compared with the propofol group. No difference in mortality was observed between the etomidate and propofol groups at postoperative month 6 (2.2% vs 3.0%; RD, -0.8%; 95% CI, -2.2% to 0.7%) and 12 (3.3% vs 3.9%; RD, -0.6%; 95% CI, -2.3% to 1.0%). More patients had pneumonia in the etomidate group than in the propofol group (2.0% vs 0.3%; RD, 1.7%; 95% CI, 0.7% to 2.8%; P = .001). Results were consistent in the per-protocol population.

Conclusions And Relevance: Results of this trial showed that, compared with propofol, etomidate anesthesia did not increase overall major in-hospital morbidity after abdominal surgery in older patients, although it induced transient adrenocortical suppression.

Trial Registration: ClinicalTrials.gov Identifier: NCT02910206.
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http://dx.doi.org/10.1001/jamasurg.2022.3338DOI Listing
August 2022

Hair Zidovudine Concentrations Predict Virologic Outcomes Among People Living with HIV/AIDS in China.

Patient Prefer Adherence 2022 3;16:1885-1896. Epub 2022 Aug 3.

Unit of AIDS Prevention and Control, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, People's Republic of China.

Background: Hair antiretroviral concentrations are an objective and non-invasive measure of adherence to long-term antiretroviral therapy (ART) and can further predict virologic outcomes among people living with HIV/AIDS (PLWH). Zidovudine, one of the mainstream antiretrovirals in China, has been verified to have high reliability in adherence assessment, especially for its hair concentrations. However, data are limited in its predicting virologic outcomes. Therefore, this study aimed to characterize whether hair zidovudine concentrations can predict virologic suppression among Chinese PLWH compared with hair lamivudine concentrations and two self-reported measures, the overall frequency of adherence behaviors and percentage adherence.

Methods: This cross-sectional study randomly recruited 564 PLWH currently treated with zidovudine, lamivudine, and other ART agents (efavirenz, nevirapine, or lopinavir/ritonavir) in Guangxi, China. Hair antiretroviral concentrations were determined using the LC-ESI-MS/MS method. Receiver operating characteristic (ROC) curves were used to estimate the optimal classification thresholds of hair concentrations of zidovudine and lamivudine, and the two self-reported measures. Based on those optimal classification thresholds, logistic regression was used to examine whether those four adherence measures can predict virologic suppression (HIV-1 RNA <200 copies/mL).

Results: ROC curves demonstrated good classification performance for association with virologic suppression of zidovudine with the optimal threshold at 58 pg/mg and lamivudine at 255 pg/mg but no self-reported measures. PLWH with hair zidovudine concentrations >58 pg/mg had an adjusted odds ratio (aOR) of 43.191 (95% confidence interval (CI) = 10.171‒183.418, < 0.001) for virologic suppression. Hair lamivudine concentrations were also associated with virologic suppression (aOR = 10.656, 95% CI = 3.670‒30.943, < 0.001). However, two self-reported measures did not predict virologic suppression (aORs = 1.157 and 2.488, s >0.149).

Conclusion: Hair zidovudine concentrations can be served as an alternative tool for clinically predicting virologic suppression among PLWH in China.
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http://dx.doi.org/10.2147/PPA.S371623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357394PMC
August 2022

Development and validation of a prognostic nomogram among patients with acute exacerbation of chronic obstructive pulmonary disease in intensive care unit.

BMC Pulm Med 2022 Aug 9;22(1):306. Epub 2022 Aug 9.

Department of Nursing, Shanghai Baoshan Luodian Hospital, 121 Luoxi Road, Baoshan District, Shanghai, 201908, China.

Background: Acute exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) contributes significantly to mortality among patients with COPD in Intensive care unit (ICU). This study aimed to develop a nomogram to predict 30-day mortality among AECOPD patients in ICU.

Methods: In this retrospective cohort study, we extracted AECOPD patients from Medical Information Mart for Intensive Care III (MIMIC-III) database. Multivariate logistic regression based on Akaike information criterion (AIC) was used to establish the nomogram. Internal validation was performed by a bootstrap resampling approach with 1000 replications. The discrimination and calibration of the nomogram were evaluated by Harrell's concordance index (C-index) and Hosmer-Lemeshow (HL) goodness-of-fit test. Decision curve analysis (DCA) was performed to evaluate its clinical application.

Results: A total of 494 patients were finally included in the study with a mean age of 70.8 years old. 417 (84.4%) patients were in the survivor group and 77 (15.6%) patients were in the non-survivor group. Multivariate logistic regression analysis based on AIC included age, pO, neutrophil-to-lymphocyte ratio (NLR), prognostic nutritional index (PNI), invasive mechanical ventilation and vasopressor use to construct the nomogram. The adjusted C-index was 0.745 (0.712, 0.778) with good calibration (HL test, P = 0.147). The Kaplan-Meier survival curves revealed a significantly lower survival probability in the high-risk group than that in the low-risk group (P < 0.001). DCA showed that nomogram was clinically useful.

Conclusion: The nomogram developed in this study could help clinicians to stratify AECOPD patients and provide appropriate care in clinical setting.
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http://dx.doi.org/10.1186/s12890-022-02100-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9364535PMC
August 2022

Oridonin Inhibits SARS-CoV-2 by Targeting Its 3C-Like Protease.

Small Sci 2022 Jun 12;2(6):2270012. Epub 2022 Jun 12.

School of Public Health (Shenzhen) Shenzhen Campus of Sun Yat-sen University Shenzhen 518107 China.

Oridonin Inhibits SARS-CoV-2 Oridonin, a natural product extracted from , possesses a wide range of pharmacological properties, including anti-inflammatory, anti-cancer, anti-microbial, neuroprotection, immunoregulation, etc. In article number 2100124, Baisen Zhong, Litao Sun, and co-workers demonstrate that Oridonin targets the SARS-CoV-2 3CL protease by covalently binding to cysteine145 in its active pocket to exert an anti-SARS-CoV-2 effect, which provides a novel candidate for the treatment of COVID-19.
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http://dx.doi.org/10.1002/smsc.202270012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9347789PMC
June 2022

Fossil samaras of from South China and their phytogeographic implications.

iScience 2022 Aug 14;25(8):104757. Epub 2022 Jul 14.

State Key Laboratory of Biocontrol & Guangdong Provincial Key Laboratory of Plant Resources, School of Life Sciences/School of Ecology, Sun Yat-sen University, Guangzhou 510275, China.

Desf. (Simaroubaceae), now widespread in southern Asia to northern Australia, was widely distributed in the Northern Hemisphere during the Cenozoic, but has few fossil records at low latitudes. Here we report the fossil samaras of Unger from South China and its occurrences indicate that this genus has been distributed in low latitude regions since the middle Eocene. According to the recent fossil records, is considered to have originated from the Indian subcontinent and dispersed rapidly to East Asia and western North America following the early Paleogene onset of the India-Eurasia collision. In the Eocene, became widespread across the Northern Hemisphere. Subsequent to global cooling, gradually disappeared in the mid-high latitudes and may have continued to spread southward from Asia to northern Australia following the Asia-Australia collision in the late Oligocene, thus forming its modern distribution pattern.
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http://dx.doi.org/10.1016/j.isci.2022.104757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356078PMC
August 2022

Dexamethasone-loaded zeolitic imidazolate frameworks nanocomposite hydrogel with antibacterial and anti-inflammatory effects for periodontitis treatment.

Mater Today Bio 2022 Dec 20;16:100360. Epub 2022 Jul 20.

Department of Stomatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, 200025, Shanghai, China.

Periodontitis is a bacterial-induced, chronic inflammatory disease characterized by progressive destruction of tooth-supporting structures. Pathogenic bacteria residing in deep periodontal pockets after traditional manual debridement can still lead to local inflammatory microenvironment, which remains a challenging problem and an urgent need for better therapeutic strategies. Here, we integrated the advantages of metal-organic frameworks (MOFs) and hydrogels to prepare an injectable nanocomposite hydrogel by incorporating dexamethasone-loaded zeolitic imidazolate frameworks-8 (DZIF) nanoparticles into the photocrosslinking matrix of methacrylic polyphosphoester (PPEMA) and methacrylic gelatin (GelMA). The injectable hydrogel could be easily injected into deep periodontal pockets, achieving high local concentrations without leading to antibiotic resistance. The nanocomposite hydrogel had high antibacterial activity and constructs with stable microenvironments maintain cell viability, proliferation, spreading, as well as osteogenesis, and down-regulated inflammatory genes expression . When evaluated on an experimental periodontitis rat model, micro-computed tomography and histological analyses showed that the nanocomposite hydrogel effectively reduced periodontal inflammation and attenuated inflammation-induced bone loss in a rat model of periodontitis. These findings suggest that the nanocomposite hydrogel might be a promising therapeutic candidate for treating periodontal disease.
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http://dx.doi.org/10.1016/j.mtbio.2022.100360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352959PMC
December 2022

Activation of aryl hydrocarbon receptor ameliorates rosacea-like eruptions in mice and suppresses the TLR signaling pathway in LL-37-induced HaCaT cells.

Toxicol Appl Pharmacol 2022 Aug 1;451:116189. Epub 2022 Aug 1.

Department of Dermatology, The First Hospital of China Medical University, Shenyang, China; NHC Key Laboratory of Immunodermatology, Ministry of Education Key Laboratory of Immunodermatology, National Joint Engineering Research Center for Diagnosis and Treatment of Immunologic Skin Diseases, The First Hospital of China Medical University, Shenyang, China. Electronic address:

Background: Toll-like receptor (TLR) 2, along with some chemokines, were found to be overexpressed in rosacea patients. Aryl hydrocarbon Receptor (AhR) activation inhibited the inflammatory responses triggered by TLR activation. The current study was conducted to evaluate the underlying mechanisms of AhR activation in rosacea models.

Materials And Methods: Seven-week-old female BALB/c mice received twice daily intradermal injections of LL-37 for 2 consecutive days. Thirty minutes after the second LL-37 injection, 1% or 0.5% AhR agonist benvitimod was administrated topically once per day for 3 consecutive days. HaCaT cells were treated with different concentrations of LL-37 and benvitimod, and were further infected with lentivirus to over-express TLR2. Expressions of TLR2, CCL5, CXCL9, CXCL10 and CXCL11 were evaluated using qRT-PCR, Western Blot or ELISA.

Results: AhR activation ameliorated LL-37-induced rosacea-like eruptions in mice by reductions in redness scores, redness areas and dermal inflammatory cell infiltrates. Elevated expressions of TLR2 and chemokines (CCL5, CXCL9, CXCL10 and CXCL11) following LL-37 treatment were decreased by AhR activation. In HaCaT cells receiving LL-37, TLR2 and the four chemokines were up-regulated, and levels of these chemokines were further enhanced after over-expressing TLR2. At 8 h after an administration of 10 μM benvitimod, gene expressions of TLR2 and the four chemokines in LL-37 treated HaCat cells were decreased, while their protein expressions were decreased for 24 h.

Conclusion: AhR activation is beneficial in treating rosacea in a LL-37-induced rosacea mouse model and involves a suppression of the TLR signaling pathway in an HaCaT cell model of rosacea.
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http://dx.doi.org/10.1016/j.taap.2022.116189DOI Listing
August 2022

Lifting the midface using a hyaluronic acid filler with lidocaine: a randomized multi-center study in a Chinese population.

J Cosmet Dermatol 2022 Aug 4. Epub 2022 Aug 4.

West China Hospital, Sichuan University, Chengdu, China.

Background: Soft-tissue augmentation of the midface is increasingly requested by patients, and hyaluronic acid (HA) fillers are frequently used in treatment.

Aims: To evaluate the efficacy and safety of treatment of midface volume/contour deficit with a firm HA filler including lidocaine (HA ).

Patients/methods: This was a 12-month, randomized, evaluator-blinded, controlled study. Chinese adults with mild to substantial volume loss were randomly assigned in a 3:1 ratio to treatment or untreated control groups.

Results: A total of 148 subjects were enrolled. The primary objective was met; results of the midface volume scale (MMVS) rated by a blinded evaluator were in favor of HA at Month 6 (p< 0.0001 vs. the untreated control group). Similar to the MMVS improvement, improved midface fullness and aesthetic appearance was observed based on the Global Aesthetic Improvement Scale (GAIS) up to 12 months by both treating investigators and subjects (at least 96% at Week 4 and 65% at Month 12). Subject satisfaction was high, and the majority of subjects considered the results to look natural (>97%). The study product was well tolerated.

Conclusions: Midfacial treatment using HA was effective, well tolerated, and led to high levels of satisfaction in a Chinese population for up to 12 months.
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http://dx.doi.org/10.1111/jocd.15286DOI Listing
August 2022

Omicron-specific mRNA vaccine elicits potent immune responses in mice, hamsters, and nonhuman primates.

Cell Res 2022 Aug 1. Epub 2022 Aug 1.

Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

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http://dx.doi.org/10.1038/s41422-022-00706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340695PMC
August 2022

Pcv-aCO2 and procalcitonin levels for the early diagnosis of bloodstream infections caused by gram-negative bacteria.

Am J Med Sci 2022 Jul 29. Epub 2022 Jul 29.

Department of Critical Care Medicine, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong, China.. Electronic address:

Background: The central venous-to-arterial carbon dioxide difference (Pcv-aCO) is a biomarker for tissue perfusion, but the diagnostic value of Pcv-aCO in bacteria bloodstream infections (BSI) caused by gram-negative (GN) bacteria remains unclear. This study evaluated the expression levels and diagnostic value of Pcv-aCO and procalcitonin (PCT) in the early stages of GN bacteria BSI.

Methods: Patients with BSI admitted to the intensive care unit at Guangdong Provincial People's Hospital between August 2014 and August 2017 were enrolled. Pcv-aCO and PCT levels were evaluated in GN and gram-positive (GP) bacteria BSI patients.

Results: A total of 132 patients with BSI were enrolled. The Pcv-aCO (8.32 ± 3.59 vs 4.35 ± 2.24 mmHg p = 0.001) and PCT (30.62 ± 34.51 vs 4.92 ± 6.13 ng/ml p = 0.001) levels were significantly higher in the GN group than in the GP group. In the diagnosis of GN bacteria BSI, the area under the receiver operating characteristic curve (AUROC) for Pcv-aCO was 0.823 (95% confidence interval (CI): 0.746-0.900). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 71.90%, 88.00%, 74.07% and 78.21%, respectively. The AUROC for PCT was 0.818 (95% CI: 0.745-0.890). The sensitivity, specificity, PPV and NPV were 57.90%, 94.67%, 71.93% and 74.67%, respectively.

Conclusions: Pcv-aCO and PCT have similar and high diagnostic value for the early diagnosis of BSI caused by GN bacteria.
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http://dx.doi.org/10.1016/j.amjms.2022.07.014DOI Listing
July 2022

Correlation of Glucose and Lipid Metabolism Levels and Serum Uric Acid Levels with Diabetic Retinopathy in Type 2 Diabetic Mellitus Patients.

Authors:
Tiantian Li Yan Wu

Emerg Med Int 2022 21;2022:9201566. Epub 2022 Jul 21.

Department of General Practice, The First People's Hospital of Lianyungang, Lianyungang 222000, Jiangsu, China.

Objective: The aim of this study was to observe the association between the development of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) and the levels of glucose and lipid metabolism and serum uric acid (SUA) levels.

Methods: A retrospective analysis was performed on 97 patients with T2DM who were admitted to our endocrinology department from June 2019 to April 2021 with complete data; the patients were divided into DR and no DR groups (NDR) according to the presence or absence of DR. Their clinical history and biochemical test indexes were collected, and the fundus was examined by fundus photography and the fundoscopic examination method, and the vascular diameter was measured by using a computer software. All clinical data, medical history, and biochemical test indexes were compared between the two groups, and logistic regression was used to analyze the risk factors of DR.

Results: The duration of DM disease, fasting blood glucose (FBG), glycosylated hemoglobin, type A1C (HbA1c) levels, cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), and SUA levels were higher in the DR group than those in the NDR group, and the differences were significant ( < 0.05). The difference between the NDR group and the DR group in terms of gender, age, BMI, DBP, SBP, family history of DM, FINS, and HDL-C levels was not significant ( > 0.05). The results of multifactorial analysis showed that the four variables of DM duration, HbA1c, TG, and SUA were still risk factors for the development of DR ( < 0.05). Further receiver operating characteristic (ROC) analysis showed that the areas under the curves (AUCs) for the duration of DM disease, HbA1c, TG, and SUA to predict the occurrence of DR were 0.740 (95% CI 0.639-0.841), 0.767 (95% 0.672-0.862), 0.721 (95% CI 0.617-0.826), and 0.693 (95% CI 0.588∼0.797), respectively.

Conclusion: The lesions of DR in T2DM patients have a close relationship with the course of DM, HbA1c, TG, and SUA, and the course of DM, HbA1c, TG, and SUA has a good predictive value for the occurrence of DR.
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http://dx.doi.org/10.1155/2022/9201566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334055PMC
July 2022

Hetero-bivalent nanobodies provide broad-spectrum protection against SARS-CoV-2 variants of concern including Omicron.

Cell Res 2022 Jul 29. Epub 2022 Jul 29.

Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

SARS-CoV-2 variants with adaptive mutations have continued to emerge, causing fresh waves of infection even amongst vaccinated population. The development of broad-spectrum antivirals is thus urgently needed. We previously developed two hetero-bivalent nanobodies (Nbs), aRBD-2-5 and aRBD-2-7, with potent neutralization activity against the wild-type (WT) Wuhan isolated SARS-CoV-2, by fusing aRBD-2 with aRBD-5 and aRBD-7, respectively. Here, we resolved the crystal structures of these Nbs in complex with the receptor-binding domain (RBD) of the spike protein, and found that aRBD-2 contacts with highly-conserved RBD residues and retains binding to the RBD of the Alpha, Beta, Gamma, Delta, Delta plus, Kappa, Lambda, Omicron BA.1, and BA.2 variants. In contrast, aRBD-5 and aRBD-7 bind to less-conserved RBD epitopes non-overlapping with the epitope of aRBD-2, and do not show apparent binding to the RBD of some variants. However, when fused with aRBD-2, they effectively enhance the overall binding affinity. Consistently, aRBD-2-5-Fc and aRBD-2-7-Fc potently neutralized all of the tested authentic or pseudotyped viruses, including WT, Alpha, Beta, Gamma, Delta, and Omicron BA.1, BA.1.1 and BA.2. Furthermore, aRBD-2-5-Fc provided prophylactic protection against the WT and mouse-adapted SARS-CoV-2 in mice, and conferred protection against the Omicron BA.1 variant in hamsters prophylactically and therapeutically, indicating that aRBD-2-5-Fc could potentially benefit the prevention and treatment of COVID-19 caused by the emerging variants of concern. Our strategy provides new solutions in the development of broad-spectrum therapeutic antibodies for COVID-19.
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http://dx.doi.org/10.1038/s41422-022-00700-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334538PMC
July 2022

Highly efficient and stable ZnO-based perovskite solar cells enabled by a self-assembled monolayer as the interface linker.

Chem Commun (Camb) 2022 Aug 16;58(66):9266-9269. Epub 2022 Aug 16.

China-Australia Institute for Advanced Materials and Manufacturing, Jiaxing University, Jiaxing 314001, P. R. China.

2-TA and 3-TA were introduced for the first time on the surface of ZnO, and used as SAMs for interfacial modification. A highest PCE of 20.6% was achieved for 2-TA PSCs with improved energy alignment and perovskite film quality, and reduced defect density. The modified ZnO exhibited better thermostability of the perovskite and resultant device stability.
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http://dx.doi.org/10.1039/d2cc03890kDOI Listing
August 2022

Severity of Hospitalized Children with Anti-NMDAR Autoimmune Encephalitis.

J Child Neurol 2022 Jul 29:8830738221075886. Epub 2022 Jul 29.

Department of endocrinology, 159388Children's Hospital of Nanjing Medical University, Nanjing , China.

Information on the clinical characteristics and severity of autoimmune encephalitis with antibodies against the -methyl-d-aspartate receptor (NMDAR) in children is attracting more and more attention in the field of pediatric research. In this retrospective cohort study, all cases (n = 67) were enrolled from a tertiary children's hospital, from 2017 to 2020. We compared severe cases that received intensive care unit (ICU) care with nonsevere cases that did not receive ICU care and used machine learning algorithm to predict the severity of children, as well as using immunologic and viral nucleic acid tests to identify possible pathogenic triggers. Mean age of children was 8.29 (standard deviation 4.09) years, and 41 (61.19%) were girls. Eleven (16.42%) were admitted to the ICU, and 56 (83.58%) were admitted to neurology ward. Ten individual parameters were statistically significant differences between severe cases and nonsevere cases ( < .05), including headache, abnormal mental behavior or cognitive impairment, seizures, concomitant tumors, sputum/blood pathogens, blood globulin, blood urea nitrogen, blood immunoglobulin G, blood immunoglobulin M, and number of polynucleated cells in cerebrospinal fluid. Random forest regression model presented that the overall prediction power of severity reached 0.806, among which the number of polynucleated cells in cerebrospinal fluid contributed the most. Potential pathogenic causes exhibited that the proportion of mycoplasma was the highest, followed by Epstein-Barr virus. Our findings provided evidence for early identification of autoimmune encephalitis in children, especially in severe cases.
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http://dx.doi.org/10.1177/08830738221075886DOI Listing
July 2022

Nicotinamide Mononucleotide Ameliorates Cellular Senescence and Inflammation Caused by Sodium Iodate in RPE.

Oxid Med Cell Longev 2022 18;2022:5961123. Epub 2022 Jul 18.

Department of Ophthalmology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.

Senescent cells have been demonstrated to have lower cellular NAD levels and are involved in the development of various age-related diseases, including age-related macular degeneration (AMD). Sodium iodate (NaIO) has been primarily used as an oxidant to establish a model of dry AMD. Results of previous studies have showed that NaIO induced retinal tissue senescence . However, the role of NaIO and the mechanism by which it induces retinal pigment epithelium (RPE) senescence remains unknown. In this study, RPE cell senescence was confirmed to be potentially induced by NaIO. The results showed that the number of senescence-associated--galactosidase (SA--gal-)-positive cells and the protein levels of p16 and p21 increased after NaIO treatment. Additionally, the senescent RPE cells underwent oxidative stress and NAD depletion. Furthermore, significant DNA damage and mitochondrial dysfunction were also detected in senescent RPE cells. The antioxidant N-acetylcysteine (NAC) could alleviate cellular senescence only by a minimal degree, whereas supplementation with nicotinamide mononucleotide (NMN) strongly ameliorated RPE senescence through the alleviation of DNA damage and the maintenance of mitochondrial function. The protective effects of NMN were demonstrated to rely on undisturbed Sirt1 signaling. Moreover, both the expression of senescence markers of RPE and subretinal inflammatory cell infiltration were decreased by NMN treatment . Our results indicate that RPE senescence induced by NaIO acquired several key features of AMD. More importantly, NMN may potentially be used to treat RPE senescence and senescence-associated pre-AMD changes by restoring the NAD levels in cells and tissues.
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http://dx.doi.org/10.1155/2022/5961123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313989PMC
July 2022

Assessing the Biodegradation of BTEX and Stress Response in a Bio-Permeable Reactive Barrier Using Compound-Specific Isotope Analysis.

Int J Environ Res Public Health 2022 Jul 20;19(14). Epub 2022 Jul 20.

State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China.

By using compound-specific isotope analysis (CSIA) in combination with high-throughput sequencing analysis (HTS), we successfully evaluated the benzene and toluene biodegradation in a bio-permeable reactive barrier (bio-PRB) and the stress response of the microbial community. Under stress conditions, a greater decline in the biodegradation rate of BTEX was observed compared with the apparent removal rate. Both an increase in the influent concentration and the addition of trichloroethylene (TCE) inhibited benzene biodegradation, while toluene biodegradation was inhibited by TCE. Regarding the stress response, the relative abundance of the dominant bacterial community responsible for the biodegradation of BTEX increased with the influent concentration. However, the dominant bacterial community did not change, and its relative abundance was restored after the influent concentration decreased. On the contrary, the addition of TCE significantly changed the bacterial community, with becoming the dominant phyla for co-metabolizing TCE and BTEX. Thus, TCE had a more significant influence on the bio-PRB than an increasing influent concentration, although these two stress conditions showed a similar degree of influence on the apparent removal rate of benzene and toluene. The present work not only provides a new method for accurately evaluating the biodegradation performance and microbial community in a bio-PRB, but also expands the application of compound-specific isotope analysis in the biological treatment of wastewater.
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http://dx.doi.org/10.3390/ijerph19148800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9322891PMC
July 2022

Distribution, behavior, and risk assessment of chlorinated paraffins in paddy plants throughout whole growth cycle.

Environ Int 2022 Sep 15;167:107404. Epub 2022 Jul 15.

State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China. Electronic address:

Paddy plants provide staple food for 3 billion people worldwide. This study explores the environmental fate and behavior of a high-volume production emerging contaminants chlorinated paraffins (CPs) in the paddy ecosystem. Very-short-, short-, medium-, and long-chain CPs (vSCCPs, SCCPs, MCCPs, and LCCPs, respectively) were analyzed in specific tissue of paddy plants at four main growth stages and soils from the Yangtze River Delta, China throughout a full rice growing season. The total CP concentrations in the paddy roots, stalks, leaves, panicles, hulls, rice, and soils ranged from 181 to 1.74 × 10, 21.7-383, 19.6-585, 108-332, 245-470, 59.6-130, and 99.6-400 ng/g dry weight, respectively. The distribution profile indicated the translocation of SCCPs and MCCPs from soils to paddy tissue, highlighting their elevated bioaccumulative potential. The evolution of CP level/mass/pattern during the whole growth cycle suggested atmospheric CPs deposition on leaves and hulls, as well as stalk-rice transfer. CSOIL plant uptake model well predicted the level, distribution pattern, and bioconcentration factors (BCFs) of SCCPs and MCCPs in paddy shoot and recognized the soil-air-shoot pathway as the major contributor. Moreover, risk evaluation indicated that MCCPs intake and subsequent risks dominated the total exposure to CPs via rice ingestion. This is the first report on the occurrence, fate and risk assessment of all CPs classes in paddy ecosystems, and the results underline the potential health effects caused by the in-use MCCPs via rice ingestion.
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http://dx.doi.org/10.1016/j.envint.2022.107404DOI Listing
September 2022

Gold nanoparticle-directed autophagy intervention for antitumor immunotherapy inhibiting tumor-associated macrophage M2 polarization.

Acta Pharm Sin B 2022 Jul 16;12(7):3124-3138. Epub 2022 Feb 16.

Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.

Tumor-associated macrophages (TAMs), one of the dominating constituents of tumor microenvironment, are important contributors to cancer progression and treatment resistance. Therefore, regulation of TAMs polarization from M2 phenotype towards M1 phenotype has emerged as a new strategy for tumor immunotherapy. Herein, we successfully initiated antitumor immunotherapy by inhibiting TAMs M2 polarization autophagy intervention with polyethylene glycol-conjugated gold nanoparticles (PEG-AuNPs). PEG-AuNPs suppressed TAMs M2 polarization in both and models, elicited antitumor immunotherapy and inhibited subcutaneous tumor growth in mice. As demonstrated by the mRFP-GFP-LC3 assay and analyzing the autophagy-related proteins (LC3, beclin1 and P62), PEG-AuNPs induced autophagic flux inhibition in TAMs, which is attributed to the PEG-AuNPs induced lysosome alkalization and membrane permeabilization. Besides, TAMs were prone to polarize towards M2 phenotype following autophagy activation, whereas inhibition of autophagic flux could reduce the M2 polarization of TAMs. Our results revealed a mechanism underlying PEG-AuNPs induced antitumor immunotherapy, where PEG-AuNPs reduce TAMs M2 polarization induction of lysosome dysfunction and autophagic flux inhibition. This study elucidated the biological effects of nanomaterials on TAMs polarization and provided insight into harnessing the intrinsic immunomodulation capacity of nanomaterials for effective cancer treatment.
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http://dx.doi.org/10.1016/j.apsb.2022.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293675PMC
July 2022

Structure-selected RBM immunogens prime polyclonal memory responses that neutralize SARS-CoV-2 variants of concern.

PLoS Pathog 2022 07 21;18(7):e1010686. Epub 2022 Jul 21.

The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.

Successful control of the COVID-19 pandemic depends on vaccines that prevent transmission. The full-length Spike protein is highly immunogenic but the majority of antibodies do not target the virus: ACE2 interface. In an effort to affect the quality of the antibody response focusing it to the receptor-binding motif (RBM) we generated a series of conformationally-constrained immunogens by inserting solvent-exposed RBM amino acid residues into hypervariable loops of an immunoglobulin molecule. Priming C57BL/6 mice with plasmid (p)DNA encoding these constructs yielded a rapid memory response to booster immunization with recombinant Spike protein. Immune sera antibodies bound strongly to the purified receptor-binding domain (RBD) and Spike proteins. pDNA primed for a consistent response with antibodies efficient at neutralizing authentic WA1 virus and three variants of concern (VOC), B.1.351, B.1.617.2, and BA.1. We demonstrate that immunogens built on structure selection can be used to influence the quality of the antibody response by focusing it to a conserved site of vulnerability shared between wildtype virus and VOCs, resulting in neutralizing antibodies across variants.
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http://dx.doi.org/10.1371/journal.ppat.1010686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302722PMC
July 2022

Flavin Containing Monooxygenase 2 Prevents Cardiac Fibrosis via CYP2J3-SMURF2 Axis.

Circ Res 2022 Jul 5:101161CIRCRESAHA122320538. Epub 2022 Jul 5.

Department of Cardiology, Cardiovascular Key Laboratory of Zhejiang Province, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China (C.N., Y.C., Y.X., J.Z., Q. Li, C.X., Y. Wu, Jingyi Wang, Yingchao Wang, Z.Z., L.Z., R.W., Q. Liu, X.W., C.K., W.Z., J.C., Jian'an Wang, X.H.).

Background: Cardiac fibrosis is a common pathological feature associated with adverse clinical outcome in postinjury remodeling and has no effective therapy. Using an unbiased transcriptome analysis, we identified FMO2 (flavin-containing monooxygenase 2) as a top-ranked gene dynamically expressed following myocardial infarction (MI) in hearts across different species including rodents, nonhuman primates, and human. However, the functional role of FMO2 in cardiac remodeling is largely unknown.

Methods: Single-nuclei transcriptome analysis was performed to identify FMO2 after MI; FMO2 ablation rats were generated both in genetic level using the CRISPR-cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) technology and lentivirus-mediated manner. Gain-of-function experiments were conducted using -promoter FMO2, miR1a/miR133a-FMO2 lentivirus, and enzymatic activity mutant FMO2 lentivirus after MI.

Results: A significant downregulation of FMO2 was consistently observed in hearts after MI in rodents, nonhuman primates, and patients. Single-nuclei transcriptome analysis showed cardiac expression of FMO2 was enriched in fibroblasts rather than myocytes. Elevated spontaneous tissue fibrosis was observed in the FMO2-null animals without external stress. In contrast, fibroblast-specific expression of FMO2 markedly reduced cardiac fibrosis following MI in rodents and nonhuman primates associated with diminished SMAD2/3 phosphorylation. Unexpectedly, the FMO2-mediated regulation in fibrosis and SMAD2/3 signaling was independent of its enzymatic activity. Rather, FMO2 was detected to interact with CYP2J3 (cytochrome p450 superfamily 2J3). Binding of FMO2 to CYP2J3 disrupted CYP2J3 interaction with SMURF2 (SMAD-specific E3 ubiquitin ligase 2) in cytosol, leading to increased cytoplasm to nuclear translocation of SMURF2 and consequent inhibition of SMAD2/3 signaling.

Conclusions: Loss of FMO2 is a conserved molecular signature in postinjury hearts. FMO2 possesses a previously uncharacterized enzyme-independent antifibrosis activity via the CYP2J3-SMURF2 axis. Restoring FMO2 expression exerts potent ameliorative effect against fibrotic remodeling in postinjury hearts from rodents to nonhuman primates. Therefore, FMO2 is a potential therapeutic target for treating cardiac fibrosis following injury.
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http://dx.doi.org/10.1161/CIRCRESAHA.122.320538DOI Listing
July 2022

Combination effect of azithromycin with TCM preparation Xiyanping injection against Klebsiella pneumoniae infection in rats.

Phytomedicine 2022 Sep 10;104:154332. Epub 2022 Jul 10.

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

Background: Klebsiella pneumoniae is known as one of the most principal opportunistic human pathogens. Although antibiotics such as the first-line agent azithromycin (AZM) usually are efficient for the treatment of K. pneumonia-related infections, growing threat from antibiotic resistance has become a major challenge. Various preparations based on traditional Chinese medicine (TCM) clinical experience have been developed to help combat such a global public health threat, including Xiyanping injection (XYP) that is made from the natural product andrographolide with potent heat-clearing and toxin-resolving functions.

Purpose: The present study aimed to demonstrate the therapeutic potential, as well as the action of mechanism of AZM in combination with XYP against K. pneumonia infection in rats.

Methods: Pneumonia model of K. pneumoniae infection in rats was established and subjected to various treatments. The lung histopathological lesions were evaluated. ELISA and Griess techniques were used to determine the level of crucial cytokines. The protein expressions of MAPKs and NF-κB pathways were analyzed by Western blotting.

Results: The combination in vivo could significantly inhibit the proliferation of K. pneumoniae in lung, improve the pathological changes of lung and reduce inflammatory factors in lung homogenate and bronchoalveolar lavage fluid, mainly by inactivating MAPKs and NF-κB signaling pathways. Combination therapy caused one-fold increase in apparent distribution volume of AZM in rats after multiple dosing, along with a significant increase of AZM level in lungs but obvious decrease in livers.

Conclusion: The combination therapy of AZM and XYP showed increased antibacterial and anti-inflammatory properties, indicating that it might be used to treat K. pneumoniae infection.
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http://dx.doi.org/10.1016/j.phymed.2022.154332DOI Listing
September 2022
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