Publications by authors named "Qiong Yang"

616 Publications

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

Brain 2022 Aug 9. Epub 2022 Aug 9.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.
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http://dx.doi.org/10.1093/brain/awac290DOI Listing
August 2022

The gut microbiome contributes to splenomegaly and tissue inflammation in a murine model of primary biliary cholangitis.

Ann Transl Med 2022 May;10(9):507

Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China.

Background: Splenomegaly is not just a consequence of numerous chronic and acute conditions but may also contribute to their severity, due to the interaction of the spleen with the gut microbiome. This study aimed to explore the effect of the gut microbiome on splenomegaly.

Methods: We used p40IL-2Rα mice as a murine model of primary biliary cholangitis (PBC) as per our previous study. Splenomegaly was evaluated by spleen weight. Severity of liver inflammation was evaluated by hepatic mononuclear cell (MNCs) number and pathological score. Changes of immune cells in the spleen and liver were detected by flow cytometry. The effects of the gut microbiome on splenomegaly and liver inflammation were observed by combined antibiotic treatment in p40IL-2Rα mice.

Results: A proportion of p40IL-2Rα mice developed splenomegaly. The results revealed that liver mononuclear cells infiltration, histological scores of hepatic inflammation, and bile duct damage were positively correlated with the degree of splenomegaly. Hepatic CD4 and CD8 T cells numbers were significantly higher in mice with splenomegaly, and this was particularly observed in activated effector memory CD4 T and CD8 T cells. A proportion of some other immune cells including granulocytes, B, natural killer (NK), and CD8 T effector memory cells were also altered in the enlarged spleen. More importantly, administration of quadruple antibiotics to deplete gut microbiota relieved the splenomegaly of p40IL-2Rα mice, significantly alleviated liver inflammation, and caused a significant reduction of liver and spleen T cell accumulation and activation; however, single antibiotics did not induce these changes.

Conclusions: Splenomegaly was associated with more severe liver inflammation in our PBC murine model, and this effect was reversed by quadruple antibiotic treatment.
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http://dx.doi.org/10.21037/atm-21-5448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9347057PMC
May 2022

Effects of bone morphogenetic protein 4 on TGF-1-induced cell proliferation, apoptosis, activation and differentiation in mouse lung fibroblasts ERK/p38 MAPK signaling pathway.

PeerJ 2022 27;10:e13775. Epub 2022 Jul 27.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.

Fibroblasts, in particular myofibroblasts, are the critical effector cells in idiopathic pulmonary fibrosis (IPF), a deadly lung disease characterized by abnormal lung remodeling and the formation of "fibroblastic foci". Aberrant activation of TGF-1 is frequently encountered and promotes fibroblast proliferation, activation, and differentiation in pulmonary fibrosis. Hence, the inhibition of TGF-1-induced lung fibroblast activation holds promise as a therapeutic strategy for IPF. The present study aimed to investigate the potential effect and underlying mechanisms of bone morphogenetic protein 4 (BMP4) on TGF-1-induced proliferation, apoptosis, activation and myofibroblast differentiation of adult lung fibroblasts. Here, we demonstrated that BMP4 expression was significantly decreased in TGF-1-stimulated mouse primary lung fibroblasts (PLFs). BMP4 inhibited proliferation and apoptosis resistance of TGF-1-stimulated mouse PLFs. BMP4 suppressed TGF-1-induced fibroblast activation and differentiation in mouse PLFs. We also found that BMP4 inhibited TGF-1-induced ERK and p38 MAPK phosphorylation. Our findings indicate that BMP4 exerts its anti-fibrotic effects by regulating fibroblast proliferation, apoptosis, activation and differentiation the inhibition of the ERK/p38 MAPK signaling pathway, and thus has a potential for the treatment of pulmonary fibrosis.
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http://dx.doi.org/10.7717/peerj.13775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338752PMC
July 2022

Synergistic effect of Si concentration and distribution on ferroelectric properties optimization of Si:HfOferroelectric thin films.

J Phys Condens Matter 2022 Aug 4;34(41). Epub 2022 Aug 4.

Key Laboratory of Low Dimensional Materials and Application Technology, Xiangtan 411105, People's Republic of China.

In this paper, a phase-field model of Si-doped hafnium oxide-based ferroelectric thin films is established. And then, the synergistic effect of Si concentration and distribution on ferroelectric properties optimization of Si:HfOferroelectric thin films is studied with the proposed model. It is found that no matter how Si dopant is distributed in the film, the volume fraction of the ferroelectric phase in the film increases first and then decreases with the increase of Si concentration. However, compared with the uniform distribution, the layered distribution is more likely to great improve ferrelectric properties. When Si dopant is uniformly distributed in the film, the highest remanent polarization value that the film can obtain via Si concentration modulation is 38.7C cm, and the corresponding Si concentration is 3.8 cat%, which is consistent with the experimental results. When Si dopant is layered in the film, and the concentration difference between the Si-rich and Si-poor layers is 7.6%, in the Si concentration range of 3.6 cat%-3.8 cat%, the residual polarization of the film reaches 46.4-46.8C cm, which is 20% higher than that when Si dopant are evenly distributed in the film. The above results show that selecting the Si layered distribution mode and controlling the concentration difference between Si-rich and Si-poor layers in an appropriate range can greatly improve the films' ferroelectric properties and broaden the Si concentration optimization range of the ferroelectric properties of the films. The result provides further theoretical guidance on using Si doping to adjust the ferroelectric properties of hafnium oxide-based films.
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http://dx.doi.org/10.1088/1361-648X/ac8513DOI Listing
August 2022

Genome-wide SNPs of vegetable leafminer, : Insights into the recent Australian invasion.

Evol Appl 2022 Jul 28;15(7):1129-1140. Epub 2022 Jun 28.

Bio21 Institute, School of BioSciences The University of Melbourne Parkville Victoria Australia.

, the vegetable leafminer, is an important agricultural pest originally from the Americas, which has now colonized all continents except Antarctica. In 2015, arrived on the Australian mainland and established on the Cape York Peninsula in the northeast of the country near the Torres Strait, which provides a possible pathway for pests to enter Australia and evade biosecurity efforts. Here, we assessed genetic variation in based on genome-wide single nucleotide polymorphisms (SNPs) generated by double digest restriction-site-associated DNA sequencing (ddRAD-seq), aiming to uncover the potential origin(s) of this pest in Australia and contribute to reconstructing its global invasion history. Our fineRADstructure results and principal component analysis suggest Australian mainland populations were genetically close to populations from the Torres Strait, whereas populations from Asia, Africa, and Papua New Guinea (PNG) were more distantly related. Hawaiian populations were genetically distinct from all other populations of included in our study. Admixture analyses further revealed that from the Torres Strait may have genetic variation originating from multiple sources including Indonesia and PNG, and which has now spread to the Australian mainland. The lineages from Asia and Africa appear closely related. Isolation-by-distance (IBD) was found at a broad global scale, but not within small regions, suggesting that human-mediated factors likely contribute to the local spread of this pest. Overall, our findings suggest that an exotic pest invaded Australia through the Indo-Papuan conduit, highlighting the importance of biosecurity programs aimed at restricting the movement of pests and diseases through this corridor.
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http://dx.doi.org/10.1111/eva.13430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9309458PMC
July 2022

Canalplasty using underwater bone drilling in transcanal endoscopic myringoplasty for patients with a narrow external auditory canal.

Acta Otolaryngol 2022 Jul 27:1-6. Epub 2022 Jul 27.

Department of Otorhinolaryngology, Head and Neck Surgery, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen, P. R. China.

Background: Canalplasty is important in microscopic ear surgery, but it has rarely been studied in otoendoscopic surgery.

Objectives: The aim of this study was to investigate the application of canalplasty due to external auditory canal stenosis caused by bony bulges in endoscopic myringoplasty.

Materials And Methods: The procedures and effects of canalplasties and myringoplasties were analysed. During the canalplasties, depending on the location of the bulges, the meatal skin flaps were elevated in different manners, and the underwater bone drilling technique was adopted to remove the bulges to enlarge the osseous canals.

Results: Canalplasties were performed in 18.5% (33/178) of myringoplasties. All surgeries were completed exclusively via the transcanal endoscopic approach. No iatrogenic injuries were found. Most of the canalplasties required drilling off bulges on multiple walls. The mean total duration of the canalplasties and myringoplasties was 76.6 ± 4.5 min, and the proportion of time required for the canalplasties was 47.3 ± 2.4%.

Conclusion: Only approximately one in five endoscopic myringoplasties require antecedent canalplasties due to concurrent canal stenosis. With the underwater bone drilling technique, transcanal endoscopic canalplasty can be safely and efficiently conducted.
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http://dx.doi.org/10.1080/00016489.2022.2099014DOI Listing
July 2022

Mapping the single-cell landscape of acral melanoma and analysis of the molecular regulatory network of the tumor microenvironments.

Elife 2022 Jul 27;11. Epub 2022 Jul 27.

Department of Dermatology, General Hospital of People's Liberation Army, Beijing, China.

Acral melanoma (AM) exhibits a high incidence in Asian patients with melanoma, and it is not well treated with immunotherapy. However, little attention has been paid to the characteristics of the immune microenvironment in AM. Therefore, in this study, we collected clinical samples from Chinese patients with AM and conducted single-cell RNA sequencing to analyze the heterogeneity of its tumour microenvironments (TMEs) and the molecular regulatory network . Our analysis revealed that genes, such as , , , and could drive the deregulation of various TME components. The molecular interaction relationships between TME cells, such as MIF-CD44 and TNFSF9-TNFRSF9, might be an attractive target for developing novel immunotherapeutic agents.
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http://dx.doi.org/10.7554/eLife.78616DOI Listing
July 2022

Polygenic resilience scores capture protective genetic effects for Alzheimer's disease.

Transl Psychiatry 2022 07 25;12(1):296. Epub 2022 Jul 25.

Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, UK.

Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer's disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast "resilient" unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.
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http://dx.doi.org/10.1038/s41398-022-02055-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9314356PMC
July 2022

BmMD-2A responds to 20-Hydroxyecdysone and regulates Bombyx mori silkworm innate immunity in larva-to-pupa metamorphose.

Insect Sci 2022 Jul 24. Epub 2022 Jul 24.

Guangdong Laboratory for Lingnan Modern Agriculture, Laboratory of Insect Molecular Biology and Biotechnology, Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.

20E-Hydroxyecdysone (20E) plays important roles in larval molting and metamorphosis in insects and is also involved in the insect innate immune response. Insect metamorphosis is a highly successful strategy for environmental adaptation and is the most vulnerable stage, during which the insect is susceptible to various pathogens. 20E regulates a series of antimicrobial peptides (AMPs) through the immunodeficiency (IMD) pathway activation in Drosophila, nevertheless, whether other immune pathways are involved in 20E-regulated insect immunity is unknown. Our previous studies showed that BmMD-2A is a member of the ML (MD-2-related lipid recognition) family of proteins that are involved in the Bombyx mori innate immunity Toll signaling pathway. In this study, we further demonstrated that BmMD-2A was also positively regulated by 20E, and the BmMD-2A neutralization experiment suggested that 20E activated some downstream immune effect factors, the AMP genes against E. coli and S. aureus, through the regulation of BmMD-2A in larval metamorphosis, implying that B. mori may use the Toll-ML signaling pathway to maintain the innate immune balance in the larval-pupal metamorphosis stage, which is a different innate immunity pathway regulated by 20E compared to the IMD pathway in Drosophila. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/1744-7917.13097DOI Listing
July 2022

Transcanal endoscopic treatment for congenital middle ear cholesteatoma in children.

Medicine (Baltimore) 2022 Jul 22;101(29):e29631. Epub 2022 Jul 22.

Department of Otolaryngology, Huazhong University of Science and Technology Union Shenzhen Hospital, Nanshan Hospital, Shenzhen, People's Republic of China.

To investigate the feasibility and efficacy of transcanal endoscopic treatment for congenital middle ear cholesteatoma in children. Eleven children diagnosed with congenital middle ear cholesteatoma, who underwent total ear endoscopic surgery under general anesthesia, were included from the Huazhong University of Science and Technology Union Shenzhen Hospital between January 2016 and December 2020. We retrospectively analyzed their operation process and surgical complications through the surgical video; moreover, we compared the pre- and postoperative hearing outcomes. One child underwent a planned second operation to reconstruct the ossicular chain. At 6 postoperative months, all 11 children underwent reexamination. There was no significant change and a significant decrease in the mean bone and air conduction hearing thresholds, respectively (P > .05 and P < .05); moreover, there was a significant reduction in the air-bone conduction difference (P < .05). Further, the air-bone conduction difference was reduced to >20 dB and >10 dB in 11 and 7 children, respectively. Follow-up of the children did not reveal sensorineural deafness, facial paralysis, and other serious complications; further, there were no cases of recurrence. Transcanal endoscopic treatment for congenital middle ear cholesteatoma in children is feasible, minimally invasive, and functional.
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http://dx.doi.org/10.1097/MD.0000000000029631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302349PMC
July 2022

Fungicides have transgenerational effects on Rhopalosiphum padi but not their endosymbionts.

Pest Manag Sci 2022 Jul 22. Epub 2022 Jul 22.

School of BioSciences, The University of Melbourne, Victoria, Australia.

Background: While several agricultural fungicides are known to directly affect invertebrate pests, including aphids, the mechanisms involved are often unknown. One hypothesis is that fungicides with antibacterial activity suppress bacterial endosymbionts present in aphids which are important for aphid survival. Endosymbiont-related effects are expected to be transgenerational, given that these bacteria are maternally inherited. Here, we test for these associations using three fungicides (chlorothalonil, pyraclostrobin and trifloxystrobin) against the bird cherry-oat aphid, Rhopalosiphum padi, using a microinjected strain that carried both the primary endosymbiont Buchnera and the secondary endosymbiont Rickettsiella.

Results: We show that the fungicide chlorothalonil did not cause an immediate effect on aphid survival, whereas both strobilurin fungicides (pyraclostrobin and trifloxystrobin) decreased survival after 48 h exposure. However, chlorothalonil substantially reduced the lifespan and fecundity of the F1 generation. Trifloxystrobin also reduced the lifespan and fecundity of F1 offspring, however, pyraclostrobin did not affect these traits. None of the fungicides consistently altered the density of Buchnera or Rickettsiella in whole aphids.

Conclusions: Our results suggest fungicides have sublethal impacts on R. padi that are not fully realized until the generation after exposure, and these sublethal impacts are not associated with the density of endosymbionts harbored by R. padi. However, we cannot rule out other effects of fungicides on endosymbionts that might influence fitness, like changes in their tissue distribution. We discuss these results within the context of fungicidal effects on aphid suppression across generations and point to potential field applications. © 2022 Society of Chemical Industry.
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http://dx.doi.org/10.1002/ps.7091DOI Listing
July 2022

Comparison of Slow and Forced Vital Capacity on Ability to Evaluate Respiratory Function in Bulbar-Involved Amyotrophic Lateral Sclerosis.

Front Neurol 2022 28;13:938256. Epub 2022 Jun 28.

Department of Neurology, Peking University Third Hospital, Beijing, China.

Background And Objective: The percent-predicted forced vital capacity (FVC%) in the pulmonary function test (PFT) is generally used to evaluate the respiratory function in amyotrophic lateral sclerosis (ALS). The slow vital capacity (SVC) is another method to evaluate the respiratory function. Some neurologists found that the FVC% was not reflective of respiratory symptoms and the percent-predicted SVC (SVC%) was found to be higher in some patients with bulbar-onset ALS. We aimed to compare the percent predicted SVC (SVC%) with FVC% in evaluating the respiratory function and investigate the associations between the associations between clinical characteristics and the difference between the SVC% and the FVC% (SVC%-FVC%) in bulbar-involved ALS patients.

Method: This prospective study included patients with bulbar-involved ALS who visited the Peking University Third Hospital between October 2020 and November 2021. They underwent comprehensive clinical assessments, including bulbar symptom assessments, revised ALS functional rating scale (ALSFRS-R), Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (Roads), and PFTs. The group differences were analyzed using parametric and non-parametric tests.

Results: A total of 59 participants were initially enrolled, and 51 of them were included in the final analysis. In patients with bulbar-involved ALS, the SVC% (73.82 ± 21.95%) was significantly higher ( = 0.013) than the FVC% (71.42 ± 23.15%). After controlling for other relevant variables, a partial correlation analysis showed a significant correlation (r = -0.352, = 0.041) between ALSFRS-R1 score and SVC%-FVC%.

Conclusion: Our prospective study found that the SVC% was significantly higher and more reflective of actual respiratory function than the FVC% in patients with bulbar-involved ALS. Furthermore, the severity of dysarthria was found to be positively correlated with SVC%-FVC%, providing a clinical marker for predicting SVC%-FVC%.
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http://dx.doi.org/10.3389/fneur.2022.938256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9275792PMC
June 2022

Erratum to "Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway".

Open Med (Wars) 2022 11;17(1):1065. Epub 2022 Jun 11.

Department of Gastroenterology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, No. 35 Jiefang Road, Hengyang City, 421001, Hunan Province, Hunan, China.

[This corrects the article DOI: 10.1515/med-2022-0453.].
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http://dx.doi.org/10.1515/med-2022-0501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9191560PMC
June 2022

Prophylactic interventions for preventing macular edema after cataract surgery in patients with diabetes: A Bayesian network meta-analysis of randomized controlled trials.

EClinicalMedicine 2022 Jul 20;49:101463. Epub 2022 May 20.

Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Medical Artificial Intelligence Research and Verification Key Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

Background: Diabetes significantly increases the risk of postoperative macular edema (PME) after cataract surgery, leading to potential worst post-operative outcomes. This study aims to compare the effect of different prophylactic interventions in improving postoperative anatomic and visual acuity outcomes of diabetes patients who underwent cataract surgery.

Methods: We searched MEDLINE, Embase, Web of Science databases from inception until February 2nd, 2022, for studies including studies reporting PME events and/or best-corrected visual acuity (BCVA) outcomes. Random-effects Bayesian network meta-analysis was performed to compare the efficiency of intravitreal anti-vascular endothelial growth factor injections (anti-VEGF), nonsteroidal anti-inflammatory drugs (NSAIDs) and topical steroids eye drop at 1 week, 1 month, 3 months, 6 months after cataract surgery.

Findings: The total of 2566 participants from 17 randomized controlled trials were included in the network meta-analysis, with moderate risk of bias and no evidence of publication of bias. Compared to placebo/steroid eye drop alone, patients received additional topical NSAIDs or intravitreal anti-VEGF injections had lower risk of PME at 1 month (NSAIDs: OR=0·221, 95% Confidence interval [CI], 0·044-0·755, =0·0%, 5 studies; anti-VEGF: OR=0·151, 95%CI, 0·037-0·413, =0·0%, 5 studies) and 3 month (NSAIDs: OR=0·370, 95%CI, 0·140-0·875, =0·0%, 8 studies; anti-VEGF: OR=0·203, 95%CI, 0·101-0·353, =0·0%, 4 studies) after cataract surgery. Further, additional anti-VEGF exhibited better BCVA outcome at 1 month (mean difference of LogMAR: -0·083, 95%CI, -0·17 to -0·014, =62·0%, 5 studies), and 3 months (mean difference of LogMAR: -0·061, 95%CI, -0·11 to -0·011, =0·0%, 5 studies) after cataract surgery. Such additional benefits did not reach statistic significant at 6 months after surgery.

Interpretation: Our data suggests that compared to placebo/steroid eye drop alone, additional prophylactic anti-VEGF intervention could be considered for preventing the occurrence of PME after cataract surgery in patients with diabetes.

Funding: Research and Development of Special (2020-1-2052); Science & Technology Project of Beijing Municipal Science & Technology Commission (Z201100005520045, Z181100001818003).
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http://dx.doi.org/10.1016/j.eclinm.2022.101463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124709PMC
July 2022

Ferulic Acid Prevents Nonalcoholic Fatty Liver Disease by Promoting Fatty Acid Oxidation and Energy Expenditure in C57BL/6 Mice Fed a High-Fat Diet.

Nutrients 2022 Jun 18;14(12). Epub 2022 Jun 18.

College of Food Science and Engineering, Northwest A&F University, Yangling, Xianyang 712100, China.

There is a consensus that ferulic acid (FA), the most prominent phenolic acid in whole grains, displays a protective effect in non-alcoholic fatty liver disease (NAFLD), though its underlying mechanism not fully elucidated. This study aimed to investigate the protective effect of FA on high-fat diet (HFD)-induced NAFLD in mice and its potential mechanism. C57BL/6 mice were divided into the control diet (CON) group, the HFD group, and the treatment (HFD+FA) group, fed with an HFD and FA (100 mg/kg/day) by oral gavage for 12 weeks. Hematoxylin and eosin (H&E) staining and Oil Red O staining were used to evaluate liver tissue pathological changes and lipid accumulation respectively. It was demonstrated that FA supplementation prevented HFD-induced NAFLD, which was evidenced by the decreased accumulation of lipid and hepatic steatosis in the HFD+FA group. Specifically, FA supplementation decreased hepatic triacylglycerol (TG) content by 33.5% ( < 0.01). Metabolic cage studies reveal that FA-treated mice have elevated energy expenditure by 11.5% during dark phases. Mechanistically, FA treatment increases the expression of rate-limiting enzymes of fatty acid oxidation and ketone body biosynthesis CPT1A, ACOX1 and HMGCS2, which are the peroxisome proliferator-activated receptors α (PPARα) targets in liver. In conclusion, FA could effectively prevent HFD-induced NAFLD possibly by activating PPARα to increase energy expenditure and decrease the accumulation of triacylglycerol in the liver.
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http://dx.doi.org/10.3390/nu14122530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230086PMC
June 2022

Long noncoding RNA PVT1 accelerates the growth of placental trophoblasts in preeclampsia through the microRNA-24-3p/HSD11B2 axis.

Mol Reprod Dev 2022 07 23;89(7):271-280. Epub 2022 Jun 23.

Department of Obstetrics, Hubei Maternal and Child Health Hospital, Wuhan, Hubei, China.

Long noncoding RNA plasmacytoma variant translocation 1 (PVT1) is essential for the maintenance of normal functions of trophoblasts in preeclampsia (PE). This study aims to decipher the concrete mechanism of PVT1 with the microRNA-24-3p/Type-2 11β-hydroxysteroid dehydrogenase (miR-24-3p/HSD11B2) axis in PE. PVT1, miR-24-3p, and HSD11B2 expression levels in normal placental tissues and PE placental tissues were defined. HTR-8/SVneo cells were transfected to determine the effects of PVT1, miR-24-3p, and HSD11B2 on the growth of HTR-8/SVneo cells. The relationships among PVT1/miR-24-3p/HSD11B2 in HTR-8/SVneo cells were identified. PVT1 and HSD11B2 were downregulated, while miR-24-3p was upregulated in the placenta of PE. Upregulated/downregulated PVT1 promoted/impeded the growth of human placental trophoblast (HTR-8/SVneo) cells in PE. Restored/knocked down miR-24-3p impeded/enhanced the growth of HTR-8/SVneo cells in PE. PVT1 inhibited miR-24-3p to mediate HSD11B2. PVT1 sponges miR-24-3p to regulate HSD11B2; thereby, the growth of placental trophoblasts is promoted in PE.
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http://dx.doi.org/10.1002/mrd.23575DOI Listing
July 2022

Effects of monthly evaluations on the rates of irrational antimicrobial prescription in the outpatient and emergency departments at Ningbo No. 6 Hospital, Ningbo, China.

Eur J Med Res 2022 Jun 22;27(1):98. Epub 2022 Jun 22.

Department of Pharmacy, Ningbo No. 6 Hospital, Ningbo, China.

Background: Antibiotic resistance is a major global public health problem. The primary cause of antibiotic resistance is inappropriate antibiotic use. In this study, we aimed to verify whether the monthly evaluation of antibiotic prescription improves clinical antibiotic use in outpatient and emergency departments.

Methods: A minimum of 25% of the prescriptions for antibacterial drugs were randomly selected at the outpatient and emergency departments to enter the monthly evaluation system from July 2016 to June 2019. We analysed the rate of irrational prescription of antibiotics, proportion of the use of antibiotics, and consistency between the evaluation and expert groups after implementing the monthly assessment to validate the role of monthly evaluations.

Results: After 3 years of monthly evaluations of antibiotic prescriptions, the utilisation rate of single antibiotics in the outpatient and emergency departments was found to increase each year. Each year, a decreasing trend was observed for the irrational use of antibiotics, whereas the proportion of antibiotics to the total drugs prescribed gradually decreased in the same period. In addition, the consistency of prescription evaluation results between the evaluation and expert groups increased continuously.

Conclusions: Monthly evaluation of antibiotic prescriptions is an effective management tool for the rational use of antibiotics in clinical practice. This practice could help reduce the combinative use of antibiotics, rate of irrational antibiotic prescription, and antibiotic use ratio, and play an important role in safe clinical drug use.
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http://dx.doi.org/10.1186/s40001-022-00728-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214680PMC
June 2022

Identification of high ecological risk areas with naturally high background value of soil Cd related to carbonate rocks.

Environ Geochem Health 2022 Jun 20. Epub 2022 Jun 20.

Guangxi Institute of Geological Survey, Nanning, 530023, People's Republic of China.

The characteristics of high concentrations or high activity levels of heavy metals, especially Cd, in soils caused by the pedogenesis of rocks are attracting increased attention. Carbonate rocks and black shales often coexist during geological deposition, but the risk characteristics of heavy metals are different after their weathering into the soil. The purpose of this study was to investigate the element concentrations of a naturally high background value area, to identify patterns of different risk areas, and to make recommendations for the safe usage of farmland. The results showed that, compared with the soil in the carbonate rock area, the soil in the black shale area was more acidified and most of the heavy metal elements were leached. Based on the soil pH value and the heavy metal concentrations, an identification method for land risk areas within naturally high background values was established, and land planning was carried out using this method. The exceeding rates of Cd in rice for the preferential protection area and strict control area were 0.0 and 50.0%, respectively. Therefore, in naturally high background area, the identified lithology can apply to maximize the use of farmland resources. This method provides a basis for preliminary ecological risk screening in naturally high background value areas using the results of the soil survey. A suggestion for the prevention and control of soil pollution in areas with naturally high background values was put forward. In carbonate rock areas, the soil should be closely monitored to prevent soil acidification.
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http://dx.doi.org/10.1007/s10653-022-01308-7DOI Listing
June 2022

Imbalance between the caudate and putamen connectivity in obsessive-compulsive disorder.

Neuroimage Clin 2022 Jun 14;35:103083. Epub 2022 Jun 14.

Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; School of Psychology, Center for Studies of Psychological Application, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, 510631 Guangzhou, China. Electronic address:

Background: Compulsive behaviors in obsessive-compulsive disorder (OCD) have been suggested to result from an imbalance in cortico-striatal connectivity. However, the nature of this impairment, the relative involvement of different striatal areas, their imbalance in genetically related but unimpaired individuals, and their relationship with cognitive dysfunction in OCD patients, remain unknown.

Methods: In the current study, striatal (i.e., caudate and putamen) whole-brain connectivity was computed in a sample of OCD patients (OCD, n = 62), unaffected first-degree relatives (UFDR, n = 53) and healthy controls (HC, n = 73) by ROI-based resting-state functional magnetic resonance imaging (rs-fMRI). A behavioral task switch paradigm outside of the scanner was also performed to measure cognitive flexibility in OCD patients.

Results: There were significantly increased strengths (Z-transformed Pearson correlation coefficient) in caudate connectivity in OCD patients. A significant correlation between the two types of connectivity strengths in the relevant regions was observed only in the OCD patient group. Furthermore, the caudate connectivity of patients was negatively associated with their task-switch performance.

Conclusions: The imbalance between the caudate and putamen connectivity, arising from the abnormal increase of caudate activity, may serve as a clinical characteristic for obsessive-compulsive disorder.
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http://dx.doi.org/10.1016/j.nicl.2022.103083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213242PMC
June 2022

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.

Kidney Int 2022 Jun 16. Epub 2022 Jun 16.

The George Institute for Global Health, University of New South Wales, Sydney, Australia.

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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http://dx.doi.org/10.1016/j.kint.2022.05.021DOI Listing
June 2022

Rare and Common Variants in in Chinese Patients With Intracerebral Hemorrhage.

Front Neurol 2022 27;13:827165. Epub 2022 May 27.

Department of Neurology, Peking University Third Hospital, Beijing, China.

Here, we screened the variants in Chinese intracerebral hemorrhage (ICH) patients to summarize the relationship between the variants and clinical characteristics. Targeted sequencing of a 65-gene panel including was performed to detect all the coding regions and ±10-bp splicing sites. In total, 568 patients were included. Regarding rare nonsynonymous variants with a minor allele frequency (MAF) <0.5%, 6 missense variants and five suspicious splice site variants, absent in 573 healthy controls, were found in 11 patients. The subgroup carrying rare variants did not show specific phenotype compared with non-variant carriers. For the single nucleotide polymorphism (SNP) loci with an MAF> 5%, we did not find a significant association between the allele or genotype distribution of the SNP loci and the risk of ICH. Rs3742207 was nominally associated with death at 1-year follow-up ( = 0.02027, OR 1.857, 95% CI 1.101-3.133) after adjusted by age, hypertension history, hematoma volume and recurrent ICH history. Nevertheless, after the Bonferroni correction, the association was no longer significant. In conclusion, rare nonsynonymous variants in were identified in 1.94% (11/568) of Chinese ICH patients, while rs3742207 maybe indicate a worse prognosis of ICH.
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http://dx.doi.org/10.3389/fneur.2022.827165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9196627PMC
May 2022

D--Inositol facilitates adiponectin biosynthesis and activates the AMPKα/PPARs pathway to inhibit high-fat diet-induced obesity and liver lipid deposition.

Food Funct 2022 Jul 4;13(13):7192-7203. Epub 2022 Jul 4.

College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi 712100, People's Republic of China.

D--Inositol (DCI) is a natural cyclohexanol isomer that widely exists in all living beings, which can effectively prevent glucose and lipid metabolism disorders in mammals. This study revealed the DCI elevated adiponectin levels to reduce obesity and hepatic lipid deposition in high-fat diet (HFD) fed mice. Twelve weeks of DCI supplementation (50 and 100 mg per kg body weight per day) lowered body weight and serum triglyceride, total cholesterol, insulin, and fasting glucose levels. Histopathology analysis revealed that DCI inhibited hepatic steatosis and adipocyte expansion. Remarkably, DCI significantly increased serum adiponectin levels and upgraded the expressions of adiponectin receptors (AdipoR1 and AdipoR2) in the liver. The results of western blot and qRT-PCR showed that DCI impeded the inhibitory effect of HFD on liver AMPKα and PPARs activities through activating AdipoRs and regulated downstream fatty acid metabolism. In addition, we analyzed the concentration difference of DCI in mouse liver and adipose tissue by the HRLC-MS/MS technology, indicating the preference of DCI in different tissues. Therefore, DCI relieved liver lipid deposition and hyperlipidemia potentially by promoting adiponectin synthesis in white adipose tissue and activating the AdipoR-AMPKα/PPARs pathway in the liver.
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http://dx.doi.org/10.1039/d2fo00869fDOI Listing
July 2022

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.

Commun Biol 2022 Jun 13;5(1):580. Epub 2022 Jun 13.

Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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http://dx.doi.org/10.1038/s42003-022-03448-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9192715PMC
June 2022

SAPHO Syndrome Complicated by Ankylosing Spondylitis Successfully Treated With Tofacitinib: A Case Report.

Front Immunol 2022 25;13:911922. Epub 2022 May 25.

Department of Pharmacy, Ningbo No. 6 Hospital, Ningbo, China.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, a type of chronic inflammatory disease, is rare and difficult to treat. Osteoarthropathy with skin involvement is the primary clinical manifestation of SAPHO syndrome. The unknown pathogenesis of SAPHO syndrome is speculated to be related to individual genetic differences, immune levels, microorganisms, and environmental factors. Tofacitinib, a novel small-molecule Janus kinase (JAK) inhibitor, has been used to treat rheumatoid arthritis. However, it also has great potential for the treatment of other immune diseases, including SAPHO syndrome. A 36-year-old man with chest and back pain for more than two months was admitted to our hospital. After admission, the patient developed a pustular rash and enteritis. SAPHO syndrome was diagnosed based on the above clinical manifestations, computed tomography (CT), and bone scintigraphy findings. Notably, the patient also had ankylosing spondylitis. Tofacitinib significantly improved the patient's skin symptoms while preventing worsening of chest and back pain when adalimumab was discontinued. We report the first case of ankylosing spondylitis with SAPHO syndrome. In addition, it is also the first successful treatment thereof with tofacitinib. We hope to provide valuable information regarding the pathogenesis and treatment of SAPHO syndrome in this case.
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http://dx.doi.org/10.3389/fimmu.2022.911922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174507PMC
June 2022

SNHG22 promotes migration and invasion of trophoblasts via miR-128-3p/PCDH11X axis and activates PI3K/Akt signaling pathway.

Clinics (Sao Paulo) 2022 6;77:100055. Epub 2022 Jun 6.

Department of Obstetrics, Maternal and Child Health Hospital of Hubei Province, Wuhan, Hubei, China. Electronic address:

Objectives: Long non-coding RNAs (LncRNAs) act as an indispensable role in the Preeclampsia (PE)-related trophoblast function, while its relationship with Small Nucleolar RNA Host Gene 22 (SNHG22) remains unknown. Hence, this study aimed to investigate the roles of lncRNA SNHG22 in the Preeclampsia (PE)-related trophoblasts function and the underlying mechanism.

Method: Normal placentas and placentas from PE patients were collected to detect the expression of lncRNA SNHG22. Then, trophoblasts HTR-8/Svneo and JEG-3 were purchased, cultured, and treated to investigate the roles of lncRNA SNHG22 on cell migration and invasion as well as its underlying regulatory mechanism.

Results: The SNHG22 was downregulated in PE patients, and it was found that SNHG22 overexpression could drive migration and invasion of trophoblasts, while SNHG22 depletion exerted a suppressive effect. Mechanistically, SNHG22 was validated to regulate microRNA-128-3p (miR-128-3p), and Protocadherin 11 X-Linked (PCDH11X) was identified as the target gene of miR-128-3p. Furthermore, it was found that SNHG22 acted as a promoter in the migration and invasion of trophoblast cells in a miR-128-3p/PCDH11X dependent manner, and SNHG22 silencing weakened the activation of PCDH11X-mediated PI3K/Akt signaling pathways through inhibiting miR-128-3p, thereby preventing migration and invasion of trophoblasts.

Conclusion: SNHG22 acted as a driver in the migration and invasion of trophoblasts and may be considered a candidate for the amelioration of PE.
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http://dx.doi.org/10.1016/j.clinsp.2022.100055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188964PMC
June 2022

Lipids, Apolipoproteins, Statins, and Intracerebral Hemorrhage: A Mendelian Randomization Study.

Ann Neurol 2022 Jun 2. Epub 2022 Jun 2.

Department of Neurology, Peking, University Third Hospital, Beijing, China.

Objective: To investigate the causal role of lipid or apolipoprotein traits in intracerebral hemorrhage (ICH) and determine the effect of lipid-lowering interventions on the disease.

Methods: Two-sample Mendelian randomization (MR) analyses were conducted to evaluate the associations of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein (Apo)B and ApoA1 levels with risks for ICH, and those of LDL-C- (HMGCR, PCSK9, and NPC1L1) and TG-lowering targets (LPL and APOC3) with ICH.

Results: Increased levels of ApoB was associated with a decreased risk of overall ICH (OR 0.623, 95% CI 0.413-0.940; p = 0.024) and lobar ICH (OR 0.579, 95% CI 0.342-0.979; p = 0.042). The inverse relationship remained stable in multivariable MR. In addition, elevated TGs showed a causal effect on lobar ICH in multivariable MR (OR 1.600, 95% CI 1.009-2.537; p = 0.046). The LDL-C-reducing genetic variation alleles at or near the HMGCR gene (mimicking the effect of statins) were predicted to increase the overall and deep ICH risk. Additionally, genetic variation at or near the APOC3 gene suggested that genetically reducing the activity of APOC3 (mimicking antisense anti-apoC3 agents) was predicted to decrease lobar ICH.

Interpretation: Genetically predicted elevated ApoB may have a protective effect on overall ICH and lobar ICH, whereas elevated TG was associated with a higher risk of lobar ICH conditional on LDL-C and ApoB. MR analysis supports the conclusion that statins may increase the risk of overall and deep ICH independent of their lipid-lowering effect. More specific lipid-lowering targets may end up being the future. ANN NEUROL 2022.
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http://dx.doi.org/10.1002/ana.26426DOI Listing
June 2022

Advances in Research on Antiviral Activities of Sulfated Polysaccharides from Seaweeds.

Pharmaceuticals (Basel) 2022 May 6;15(5). Epub 2022 May 6.

Marine College, Shandong University, Weihai 264209, China.

In recent years, various viral diseases have suddenly erupted, resulting in widespread infection and death. A variety of biological activities from marine natural products have gradually attracted the attention of people. Seaweeds have a wide range of sources, huge output, and high economic benefits. This is very promising in the pharmaceutical industry. In particular, sulfated polysaccharides derived from seaweeds, considered a potential source of bioactive compounds for drug development, have shown antiviral activity against a broad spectrum of viruses, mainly including common DNA viruses and RNA viruses. In addition, sulfated polysaccharides can also improve the body's immunity. This review focuses on recent advances in antiviral research on the sulfated polysaccharides from seaweeds, including carrageenan, galactan, fucoidan, alginate, ulvan, p-KG03, naviculan, and calcium spirulan. We hope that this review will provide new ideas for the development of COVID-19 therapeutics and vaccines.
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http://dx.doi.org/10.3390/ph15050581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9147703PMC
May 2022

Fluorescent Labeling of Polymannuronic Acid and Its Distribution in Mice by Tail Vein Injection.

Mar Drugs 2022 Apr 25;20(5). Epub 2022 Apr 25.

Marine College, Shandong University, Weihai 264209, China.

Polymannuronic acid (PM) possesses more pharmacological activities than sodium alginate, but there have been few studies on its absorption mechanism, tissue distribution, and pharmacokinetics. Studies of pharmacokinetics and tissue distribution are necessary to elucidate the pharmacological effects of PM. Thus, we used fluorescein isothiocyanate (FITC) to produce fluorescently labeled PM (FITC-PM) and detected the distribution and pharmacokinetics of PM in vivo via tail vein injection. The results demonstrate that the FITC-PM showed high stability in different pH solutions. After the tail vein injection, FITC-PM tended to be distributed in the kidney, followed by the liver and in the heart, spleen, and lungs at lower concentrations. Pharmacokinetic analysis showed that the elimination rate constant of FITC-PM was 0.24, the half-life time was 2.85 h, the peak concentration was 235.17 μg/mL, the area under the curve was 631.48 μg/mL·h, the area under the curve by statistical moment was 1843.15 μg/mL·h, the mean residence time was 2.92 h, and the clearance rate was 79.18 mL/h. These results indicate that FITC-PM could be used for PM distribution and pharmacokinetic studies, and the studies of pharmacokinetics and tissue distribution provided basic information that can be used to further clarify PM pharmacodynamic mechanisms.
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http://dx.doi.org/10.3390/md20050289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9145981PMC
April 2022

Study on the regulatory effect of leech peptide HE-D on macrophages in atherosclerosis by transcriptome sequencing.

J Ethnopharmacol 2022 Aug 16;294:115380. Epub 2022 May 16.

Marine College, Shandong University, Weihai, 264209, China; Shandong University Weihai Research Institute of Industrial Technology, Weihai, 264209, China. Electronic address:

Ethnopharmacological Relevance: The incidence of atherosclerotic cardiovascular disease is a serious threat to human health. Leeches are used in traditional Chinese medicine to treat cardiovascular diseases. HE-D is an active peptide extracted and isolated from leeches, which can inhibit the migration of RAW264.7 macrophages.

Aim: This study shows the effects of HE-D on macrophages in atherosclerosis and the mechanism of inhibition on the migration of macrophages based on transcriptome sequencing (RNA-Seq).

Materials And Methods: The transwell method was used to detect the activity of HE-D in inhibiting the migration of macrophages. Macrophages were divided into control group, lipopolysaccharide group, and HE-D group. Samples were collected and RNA-Seq performed. The DEseq2 method detected significantly differentially expressed genes (DEGs), GO and KEGG Pathway databases were used to analyze the functions and pathway enrichment of DEGs. Finally, qRT-PCR and Western blotting were used to verify the genes screened by RNA-Seq analyses.

Results: Cell experiments showed that HE-D can inhibit the migration of RAW264.7 macrophages induced by LPS. DEseq2 analyses showed that there were 363 DEGs after HE-D administration in the result of RNA-Seq. The GO function of DEGs was significantly enriched in cell migration and inflammation, and the DEGs related to cell migration were significantly enriched in the NF-κB signaling pathway. qRT-PCR and Western blot analyses, showed that when compared with the LPS group, the related genes IKKα, IKKγ, TRAF6, TLR4, and TRAF5 in the NF-κB pathway were significantly down-regulated in the HE-D group. In addition, it was found that the inflammatory factors iNOS and TNF-α were significantly down-regulated, and Arg-1 and IL-10 were up-regulated.

Conclusion: HE-D can inhibit the migration of macrophages by inhibiting IKKα and IKKγ in the NF-κB signaling pathway, and promote the transformation of macrophages from M1to M2 subtypes. Therefore, HE-D can potentially be used as a drug for the treatment of atherosclerosis.
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http://dx.doi.org/10.1016/j.jep.2022.115380DOI Listing
August 2022

Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate.

Brain 2022 06;145(6):1992-2007

University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, Team ELEANOR, UMR 1219, F-33000 Bordeaux, France.

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.
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http://dx.doi.org/10.1093/brain/awab432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255380PMC
June 2022
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