Publications by authors named "Jian Shi"

731 Publications

Correction to Modulating Mechanical Properties of Collagen-Lignin Composites.

ACS Appl Bio Mater 2021 Jun 13;4(6):5391. Epub 2021 May 13.

Biological and Agricultural Engineering, Louisiana State University, 149 E.B. Doran Hall, Baton Rouge, Louisiana 70803, United States.

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http://dx.doi.org/10.1021/acsabm.1c00491DOI Listing
June 2021

3D Printing Improve the Effectiveness of Fracture Teaching and Medical Learning: A Comprehensive Scientometric Assessment and Future Perspectives.

Front Physiol 2021 24;12:726591. Epub 2021 Dec 24.

Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China.

Fractures of complex body parts are often serious and difficult to handle, and they have high technical and training requirements. However, the realistic situation is that there are few opportunities for the junior residents, trainee doctors, and especially medical students to contact enough clinical practice and see such fracture patients. Fortunately, with the rapid development and continuous progress of 3D printing and related technologies, this situation has gradually gotten better and better. In this research, we confirmed that 3D printing technology could improve the effectiveness of fracture teaching and medical learning from multiple dimensions. We comprehensively screened and assessed 223 papers from the Web of Science (WoS) Core Collection on October 3, 2021, with "((3D) AND ((printing) OR (printed)) AND (fracture)) AND ((education) OR (training) OR (teaching))" as the retrieval strategy. Additionally, we used the VOSviewer software to analyze the keywords and countries and the organizations of the publications, then a series of scientometric and visualized analyses were made based on the retrieval results. Afterward, multiple databases were retrieved according to our selection criteria, we selected eight studies for the extensive literature analysis. The extracted data contained information of authors, problems solved, participants, methods, assessments, results, and benefits/limitations. These intuitive and in-depth analyses further confirmed and appraised the advantages of 3D printing in complex fracture models more objectively. In conclusion, 3D printing could improve the effectiveness and extension of fracture teaching, as well as medical learning, by providing the powerful interaction with 3D effect, wakening students learning interest, and allowing the junior residents, trainee doctors to have as realistic a virtual practice experience as possible. Through this research, it is expected that more researchers could be attracted to conduct more comprehensive and thorough studies on the application of 3D printing for training and educational propose, to promote the development of 3D technology-based medical education practice and further deepen the reform of medical education and improve the quality of fracture education and learning.
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http://dx.doi.org/10.3389/fphys.2021.726591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740219PMC
December 2021

GM-CSF impairs erythropoiesis by disrupting erythroblastic island formation via macrophages.

J Transl Med 2022 Jan 3;20(1):11. Epub 2022 Jan 3.

Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.

Anemia is a significant complication of chronic inflammation and may be related to dysregulated activities among erythroblastic island (EBI) macrophages. GM-CSF was reported to be upregulated and attracted as a therapeutic target in many inflammatory diseases. Among EBIs, we found that the GM-CSF receptor is preferentially and highly expressed among EBI macrophages but not among erythroblasts. GM-CSF treatment significantly decreases human EBI formation in vitro by decreasing the adhesion molecule expression of CD163. RNA-sequence analysis suggests that GM-CSF treatment impairs the supporting function of human EBI macrophages during erythropoiesis. GM-CSF treatment also polarizes human EBI macrophages from M2-like type to M1-like type. In addition, GM-CSF decreases mouse bone marrow (BM) erythroblasts as well as EBI macrophages, leading to a reduction in EBI numbers. In defining the molecular mechanism at work, we found that GM-CSF treatment significantly decreases the adhesion molecule expression of CD163 and Vcam1 in vivo. Importantly, GM-CSF treatment also decreases the phagocytosis rate of EBI macrophages in mouse BM as well as decreases the expression of the engulfment-related molecules Mertk, Axl, and Timd4. In addition, GM-CSF treatment polarizes mouse BM EBI macrophages from M2-like type to M1-like type. Thus, we document that GM-CSF impairs EBI formation in mice and humans. Our findings support that targeting GM-CSF or reprogramming EBI macrophages might be a novel strategy to treat anemia resulting from inflammatory diseases.
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http://dx.doi.org/10.1186/s12967-021-03214-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721478PMC
January 2022

Quantitative Analysis and Visualization of the Interaction Between Intestinal Microbiota and Type 1 Diabetes in Children Based on Multi-Databases.

Front Pediatr 2021 15;9:752250. Epub 2021 Dec 15.

Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.

As an important autoimmune disease, type 1 diabetes (T1D) is often diagnosed in children, but due to the complexity of the etiology of diabetes and many other factors, the disease pathogenesis of diabetes is still unclear. The intestinal microbiota has been proved to have close relationships with T1D in recent years, which is one of the most important molecular bases of pathogenesis and prognosis factors for T1D. Using the multi-omics and multicenter sample analysis method, a number of intestinal microbiota in T1D have been discovered and explained, which has provided comprehensive and rich information. However, how to find more useful information and get an intuitive understanding that people need conveniently in the huge data sea has become the focus of attention. Therefore, quantitative analysis and visualization of the interaction between intestinal microbiota and T1D in children are urgently needed. We retrieved the detailed original data from the National Center for Biotechnology Information, GMREPO, and gutMEGA databases and other authoritative multiple projects with related research; the ranking of intestinal microbiota abundance from healthy people, overall T1D patients, and T1D in children (0-18 years old) were detailed analyzed, classified, and visualized. A total of 515 bacterial species and 161 related genera were fully analyzed. Also, was led by 21.25% average abundance, followed by of 10.39% in all-cross T1D patients. For children with T1D, has high abundance in all age periods, whereas the abundance of each intestinal microbiota was more uniform in female samples, with the ranking from high to low as 9.56%, 9.53%, 8.15%, and 7.53%, whereas in male samples, was accounted for the largest by 22.72%. The interaction between intestinal microbiota and comparison between healthy people and children with T1D was also detailed analyzed. This study provides a new method and comprehensive perspectives for the evaluation of the interaction between intestinal microbiota and T1D in children. A set of useful information of intestinal microbiota with its internal interaction and connections has been presented, which could be a compact, immediate, and practical scientific reference for further molecular biological and clinical translational research of T1D in children.
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http://dx.doi.org/10.3389/fped.2021.752250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8715853PMC
December 2021

Effects of Overexpression of Fibroblast Growth Factor 15/19 on Hepatic Drug Metabolizing Enzymes.

Drug Metab Dispos 2021 Dec 29. Epub 2021 Dec 29.

Pharmacology and Toxicology, Rutgers University, United States

Fibroblast growth factor 15/19 (FGF15/19) are endocrine growth factors that play an important role in bile acid homeostasis. FGF15/19 based therapies are currently being tested in clinical trials for the treatment of non-alcoholic steatohepatitis and cholestatic liver diseases. To determine the physiological impact of long-term elevations of FGF15/19, we developed a transgenic mouse model to overexpress ( Tg). In the current study, RNA-seq analysis revealed elevations of the expression of several genes encoding phase I drug metabolizing enzymes, including and , in Tg mice. We found that the induction of several isoforms resulted in increased function of CYP2B in microsomal metabolism and pharmacokinetics studies. Because CYP2B family is known to be induced by constitutive androstane receptor (CAR), to determine the role of CAR in the observed inductions, we crossed Tg mice with CAR knockout mice and found that CAR played a minor role in the observed alterations in drug metabolizing enzyme expression. Interestingly, we found that the overexpression of resulted in a phenotypical switch from a male hepatic expression pattern of drug metabolizing enzymes in wild type mice to a female expression pattern in Tg mice. Growth hormone differences between males and females is known to drive sexually dimorphic expression patterns in the livers of rodents in a STAT5b dependent manner. We found that male Tg mice presented with many features similar to wild type female mice, including lowered body length and weight, and expression, and STAT5 signaling. The overexpression of in mice causes an alteration in DMEs at the mRNA, protein, and functional levels, which is not entirely due to CAR activation but associated with lower GH signaling.
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http://dx.doi.org/10.1124/dmd.121.000416DOI Listing
December 2021

Generation of an induced pluripotent stem cell line (SYSUi005-A) from a patient with hypertrophic cardiomyopathy.

Stem Cell Res 2022 Jan 13;58:102626. Epub 2021 Dec 13.

Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China. Electronic address:

Hypertrophic cardiomyopathy (HCM) is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. Here, we reprogrammed peripheral blood mononuclear cells (PBMCs) isolated from peripheral blood of a patient who suffered from hypertrophic cardiomyopathy, into pluripotent stem cells (iPSC) (SYSUi005-A) using Sendai-virus. The established hiPSC line displayed a normal 46XY karyotype, showing strong expression of pluripotency markers and differentiation potential. This cell line may represent a valuable tool for investigating the pathogenesis and therapeutic strategies of HCM.
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http://dx.doi.org/10.1016/j.scr.2021.102626DOI Listing
January 2022

Poly(-phenylglycine)/MoS Nanohybrid with Synergistic Solar-Thermal Conversion for Efficient Water Purification and Thermoelectric Power Generation.

ACS Appl Mater Interfaces 2022 Jan 22;14(1):1034-1044. Epub 2021 Dec 22.

Faculty of Systems Science and Technology, Akita Prefectural University, 84-4 Aza Ebinokuchi, Tsuchiya, Yurihonjo, Akita 015-0055, Japan.

Solar interfacial evaporation is an emerging technology in solar energy harvesting developed to remedy the global energy crisis and the lack of freshwater resources. However, developing fully enhanced thermal management to optimize solar-heat utilization efficiency and form remains a great challenge. We created a synergistic photothermal layer from a poly(-phenylglycine) (PNPG)/MoS nanohybrid via electrostatic-induced self-assembly for a broad-spectrum and efficient solar absorption. The PNPG/MoS system provided effective synergistic photothermal conversion and good water transmission, enabling rapid solar steam escape. Notably, synergistic coupling of solar evaporation-thermoelectric (TE) power generation was also achieved, providing more efficient exploitation of solar heat. The system demonstrated a solar evaporation rate of up to 1.70 kg m h and achieved a maximum thermoelectric output power with 0.23 W m under one sun. The high-performance PNPG/MoS synergistic photothermal system developed in this study offers potential opportunities for coupling solar water purification with thermoelectric power generation to meet the needs of resource-scarce areas.
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http://dx.doi.org/10.1021/acsami.1c20393DOI Listing
January 2022

Generation of Alveolar Epithelium Using Reconstituted Basement Membrane and hiPSC-Derived Organoids.

Adv Healthc Mater 2021 Dec 22:e2101972. Epub 2021 Dec 22.

École Normale Supérieure-PSL Research University, Sorbonne Universités - UPMC Univ Paris 06, CNRS UMR 8640 PASTEUR, 24, rue Lhomond, Paris, 75005, France.

In vitro modeling of alveolar epithelium needs to recapitulate features of both cellular and noncellular components of the lung tissues. Herein, a method is presented to generate alveolar epithelium by using human induced pluripotent stem cells (hiPSCs) and reconstituted or artificial basement membrane (ABM). The ABM is obtained by self-assembling type IV collagen and laminin with a monolayer of crosslinked gelatin nanofibers as backbone and a patterned honeycomb microframe for handling. Alveolar organoids are obtained from hiPSCs and then dissociated into single cells. After replating the alveolar cells on the ABM and a short-period incubation under submerged and air-liquid interface culture conditions, an alveolar epithelium is achieved, showing high-level expressions of both alveolar cell-specific proteins and characteristic tight junctions. Besides, endothelial cells derived from the same hiPSCs are cocultured on the backside of the epithelium, forming an air-blood barrier. The method is generic and can potentially be applied to other types of artificial epithelium and endothelium.
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http://dx.doi.org/10.1002/adhm.202101972DOI Listing
December 2021

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Drug Metab Dispos 2021 Dec 21. Epub 2021 Dec 21.

University of Michigan, United States

The prodrug tenofovir alafenamide (TAF) is a first-line antiviral agent for the treatment of chronic hepatitis B infection. TAF activation involves multiple steps, and the first step is an ester hydrolysis reaction catalyzed by hydrolases. This study was to determine the contributions of carboxylesterase 1 (CES1) and cathepsin A (CatA) to TAF hydrolysis in the human liver. Our incubation studies showed that both CatA and CES1 catalyzed TAF hydrolysis in a pH-dependent manner. At their physiological pH environment, the activity of CatA (pH 5.2) was approximately 1,000-fold higher than that of CES1 (pH 7.2). Given that the hepatic protein expression of CatA was approximately 200-fold lower than that of CES1, the contribution of CatA to TAF hydrolysis in the human liver was estimated to be much greater than that of CES1, which is contrary to the previous perception that CES1 is the primary hepatic enzyme hydrolyzing TAF. The findings were further supported by a TAF incubation study with the CatA inhibitor telaprevir and the CES1 inhibitor bis-(p-nitrophenyl) phosphate. Moreover, an study revealed that the CES1 variant G143E (rs71647871) is a loss-of-function variant for CES1-mediated TAF hydrolysis. In summary, our results suggest that CatA may play a more important role in the hepatic activation of TAF than CES1. Additionally, TAF activation in the liver could be affected by CES1 genetic variation, but the magnitude of impact appears to be limited due to the major contribution of CatA to hepatic TAF activation. Contrary to the general perception that carboxylesterase 1 (CES1) is the major enzyme responsible for tenofovir alafenamide (TAF) hydrolysis in the human liver, the present study demonstrated that cathepsin A (CatA) may play a more significant role in TAF hepatic hydrolysis. Furthermore, the CES1 variant G143E (rs71647871) was found to be a loss-of-function variant for CES1-mediated TAF hydrolysis.
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http://dx.doi.org/10.1124/dmd.120.000323DOI Listing
December 2021

Speech After Long Silence-An Appraisee-Based Comprehensive Analysis With Retrospective and Future Perspectives on Current ID Policy of Transpersons in China.

Front Public Health 2021 30;9:793162. Epub 2021 Nov 30.

Health Law Research Center, School of Law, Central South University, Changsha, China.

As the sexual minority in China, transpersons remain faced with various realistic challenges. In recent years, however, there has been a significant progress made in the protection given to the rights that transpersons deserve. Currently, the citizens who have changed their gender through sex reassignment surgery can make applications to the local police station for changing their gender registration and get issued a new ID card. This is regarded as a crucial milestone in reducing the bias against transpersons and protecting their legitimate rights in China. Highlighted by the case of an extraordinary appraisee who have received SRS to change from male to female and started a new life with a new ID, not only does this article construe the current ID policy and the detailed process of ID card change for transpersons in China, it also reveals the living and developmental conditions facing transpersons in China. Finally, the visibility of the community of transpersons is improved to eradicate the discrimination against transpersons.
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http://dx.doi.org/10.3389/fpubh.2021.793162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669387PMC
November 2021

The Multi-Modal Risk Analysis and Medical Prevention of Lumbar Degeneration, Fatigue, and Injury Based on FEM/BMD for Elderly Chinese Women Who Act as Stay-Home Grandchildren Sitters.

Front Public Health 2021 19;9:700148. Epub 2021 Nov 19.

Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.

An increasing number of Chinese elderly women stay at home and act as grandchildren sitters. In consequence of the frequent load-bearing, chronic lumbar fatigue probably caused a higher risk of lumbar degeneration, fatigue, and injury which has become one of the most important aging and health problems in China. In this study, a multi-mode lumbar finite element model (FEM) with specific bone mineral density (BMD) were developed and validated for further spine injury prevention and control. The material properties of lumbar vertebra were modified according to degenerated bone mineral density, and geometry was adjusted based on intervertebral disc height. The motion of lifting children was simulated by a 76 year-old Chinese women's FEM, and the stress distribution was calculated and predicted. The pressure of L5-S intervertebral disc in the bending 3-year-old dummy lifting posture was significantly higher than the same posture without lifting, the maximum effective stress of endplate cartilage in the upright child lifting posture was 1.6 times that of the bending without lifting posture. And the fatigue risk limitation frequency of the upright with dummy posture was predicted with the functional equation of fatigue and stress which was deduced by genetic algorithm, which combined with the effective stress of lumbar vertebrae spongy bone calculated from FEM. The child-lifting motion could increase the risk of lumbar degeneration, fatigue, and injury in elderly women, and they should keep below the frequency limit of the motion of lifting children in their daily life. This study could put forward scientific injury prevention guidance to Chinese elderly women who lift children in daily life frequently.
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http://dx.doi.org/10.3389/fpubh.2021.700148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8648567PMC
November 2021

Blocking HMGB1/RAGE Signaling by Berberine Alleviates A1 Astrocyte and Attenuates Sepsis-Associated Encephalopathy.

Front Pharmacol 2021 15;12:760186. Epub 2021 Nov 15.

The Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha, China.

As a life-threatening multiple organ dysfunction attributable to maladjusted host immune responses to infection, sepsis is usually the common pathway to serious prognosis and death for numerous infectious diseases all over the world. Sepsis-associated encephalopathy (SAE) is frequently complicated by septic conditions, and is one of the most important reasons for increased mortality and poor outcomes in septic patients which is still an urgent clinical problem need to be solved. In this research, a conspicuously discovery of treatment-related translational use for berberine was elaborated. The results revealed that berberine treatment significantly restored cognitive impairment in sepsis mice. Reduced expression levels of TNF-α, IL-1α, and C1qA were exhibited in the hippocampus of the berberine treatment group, and attenuated effect of declining neo-neuron, activation of microglia and astrocytes in the hippocampus of mice with sepsis were also found. Moreover, berberine inhibits microglia-stressed A1 astrocytes by inhibiting HMGB1 signaling was revealed, then the molecular mechanism of HMGB1/RAGE signaling inhibition leads to the better outcome of SAE was elucidated. To summarize, this research indicated that berberine targets HMGB1/RAGE signaling to inhibit microglia-stressed A1 astrocyte and neo-neuron decline, which consequently alleviates sepsis-induced cognitive impairment. Collectively, berberine may serve as potential therapeutic drug and HMGB1/RAGE signaling would be a novel target for medicine development for treating SAE.
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http://dx.doi.org/10.3389/fphar.2021.760186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634440PMC
November 2021

Identification of candidate biomarker and its prognostic potential in clear cell renal cell carcinoma.

Front Biosci (Landmark Ed) 2021 11;26(11):1176-1190

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China.

: Clear cell renal cell carcinoma (ccRCC) is considered the second most common urogenital tract carcinoma, plaguing patients worldwide due to its high incidence and resistance to treatment. Thus, it is urgent to screen new biomarkers and decipher their molecular mechanisms to support early clinical diagnosis and targeted therapy of ccRCC. It is reported that epithelial membrane protein 3 () acts as a tumor-promoting or suppressing factor in a variety of malignant tumors, but its relationship with ccRCC remains to be explored. : The Cancer Genome Atlas (TCGA) and Oncomine database were utilized to screen the differentially expressed genes in ccRCC. Western blot and qPCR were used to verify the expression of our subject of interest, in ccRCC tissues and cell lines. Next, a series of functional experiments were conducted to explore the biological functions of in tumor cells, including cell counting kit-8, transwell, wound healing assays, Oil red O staining and triglyceride determination. Western blotting was used to explore the potential mechanism of induced ccRCC deterioration. Finally, the TIMER2.0 database was used to explore the effect of on tumor immune infiltration and its relationship with multiple immune checkpoints. : In this study, we uncovered that was more prominently expressed in ccRCC and its expression level had a significant positive correlation with the clinical stage and histopathological grade of tumor patients. Based on the TCGA database, the Receiver operating characteristic (ROC) curves showed that could be potentially utilized as a specific biomarker in diagnosing ccRCC patients. Meanwhile, six independent prognostic factors were determined and integrated into our nomogram, with an OS concordance index (C-index) of 0.760 (95% CI: 0.689-0.831). Furthermore, depletion of could alleviate the proliferation, migration, invasion, and lipid storage in ccRCC cells. Mechanistically, was shown to enhance the malignant potential of tumor cells by promoting epithelial-mesenchymal transition (EMT) and lipid accumulation. In addition, the expression of was closely related to the infiltration of a variety of immune cells, and was positively related to PD-L1, suggesting that it may be a tight connection with tumor immune escape. : Our results revealed that might be a candidate biomarker and independent prognostic indicator, and related to EMT process, lipid accumulation, as well as immune infiltration in ccRCC. Targeted therapy might be a promising and effective treatment strategy for ccRCC patients.
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http://dx.doi.org/10.52586/5018DOI Listing
November 2021

Human antibody C10 neutralizes by diminishing Zika but enhancing dengue virus dynamics.

Cell 2021 12 30;184(25):6067-6080.e13. Epub 2021 Nov 30.

Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore; Department of Chemistry, Huck Institutes of the Life Sciences, The Pennsylvania State University, 104 Chemistry Building, University Park, PA 16802, USA. Electronic address:

The human monoclonal antibody (HmAb) C10 potently cross-neutralizes Zika virus (ZIKV) and dengue virus. Analysis of antibody fragment (Fab) C10 interactions with ZIKV and dengue virus serotype 2 (DENV2) particles by cryoelectron microscopy (cryo-EM) and amide hydrogen/deuterium exchange mass spectrometry (HDXMS) shows that Fab C10 binding decreases overall ZIKV particle dynamics, whereas with DENV2, the same Fab causes increased dynamics. Testing of different Fab C10:DENV2 E protein molar ratios revealed that, at higher Fab ratios, especially at saturated concentrations, the Fab enhanced viral dynamics (detected by HDXMS), and observation under cryo-EM showed increased numbers of distorted particles. Our results suggest that Fab C10 stabilizes ZIKV but that with DENV2 particles, high Fab C10 occupancy promotes E protein dimer conformational changes leading to overall increased particle dynamics and distortion of the viral surface. This is the first instance of a broadly neutralizing antibody eliciting virus-specific increases in whole virus particle dynamics.
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http://dx.doi.org/10.1016/j.cell.2021.11.009DOI Listing
December 2021

HIF2α promotes tumour growth in clear cell renal cell carcinoma by increasing the expression of NUDT1 to reduce oxidative stress.

Clin Transl Med 2021 11;11(11):e592

Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.

Background: The key role of hypoxia-inducible factor 2alpha (HIF2α) in the process of renal cancer has been confirmed. In the field of tumour research, oxidative stress is also considered to be an important influencing factor. However, the relationship and biological benefits of oxidative stress and HIF2α in ccRCC remain unclear. This research attempts to explore the effect of oxidative stress on the cancer-promoting effect of HIF2α in ccRCC and reveal its mechanism of action.

Methods: The bioinformatics analysis for ccRCC is based on whole transcriptome sequencing and TCGA database. The detection of the expression level of related molecules is realised by western blot and PCR. The expression of Nucleoside diphosphate-linked moiety X-type motif 1 (NUDT1) was knocked down by lentiviral infection technology. The functional role of NUDT1 were further investigated by CCK8 assays, transwell assays and cell oxidative stress indicator detection. The exploration of related molecular mechanisms is realised by Luciferase assays and Chromatin immunoprecipitation (ChIP) assays.

Results: Molecular screening based on knockdown HIF2α sequencing data and oxidative stress related data sets showed that NUDT1 is considered to be an important molecule for the interaction of HIF2α with oxidative stress. Subsequent experimental results showed that NUDT1 can cooperate with HIF2α to promote the progression of ccRCC. And this biological effect was found to be caused by the oxidative stress regulated by NUDT1. Mechanistically, HIF2α transcription activates the expression of NUDT1, thereby inhibiting oxidative stress and promoting the progression of ccRCC.

Conclusions: This research clarified a novel mechanism by which HIF2α stabilises sirtuin 3 (SIRT3) through direct transcriptional activation of NUDT1, thereby inhibiting oxidative stress to promote the development of ccRCC. It provided the possibility for the selection of new therapeutic targets for ccRCC and the study of combination medication regimens.
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http://dx.doi.org/10.1002/ctm2.592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567048PMC
November 2021

Downregulation of miR-29c promotes muscle wasting by modulating the activity of leukemia inhibitory factor in lung cancer cachexia.

Cancer Cell Int 2021 Nov 27;21(1):627. Epub 2021 Nov 27.

Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.

Background: Cancer cachexia is a wasting disorder characterized by significant weight loss, and is attributed to skeletal muscle weakness. In the process of cancer development, microRNAs act as oncogenes or tumor suppressors. Moreover, they are implicated in muscle development and wasting. This study sought to explore the mechanisms and correlation between miR-29c and muscle wasting in lung cancer cachexia.

Methods: Data for expression analysis were retrieved from the Cancer Genome Atlas (TCGA) database. qRT-PCR analyses were performed to explore the expression levels of miR-29c and Leukemia Inhibitory Factor (LIF). Lewis lung carcinoma (LLC) cell line was used to establish a cachexia model to explore the functions of miR-29c and LIF in lung cancer cachexia. Furthermore, in vitro (in C2C12 myotubes) and in vivo (in LLC tumor-bearing mice) experiments were performed to explore the mechanisms of miR-29c and LIF in lung cachexia.

Results: Analysis of the lung cancer cachexia model showed that miR-29c was down-regulated, and its expression was negatively correlated with muscle catabolic activity. Overexpression of miR-29c mitigated the cachectic phenotype. Mechanistic studies showed that LIF was a direct target gene of miR-29c, and LIF was upregulated in vitro and in vivo. Analysis showed that LIF promoted muscle wasting through the JAK/STAT and MAP-kinase pathways.

Conclusions: The findings indicated that miR-29c was negatively correlated with the cachectic phenotype, and the miR-29c-LIF axis is a potential therapeutic target for cancer cachexia.
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http://dx.doi.org/10.1186/s12935-021-02332-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626920PMC
November 2021

Study on a High-Boron-Content Stainless Steel Composite for Nuclear Radiation.

Materials (Basel) 2021 Nov 19;14(22). Epub 2021 Nov 19.

School of Nuclear Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.

In this research, a high-boron-content composite material with both neutron and γ rays shielding properties was developed by an optimized design and manufacture. It consists of 304 stainless steel as the matrix and spherical boron carbide (BC) particles as the functional particles. The content of BC is 24.68 wt%, and the particles' radius is 1.53 mm. The density of the newly designed material is 5.17 g·cm, about 68.02% of that of traditional borated stainless steel containing 1.7 wt% boron, while its neutrons shielding performance is much better. Firstly, focusing on shielding properties and material density, the content and the size of BC were optimized by the Genetic Algorithm (GA) program combined with the MCNP program. Then, some samples of the material were manufactured by the infiltration casting technique according to the optimized results. The actual density of the samples was 5.21 g cm. In addition, the neutron and γ rays shielding performance of the samples and borated stainless steel containing 1.7 wt% boron was tested by using an Am-Be neutron source and Co and Cs γ rays sources, respectively, and the results were compared. It can be concluded that the new designed material could be used as a material for nuclear power plants or spent-fuel storage and transportation containers with high requirements for mobility.
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http://dx.doi.org/10.3390/ma14227004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620793PMC
November 2021

The silent epidemic of urogenital atrophy.

Br J Gen Pract 2021 Dec 25;71(713):538-539. Epub 2021 Nov 25.

Department of Women's and Children's Health, Centre for Women's Health Research, Institute of Life Course and Medical Sciences, University of Liverpool, UK.

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http://dx.doi.org/10.3399/bjgp21X717725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8686435PMC
December 2021

Academic Publication of Neurodegenerative Diseases From a Bibliographic Perspective: A Comparative Scientometric Analysis.

Front Aging Neurosci 2021 4;13:722944. Epub 2021 Nov 4.

Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.

For measuring the impact in clinical and scientific research, the citation count of the articles is used in the bibliometric analysis, although there is no comprehensive summary of neurodegenerative disease research. This study intends to provide the neuroscientists and investigators with a practical reference guide to appraise the most important and influential articles written on this subject through a macroscopic view of the research activities on neurodegenerative diseases. The Clarivate Analytics Web of Science was searched in July 2020. To ensure the breadth of the search scope, the search terms were confirmed as "multiple sclerosis" (MS) or "amyotrophic lateral sclerosis" (ALS) or "Parkinson's" or "Alzheimer's" or "Huntington's" or "neurodegenerative." After excluding completely unrelated articles, the top-cited articles were collected and evaluated from special characteristics. The data analysis was performed using SPSS 18.0. The articles were characterized by citation number, publication year, topic, study type, authorship, journal, country, and institute of responding author and foundation. The query identified 593,050 articles. A total of 45% of the top-cited articles were published during 2000-2009, followed by 30 articles from 1990-1999. Diagnosis and pathology were the main research categories ( = 62). Alzheimer's disease (AD) was the main study topic ( = 43). Meanwhile, the United States confirmed the tremendous impact on the field of neurodegenerative diseases. Notably, 69 of 100 articles were studied in the United States, and the National Institutes of Health sponsored 49 articles. There were only 22 articles that can be divided by evidence level. No article was categorized as level 1 evidence. In the journal list with multiple articles, seven of 15 were general journals. The 58 authors, who contributed to more than one article, have been identified by VOSviewer, and the clusters of authors reveal the evolution of research focus in neurodegenerative diseases. This study analyzed the bibliometric characteristics and connections of 100 top-cited articles in the field of neurodegenerative diseases in the Web of Science. Their main outcomes were as follows: First, the pathology and diagnostic researches took a major role in top-cited articles while the therapy articles are relatively less. Second, the United States confirmed the tremendous impact on the field of neurodegenerative diseases. Third, researchers also submitted their researches to general journals, not just focused on specialty journals.
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http://dx.doi.org/10.3389/fnagi.2021.722944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601281PMC
November 2021

Butyric Acid Protects Against Renal Ischemia-Reperfusion Injury by Adjusting the Treg/Th17 Balance HO-1/p-STAT3 Signaling.

Front Cell Dev Biol 2021 2;9:733308. Epub 2021 Nov 2.

The Third Affiliated Hospital of Soochow University, Changzhou, China.

Immune regulation plays a vital role in ischemia-reperfusion injury (IRI). Butyric acid (BA) has immunomodulatory effects in many diseases, but its immunomodulatory effects during renal IRI are still unclear. Our research shows that BA protected against IRI and significantly improved renal IRI . studies showed that BA inhibits Th17 cell differentiation and induces Treg cell differentiation. Mechanism studies have shown that heme oxygenase 1 (HO-1)/STAT3 signaling pathway was involved in the inhibitory effect of BA on Th17 cell differentiation. HO-1 inhibitors can significantly rescue the BA-mediated inhibition of Th17 cell differentiation. We confirmed that BA promotes the differentiation of Th17 cells into Treg cells by regulating the pathway and reduces renal IRI.
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http://dx.doi.org/10.3389/fcell.2021.733308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593469PMC
November 2021

Generation of Interconnected Neural Clusters in Multiscale Scaffolds from Human-Induced Pluripotent Stem Cells.

ACS Appl Mater Interfaces 2021 Dec 17;13(47):55939-55952. Epub 2021 Nov 17.

PASTEUR, Département de Chimie, École Normale Supérieure, PSL Université, Sorbonne Université, CNRS, 75005 Paris, France.

The development of in vitro neural networks depends to a large extent on the scaffold properties, including the scaffold stiffness, porosity, and dimensionality. Herein, we developed a method to generate interconnected neural clusters in a multiscale scaffold consisting of a honeycomb microframe covered on both sides with a monolayer of cross-linked gelatin nanofibers. Cortical neural precursor cells were first produced from human-induced pluripotent stem cells and then loaded into the scaffold for a long period of differentiation toward cortical neural cells. As a result, neurons and astrocytes self-organized in the scaffold to form clusters in each of the honeycomb compartments with remarkable inter-cluster connections. These cells highly expressed neuron- and astrocyte-specific proteins, including NF200, tau, synapsin I, and glial fibrillary acidic protein, and showed spatially correlated neural activities. Two types of neural clusters, that is, spheroid-like and hourglass-like clusters, were found, indicating the complexity of neural-scaffold interaction and the variability of three-dimensional neural organization. Furthermore, we incorporated a reconstituted basement membrane into the scaffold and performed co-culture of the neural network with brain microvascular endothelial cells. As a proof of concept, an improved neurovascular unit model was tested, showing large astrocytic end-feet on the back side of the endothelium.
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http://dx.doi.org/10.1021/acsami.1c18465DOI Listing
December 2021

Multidimensional Analysis of the Role of Charged Multivesicular Body Protein 7 in Pan-Cancer.

Int J Gen Med 2021 9;14:7907-7923. Epub 2021 Nov 9.

Department of the General Surgery, Jilin University Second Hospital, Changchun, Jilin, People's Republic of China.

Background: Charged multivesicular body protein 7 is briefly referred to as CHMP7, and it plays a significant role in the endosomal sorting pathway. CHMP7 can form a complex with ESCRTIII to jointly complete the process of contraction, shear bud neck and final membrane shedding.

Methods: TCGA, GEO and CPTAC were chosen for the analysis of the role of CHMP7 in pan-cancer. Role of CHMP7 in pan-cancer was analyzed using R software and tools such as TIMER, GEPIA, UALCAN, String and DiseaseMeth. It includes differential expression analysis of CHMP7, survival analysis, genetic variation analysis, DNA methylation analysis, post-translationally modified protein phosphorylation analysis and functional enrichment analysis.

Results: CHMP7 presents low expression in the majority of tumor tissues and the prognosis is poor in the low expression group. The common gene mutation in CHMP7 is deep deletion, which may lead to frameshift mutations, resulting in a poor prognosis. Functional alterations due to DNA methylation and post-transcriptional protein modifications may be closely associated with tumors. GO analysis revealed that CHMP7-related genes are involved in the composition of the various ESCRT complexes. In terms of molecular function, they mainly bind to GTP, exert GTPase activity and promote multivesicular bodies assembly. In the KEGG enrichment analysis, the main pathways expressed by CHMP7 and related genes were endocytosis, gap junction and phagosome.

Conclusion: Pan-cancer analysis showed that CHMP7 expression was statistically correlated with clinical prognosis, DNA methylation, protein phosphorylation and immune cell infiltration, which may provide new ideas or targets for the diagnosis or treatment.
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http://dx.doi.org/10.2147/IJGM.S337876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590578PMC
November 2021

Excessive DNA damage mediates ECM degradation via the RBBP8/NOTCH1 pathway in sporadic aortic dissection.

Biochim Biophys Acta Mol Basis Dis 2022 Feb 12;1868(2):166303. Epub 2021 Nov 12.

Department of Thoracic and Cardiovascular Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Institute of Cardiothoracic Vascular Disease, Nanjing University, Nanjing 210008, China. Electronic address:

Stanford type A aortic dissection (TA-AD) is a life-threatening disease. Most cases of aortic dissection (AD) are sporadic rather than inherited. Unlike that of inherited AD, the pathogenesis of sporadic AD is still unclear. In the current study, we aimed to explore the pathogenesis of sporadic AD through transcriptome sequencing data analyses. We downloaded sporadic TA-AD transcriptome profiles from Gene Expression Omnibus (GEO) and found response to DNA damage stimulus was activated in AD. Furthermore, by conducting mouse AD tissue single cell RNA sequencing and immunostaining, we found that DNA damage mainly occurred in smooth muscle cells (SMCs) and fibroblasts. Next, we examined the repair patterns in response to DNA damage and found the linker molecules RBBP8/NOTCH1 between DNA damage/repair and extracellular matrix (ECM) organization through protein-protein interaction analysis. Thus, we proposed that DNA damage could contribute to AD by regulating ECM changes. To explore the underlying mechanism, we knocked down the DNA repair-related gene RBBP8 in aortic SMCs, which could exacerbate DNA damage, and observed decreased expression level of NOTCH1. Inhibition of NOTCH1 with crenigacestat in vivo accelerated β-aminopropionitrile-induced formation of AD and increased mortality. Meanwhile, phenotype switching of SMCs was induced by Notch1 knockdown or inhibition; this switching occurred via a pathway involving downregulation of contractile marker gene expression and upregulation of MMP2 expression, which might aggravate ECM degradation. In conclusion, excessive DNA damage is a characteristic pathological change of sporadic aortic dissection, which might contribute to ECM changes and AD development via action on the NOTCH1 pathway.
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http://dx.doi.org/10.1016/j.bbadis.2021.166303DOI Listing
February 2022

Understanding longevity in Hong Kong: a comparative study with long-living, high-income countries.

Lancet Public Health 2021 12 10;6(12):e919-e931. Epub 2021 Nov 10.

School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; Laboratory of Data Discovery for Health (D(2)4H), Hong Kong Science Park, Hong Kong Special Administrative Region, China.

Background: Since 2013, Hong Kong has sustained the world's highest life expectancy at birth-a key indicator of population health. The reasons behind this achievement remain poorly understood but are of great relevance to both rapidly developing and high-income regions. Here, we aim to compare factors behind Hong Kong's survival advantage over long-living, high-income countries.

Methods: Life expectancy data from 1960-2020 were obtained for 18 high-income countries in the Organisation for Economic Co-operation and Development from the Human Mortality Database and for Hong Kong from Hong Kong's Census and Statistics Department. Causes of death data from 1950-2016 were obtained from WHO's Mortality Database. We used truncated cross-sectional average length of life (TCAL) to identify the contributions to survival differences based on 263 million deaths overall. As smoking is the leading cause of premature death, we also compared smoking-attributable mortality between Hong Kong and the high-income countries.

Findings: From 1979-2016, Hong Kong accumulated a substantial survival advantage over high-income countries, with a difference of 1·86 years (95% CI 1·83-1·89) for males and 2·50 years (2·47-2·53) for females. As mortality from infectious diseases declined, the main contributors to Hong Kong's survival advantage were lower mortality from cardiovascular diseases for both males (TCAL difference 1·22 years, 95% CI 1·21-1·23) and females (1·19 years, 1·18-1·21), cancer for females (0·47 years, 0·45-0·48), and transport accidents for males (0·27 years, 0·27-0·28). Among high-income populations, Hong Kong recorded the lowest cardiovascular mortality and one of the lowest cancer mortalities in women. These findings were underpinned by the lowest absolute smoking-attributable mortality in high-income regions (39·7 per 100 000 in 2016, 95% CI 34·4-45·0). Reduced smoking-attributable mortality contributed to 50·5% (0·94 years, 0·93-0·95) of Hong Kong's survival advantage over males in high-income countries and 34·8% (0·87 years, 0·87-0·88) of it in females.

Interpretation: Hong Kong's leading longevity is the result of fewer diseases of poverty while suppressing the diseases of affluence. A unique combination of economic prosperity and low levels of smoking with development contributed to this achievement. As such, it offers a framework that could be replicated through deliberate policies in developing and developed populations globally.

Funding: Early Career Scheme (RGC ECS Grant #27602415), Research Grants Council, University Grants Committee of Hong Kong.
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http://dx.doi.org/10.1016/S2468-2667(21)00208-5DOI Listing
December 2021

Enteral nutrition management in stroke patients: a narrative review.

Ann Palliat Med 2021 10;10(10):11191-11202

Department of Nutrition, The Second Hospital of Hebei Medical University, Shijiazhuang, China.

Objective: We aimed to summarize the enteral nutrition (EN) management of stroke patients according to recent evidence.

Background: Stroke patients have a high incidence of dysphagia, which is the main cause of malnutrition, and stroke with malnutrition leads to high recurrence and mortality. Insufficient food intake caused by dysphagia is the main cause of malnutrition in stroke patients, which is associated with poor prognosis, increased mortality, and deteriorated outcomes in patients with stroke. Dehydration is also worthy of attention.

Methods: Non-systematic searches of the PubMed database were conducted to retrieve relevant English-language articles, and the CNKI and Wanfang database were searched for relevant Chinese-language articles. Fifteen recent guidelines or expert consensuses on the clinical nutritional management of stroke patients were published between 2013 and 2021, of which eight are from China.

Conclusions: Before providing nutritional support, swallowing, hydration, and risk of malnutrition need to be screened by a dietitian or professional. Although the initiation time of nutritional support is different in each guideline, tube feeding is preferable for patients with dysphagia. The appropriate dosage, formula, and treatment of complications need to be further studied. Also, nutritional support for stroke patients at different stages needs to be further improved. The continuous improvement and details of stroke nutrition guidelines contribute to standardized clinical nutrition practices and benefit patients.
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http://dx.doi.org/10.21037/apm-21-2922DOI Listing
October 2021

Diagnostic performance of noninvasive imaging modalities for localization of insulinoma: A meta-analysis.

Eur J Radiol 2021 Dec 3;145:110016. Epub 2021 Nov 3.

Department of Radiology, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, PR China. Electronic address:

Background: Insulinoma is the most common functional neuroendocrine tumor found only in the pancreas. The early detection of insulinoma is of importance. Studies comparing the performance of noninvasive modalities were limited by sample size and heterogeneity between studies. The aim of this meta-analysis was to evaluate the diagnostic performance of PET/CT, SPECT/CT, CT and MRI for the localization of insulinoma, and to provide evidence for clinical practice.

Methods: PubMed, Embase, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure were searched from inception to May 31, 2021. Pooled sensitivity, specificity, positive Likelihood Ratio (+LR) and negative Likelihood Ratio (-LR), diagnostic odds ratio (DOR), and concordance rate were calculated.

Results: A total of 19 studies including 708 patients of insulinoma reached the inclusion criteria. PET/CT imaging demonstrated a pooled sensitivity of 0.79 (95% CI: 0.54-0.92) and a pooled specificity of 0.84 (95% CI: 0.20-0.99). The pooled sensitivity and specificity of SPECT/CT were 0.77 (95% CI: 0.46-0.93) and 0.45 (95% CI: 0.22-0.70). CT showed an overall sensitivity of 0.54 (95% CI: 0.35-0.72) and specificity of 0.75 (95% CI: 0.54-0.88). The pooled sensitivity and specificity for MRI were 0.54 (95% CI: 0.31-0.75) and 0.65 (95% CI: 0.39-0.84), respectively. The concordance rates of PET, SPECT, CT, and MRI were 78% (95% CI: 66-90%), 74% (95% CI: 52-97%), 56% (95% CI: 41-72%), and 53% (95% CI: 33-73%), respectively.

Conclusion: Results of this study indicate that PET/CT demonstrated superior performance than SPECT/CT, CT and MRI for the localization of insulinoma. GLP-1R based PET/CT manifested better diagnostic performance in comparison with SSTR based PET/CT imaging modality.
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http://dx.doi.org/10.1016/j.ejrad.2021.110016DOI Listing
December 2021

The multiscale solvation effect on the reactivity of β-O-4 of lignin dimers in deep eutectic solvents.

Phys Chem Chem Phys 2021 Nov 24;23(45):25699-25705. Epub 2021 Nov 24.

Department of Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky 40506, USA.

Deep eutectic solvents (DESs) emerge as a medium to enhance the depolymerization of lignin. One critical question is how the solvation of lignin in DESs may affect the reactivity of lignin. To shed light on this question, we investigate the solvation of four lignin dimers in three DES solutions using molecular dynamics simulations and quantum mechanical calculations. The four lignin dimers are composed of guaiacyl and syringyl units and are used as the models for lignin. The three DES solutions are composed of choline, Cl and three acids: lactic acid, levulinic acid and oxalic acid. We investigate the preferential accumulation of individual DES components in the solvation shells and the exposure area and electrostatic potential of the β-O-4 linkage of the four lignin dimers in the three DESs. The results show that DESs could influence the affinity and nucleophilicity of the β-O-4 linkage through three effects: (1) forming a charged solvation shell, (2) varying the exposure of the β-O-4 linkage and (3) adjusting the electrostatic potential of the β-O-4 linkage. Our simulations indicate a comprehensive and multiscale effect of DESs on lignin decomposition.
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http://dx.doi.org/10.1039/d1cp04342kDOI Listing
November 2021

Plasma Carboxylesterase 1 Predicts Methylphenidate Exposure: A Proof-of-Concept Study Using Plasma Protein Biomarker for Hepatic Drug Metabolism.

Clin Pharmacol Ther 2021 Nov 7. Epub 2021 Nov 7.

Department of Clinical Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.

Hepatic drug-metabolizing enzymes (DMEs) play critical roles in determining the pharmacokinetics and pharmacodynamics of numerous therapeutic agents. As such, noninvasive biomarkers capable of predicting DME expression in the liver have the potential to be used to personalize pharmacotherapy and improve drug treatment outcomes. In the present study, we quantified carboxylesterase 1 (CES1) protein concentrations in plasma samples collected during a methylphenidate pharmacokinetics study. CES1 is a prominent hepatic enzyme responsible for the metabolism of many medications containing small ester moieties, including methylphenidate. The results revealed a significant inverse correlation between plasma CES1 protein concentrations and the area under the concentration-time curves (AUCs) of plasma d-methylphenidate (P = 0.014, r = -0.617). In addition, when plasma CES1 protein levels were normalized to the plasma concentrations of 24 liver-enriched proteins to account for potential interindividual differences in hepatic protein release rate, the correlation was further improved (P = 0.003, r = -0.703), suggesting that plasma CES1 protein could explain ~ 50% of the variability in d-methylphenidate AUCs in the study participants. A physiologically-based pharmacokinetic modeling simulation revealed that the CES1-based individualized dosing strategy might significantly reduce d-methylphenidate exposure variability in pediatric patients relative to conventional trial and error fixed dosing regimens. This proof-of-concept study indicates that the plasma protein of a hepatic DME may serve as a biomarker for predicting its metabolic function and the pharmacokinetics of its substrate drugs.
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http://dx.doi.org/10.1002/cpt.2486DOI Listing
November 2021

Swimming start model and determination of the optimal breakout position.

Sports Biomech 2021 Oct 27:1-21. Epub 2021 Oct 27.

Sports Training Research Center, China Institute of Sport Science, Beijing, China.

While many parameters contribute to swimming start performance, a few have been proven to affect the overall start performance more significantly than others; these include take-off velocity, flight time, entry water distance, time underwater during descent and ascent, and free-swimming velocity. This study aims to analyse the influential trajectory of these key parameters on the overall start performance, particularly focusing on determining the optimal breakout point. Ten national-level swimmers participated in this study, which combined kinematics and statistical analysis to propose a novel start model that can be used to explore the influential trajectory of key parameters on the overall start performance and assess the effect of some training factors for performance improvement. Further, this study investigated the optimal breakout position via a mathematical model. This is the first study to provide a solution to determine this parameter. The solution is verified to be practical through trial data, and the overall start performance is improved by 0.71-3.29%, depending on the swimmer's current level. Therefore, the results can be used as a reference for swimming start training and improvement.
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http://dx.doi.org/10.1080/14763141.2021.1983014DOI Listing
October 2021

Activation of Tenofovir Alafenamide and Sofosbuvir in the Human Lung and Its Implications in the Development of Nucleoside/Nucleotide Prodrugs for Treating SARS-CoV-2 Pulmonary Infection.

Pharmaceutics 2021 Oct 11;13(10). Epub 2021 Oct 11.

Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.

ProTide technology is a powerful tool for the design of nucleoside/nucleotide analog prodrugs. ProTide prodrug design improves cell permeability and enhances intracellular activation. The hydrolysis of the ester bond of a ProTide is a determinant of the intracellular activation efficiency and final antiviral efficacy of the prodrug. The hydrolysis is dictated by the catalytic activity and abundance of activating enzymes. The antiviral agents tenofovir alafenamide (TAF) and sofosbuvir (SBV) are typical ProTides. Both TAF and SBV have also been proposed to treat patients with COVID-19. However, the mechanisms underlying the activation of the two prodrugs in the lung remain inconclusive. In the present study, we profiled the catalytic activity of serine hydrolases in human lung S9 fractions using an activity-based protein profiling assay. We evaluated the hydrolysis of TAF and SBV using human lung and liver S9 fractions and purified enzymes. The results showed that CatA and CES1 were involved in the hydrolysis of the two prodrugs in the human lung. More specifically, CatA exhibited a nearly 4-fold higher hydrolytic activity towards TAF than SBV, whereas the CES1 activity on hydrolyzing TAF was slightly lower than that for SBV. Overall, TAF had a nearly 4-fold higher hydrolysis rate in human lung S9 than SBV. We further analyzed protein expression levels of CatA and CES1 in the human lung, liver, and primary cells of the two tissues using proteomics data extracted from the literature. The relative protein abundance of CatA to CES1 was considerably higher in the human lung and primary human airway epithelial cells than in the human liver and primary human hepatocytes. The findings demonstrated that the high susceptivity of TAF to CatA-mediated hydrolysis resulted in efficient TAF hydrolysis in the human lung, suggesting that CatA could be utilized as a target activating enzyme when designing antiviral ester prodrugs for the treatment of respiratory virus infection.
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http://dx.doi.org/10.3390/pharmaceutics13101656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540046PMC
October 2021
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