Publications by authors named "Qing Jiang"

622 Publications

Sufu negatively regulates both initiations of centrosome duplication and DNA replication.

Proc Natl Acad Sci U S A 2021 Jul;118(28)

Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing 100871, China;

Centrosome duplication and DNA replication are two pivotal events that higher eukaryotic cells use to initiate proliferation. While DNA replication is initiated through origin licensing, centrosome duplication starts with cartwheel assembly and is partly controlled by CP110. However, the upstream coordinator for both events has been, until now, a mystery. Here, we report that suppressor of fused protein (Sufu), a negative regulator of the Hedgehog (Hh) pathway playing a significant role in restricting the trafficking and function of glioma-related (Gli) proteins, acts as an upstream switch by facilitating CP110 phosphorylation by CDK2, promoting intranuclear Cdt1 degradation and excluding prereplication complex (pre-RC) components from chromosomes, independent of its canonical function in the Hh pathway. We found that Sufu localizes to both the centrosome and the nucleus and that knockout of Sufu induces abnormalities including centrosome amplification, increased nuclear size, multipolar spindle formation, and polyploidy. Serum stimulation promotes the elimination of Sufu from the centrosome by vesicle release at the ciliary tip and from the nucleus via protein degradation, which allows centrosome duplication and DNA replication to proceed. Collectively, this work reveals a mechanism through which Sufu negatively regulates the G1-S transition.
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http://dx.doi.org/10.1073/pnas.2026421118DOI Listing
July 2021

Stimuli-responsive biphenyl-tripeptide supramolecular hydrogels as biomimetic extracellular matrix scaffolds for cartilage tissue engineering.

Acta Biomater 2021 Jul 8. Epub 2021 Jul 8.

National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan, 610064, PR China.

Supramolecular hydrogel composed of aromatic short peptide gelator was an attractive biomaterial owing to its simple and convenient synthetic route, nano-fibrillar microstructure resembling natural collagen fibers and intelligent response to external stimulus. Herein, stimuli-responsive biphenyl-tripeptide supramolecular hydrogels was prepared to simulate extracellular matrix scaffolds by temperature switch, ion induction and pH switch. The amino acid arrangement substantially affected gelation behavior, only BPAA-βAFF and BPAA-FFβA could form nanostructured supramolecular hydrogels with 8-10 nm nanotubes or nanofibers by potential intermolecular hydrogen bond interactions and π-π stacking. The minimum gelation concentration (MGC) and maximum storage modulus were 0.4 mM (0.023 wt%) and around 8.2 KPa. The two supramolecular hydrogels could support adhesion and proliferation of L929 cells. Moreover, the BPAA-βAFF hydrogel promoted proliferation and ECM secretion of chondrocytes in vitro, and facilitate the phenotype maintenance of hyaline cartilage. All the results demonstrated that BPAA-βAFF hydrogel hold great potential application prospects in cartilage tissue engineering. STATEMENT OF SIGNIFICANCE: Diphenylalanine was served as a core segment conjugating with 4-biphenylacetic acid (BPAA) to produce biphenyl-tripeptide compounds with transforming amino sequence, and multiple external stimuli was applied to study the gelation properties of the aromatic short peptide gelators. "FF" brick (phenylalanine-phenylalanine) was crucial for formation of fibrous supramolecular hydrogels. Meanwhile, the sequence of amino acids arrangement also had an essential effect on the gelation behavior. Optimal BPAA-βAFF with ultra-low minimum gelation concentration (0.4 mM, about 0.023 wt%) and similar microstructure to extracellular matrix (ECM) of nature cartilage tissue could promote the proliferation and ECM secretion of chondrocytes in vitro, and facilitate the formation of hyaline cartilage.
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http://dx.doi.org/10.1016/j.actbio.2021.07.007DOI Listing
July 2021

A multicenter retrospective study on evaluation of predicative factors for positive biopsy of prostate cancer in real-world setting.

Curr Med Res Opin 2021 Jul 19:1-9. Epub 2021 Jul 19.

Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, China.

Objective: This study aimed to evaluate the predictors for positive biopsy in prostate cancer (PCa) patients and develop a risk-stratification score model for positive biopsy rate in patients with prostate specific antigen (PSA) in the gray zone.

Methods: In this retrospective, multicenter, real-world study, Chinese patients receiving prostate biopsy for the first time were included. The study evaluated the positive biopsy rate, predictors for positive biopsy and a risk prediction model for PSA 4-10 ng/mL PCa was developed. The univariate and multivariate logistic regression analyses were used to identify the risk factors.

Results: A total of 2426 patients were included in the study. The biopsy positive rate was 47.57%, 25.77%, and 60.57% among overall patients, total PSA (t-PSA) 4-10 ng/mL patients, and PSA > 10 ng/mL patients respectively. Elderly age 60-74, ≥75, multi parametric magnetic resonance imaging (MP-MRI), pre-operative PSA > 10 and PSA density (PSAD) significantly increased the positive rate in overall population, and elderly age, MP-MRI, positive digital rectal examination and f-PSA were significant predictors for positive biopsy in PSA 4-10 ng/mL population. A risk prediction model for positive biopsy rate in patients with PSA in the gray zone was developed. Area under curve (AUC) was associated with low accuracy for all the variables used such as tPSA (0.53), PSAD (0.57), frequency of puncture (0.53) and MP-MRI (0.64) in prediction of biopsy positive rate.

Conclusion: Our study evaluated the significant predicative factors for positive biopsy and the PCa risk prediction model developed might help Clinicians to avoid unnecessary biopsy in patients with PSA in gray zone.
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http://dx.doi.org/10.1080/03007995.2021.1949270DOI Listing
July 2021

Understanding water slippage through carbon nanotubes.

Phys Chem Chem Phys 2021 Jul;23(27):14737-14745

Key Laboratory of Automobile Materials (Jilin University), Ministry of Education, Department of Materials Science and Engineering, Jilin University, Changchun 130022, China.

It is a formidable challenge to understand water slippage through carbon nanotubes (CNTs), despite its great significance in fundamental research and technology. Herein, we propose an effective scheme to describe water slippage properties by extending two friction models - the phononic friction model and Einstein's diffusion model, both relying on the potential corrugation of water slippage. Our scheme effectively captures the tube-size effect on the viscosity and slippage of water molecules through CNTs. It also identifies the experimentally reported size-dependent transition from continuum to sub-continuum flow and further reveals that this transition is likely to be determined by the hydrogen bond instead of the structural transition or entropic change. Besides, the size-dependence of slip lengths is found to be controllable by temperature. Our methods are thus expected to be a useful basis for further studies on substance transport under confinement.
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http://dx.doi.org/10.1039/d1cp01148kDOI Listing
July 2021

The Validity of Neutrophil/lymphocyte Ratio as A Predictive Factor for Systemic Inflammatory Response Syndrome after Flexible Ureteroscopy Lithotripsy.

Urol J 2021 06 15. Epub 2021 Jun 15.

Department of Urology, the Second Affiliated Hospital of Chongqing Medical University, China 74#Linjiang Road, Chongqing, CN 400010.

Purpose: To explore the risk factors and predictive factors of systemic inflammatory response syndrome (SIRS) after flexible ureteroscopy (fURS) for upper urinary tract stones.

Materials And Methods: Patients experienced fURS from January 2014 to September 2019 were retrospectively analyzed, which were divided into the SIRS group and non-SIRS group. Clinical data of all patients, including gender, age, American society of anesthesia score, diabetes, etc., were collected. Univariate and multivariate logistic regression was used to determine the independent risk factors for SIRS after fURS, and the receiver operating characteristic (ROC) curve was drawn to verify the validity of results. In addition, patients from October 2019 to January 2020 were prospectively collected to verify the results.

Results: A total of 369 patients were retrospectively included. Univariate analysis showed significant differences in postoperative stone residuals (P = 0.039), preoperative neutrophil/ lymphocyte ratio (NLR) (P < 0.001), and lymphocyte/monocyte ratio (LMR) (P = 0.001) between two groups. Further, preoperative NLR and postoperative stone residuals were independent according to multivariate logistic regression analysis. The optimal cut-off value of preoperative NLR by ROC curve was 2.61, and the area under ROC curve was 77.9%. Prospective analysis based on 53 patients showed that the incidence of SIRS in patients with NLR > 2.61 was significantly higher than that in other patients. (RR = 4.932, P = 0.040).

Conclusion: Preoperative NLR can be used as a predictive factor for SIRS in patients with fURS according to our study. It may provide an evidence for clinicians to make preoperative decisions or medical plans.
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http://dx.doi.org/10.22037/uj.v18i.6570DOI Listing
June 2021

Disturbed craving regulation to gaming cues in internet gaming disorder: Implications for uncontrolled gaming behaviors.

J Psychiatr Res 2021 Jun 1;140:250-259. Epub 2021 Jun 1.

Center for Cognition and Brain Disorders, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang Province, China; Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Hangzhou, Zhejiang Province, China. Electronic address:

Background: The ability to control craving for games is very important to abstain from Internet gaming disorder (IGD) and abundant clinical evidence has suggested that craving dysregulation is the essential pathogenesis for IGD. However, the neural mechanism underlying this feature remains unclear.

Methods: Subjective evaluation and fMRI data from 44 participants (IGD participants: 21; recreational Internet game users (RGUs): 23) were collected while they were performing a regulation of craving task. We analyzed and compared their brain features while they regulated cravings to gaming stimuli.

Results: Compared to RGUs, IGD participants showed enhanced brain activation in the right anterior cingulate cortex, posterior cingulate cortex (PCC), orbitofrontal cortex and middle temporal gyrus and in the left dorsolateral prefrontal cortex and thalamus during the regulation of craving task. Generalized psychophysiological interaction (gPPI) analysis revealed that IGD participants showed decreased functional connectivity between the right PCC and right inferior parietal lobule compared to that in RGU participants.

Conclusions: The results suggested that deficits of craving regulation in IGD participant were associated with the imbalanced coordination between the reward network and the executive network. Enhanced game-seeking motivation and disturbed executive control are responsible for craving dysregulation in IGD participants. These findings suggest a biological mechanism for IGD that may help in finding potential interventions.
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http://dx.doi.org/10.1016/j.jpsychires.2021.05.051DOI Listing
June 2021

Bioinspired polysaccharide hybrid hydrogel promoted recruitment and chondrogenic differentiation of bone marrow mesenchymal stem cells.

Carbohydr Polym 2021 Sep 19;267:118224. Epub 2021 May 19.

National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, Sichuan 610064, PR China; College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China.

Cartilage regeneration by biomimetic cartilage matrix with synchronously recruited stem cells was one of ideal strategies. Inspired by catechol for proteins adhesion, dopamine modified polysaccharide hybrid hydrogel (HD-C) was prepared by integrating collagen I (Col I) and hyaluronic acid derivatives (HA-DN) with sulfhydryl modified polysaccharide hybrid hydrogel (HS-C) as control. Because of double-crosslinking architecture, HD-C hydrogel was endowed with a more compact pore structure, higher mechanical properties and water retention ability in comparison with those of HS-C hydrogel. Meanwhile, it significantly promoted the proliferation and spread of rabbit bone marrow stem cells (rBMSCs), and accelerated cartilaginous matrix secretion. RT-PCR results also verified higher related gene expression of chondrogenesis (Sox 9, Agg and Col II). Moreover, HD-C hydrogel could enhance the enrichment and migration of rBMSCs in vitro by potential functional protein adsorption mechanisms, and this phenomenon was further confirmed by more rBMSCs migration in short-term joint implantation experiments in vivo.
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http://dx.doi.org/10.1016/j.carbpol.2021.118224DOI Listing
September 2021

Runt-related transcription factor-2 (Runx2) is required for bone matrix protein gene expression in committed osteoblasts in mice.

J Bone Miner Res 2021 Jun 8. Epub 2021 Jun 8.

Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Runt-related transcription factor-2 (Runx2) is an essential transcription factor for osteoblast differentiation. However, its functions after the commitment into osteoblasts are controversial and remain to be clarified. We generated enhanced green fluorescent protein (EGFP)-Cre transgenic mice driven by the 2.3-kilobase (kb) Col1a1 promoter, and Runx2 was deleted in osteoblasts and odontoblasts in Runx2 mice. The sutures and fontanelles were more widely opened in Runx2 newborns than in Runx2 newborns. Runx2 mice exhibited dwarfism with shorter incisors and 37% had irregularly aligned incisors. The volume of trabecular bone in femurs and vertebrae and their bone mineral density (BMD), in addition to the cortical thickness and BMD were reduced in Runx2 mice compared with Runx2 mice in both sexes. The bone formation of both trabecular and cortical bone, osteoblast number, osteoclast surface, osteoblast proliferation, and the serum levels of procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase 5b (TRAP5b), and C-terminal cross-linked telopeptide of type 1 collagen (CTX1) were reduced in Runx2 mice. The expression of major bone matrix protein genes, including Col1a1, Col1a2, Spp1, Ibsp, and Bglap&Bglap2, and of Tnfsf11 was lower in Runx2 mice than in Runx2 mice. The expression of Runx2 target genes, including Ihh, Fgfr1, Fgfr2, Fgfr3, Tcf7, Wnt10b, Pth1r, Sp7, and Dlx5, was also reduced. Osteoblasts in Runx2 mice were cuboidal and contained abundant type I collagen α1 (Col1a1), whereas those in Runx2 mice were deflated and contained a small amount of Col1a1. Runx2 activated the reporter activity of the 2.3-kb Col1a1 promoter and bound the region around the Col1a1 transcription start site. The deletion of Runx2 by Cre-expressing adenovirus in Runx2 primary osteoblasts impaired osteoblast differentiation and the expression of genes encoding major bone matrix proteins, and osteoclastogenesis was inhibited due to the reduction of Tnfsf11 expression in the osteoblasts. This study demonstrated that Runx2 is required for the expression of the major bone matrix protein genes and Tnfsf11 after commitment into osteoblasts in mice. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4386DOI Listing
June 2021

Viral Metagenome-Based Precision Surveillance of Pig Population at Large Scale Reveals Viromic Signatures of Sample Types and Influence of Farming Management on Pig Virome.

mSystems 2021 Jun 8;6(3):e0042021. Epub 2021 Jun 8.

Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, Jilin Province, China.

Pigs are a major meat source worldwide and a pillar of Chinese animal husbandry; hence, their health and safety are a prioritized concern of the national economy. Although pig viruses have been continuously investigated, the full extent of the pig virome has remained unknown and emerging viruses are still a major threat to the pig industry. Here, we report a comprehensive study to delineate the pig virome of 1,841 healthy weaned pigs from 45 commercial farms collected from 25 major pig-producing regions across China. A viromic sequence data set, named Pigs_VIRES, which matched 96,586 viral genes from at least 249 genera within 66 families and which almost tripled the number of previously published pig viromic genes, was established. The majority of the mammalian viruses were closely related to currently known ones. A comparison with previously published viromes of bovines, avians, and humans has revealed the distinct composition of Pigs_VIRES, which has provided characteristic viromic signatures of serum, pharyngeal, and anal samples that were significantly influenced by farming management and disease control measures. Taken together, Pigs_VIRES has revealed the most complete viromic data set of healthy pigs to date. The compiled data also provide useful guidance to pig viral disease control and prevention and the biosafety management of pig farms. Especially, the established viromic protocol has created a precision surveillance strategy to potentially innovate currently used surveillance methods of animal infectious diseases, particularly by making precision surveillance available to other animal species on a large scale or even during a nationwide surveillance campaign. Pigs are deeply involved in human lives; hence, their viruses are associated with public health. Here, we established the most comprehensive virome of healthy piglets to date, which provides a viromic baseline of weaned pigs for disease prevention and control, highlighting that longitudinal viromic monitoring is needed to better understand the dynamics of the virome in pig development and disease occurrence. The present study also shows how high standards of animal farm management with strict biosafety measures can significantly minimize the risk of introduction of pathogenic viruses into pig farms. Particularly, the viromic strategy established, i.e., high-throughput detection and analyses of various known and unknown pathogenic viruses in a single test at large scale, has completely innovated current surveillance measures in provision of timely and precise detection of all potentially existing pathogenic viruses and can be widely applied in other animal species.
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http://dx.doi.org/10.1128/mSystems.00420-21DOI Listing
June 2021

Andrographolide attenuates synovial inflammation of osteoarthritis by interacting with tumor necrosis factor receptor 2 trafficking in a rat model.

J Orthop Translat 2021 Jul 24;29:89-99. Epub 2021 May 24.

State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, PR China.

Background: Synovial inflammation plays a major role in the pathogenesis of osteoarthritis (OA). This study investigated the effect of andrographolide (Andro) on synovial inflammation mediated by tumor necrosis factor-alpha receptor 2 (TNFR2) trafficking and its utility in attenuating OA progression.

Methods: Knee joints were harvested from rats subjected to radial transection of the medial collateral ligament (MCLT) and medial meniscus (MMT) to examine the effect of Andro on synovial inflammation and OA progression. Quantitative real-time polymerase chain reaction was used to evaluate the expression of inflammatory factors in primary fibroblast-like synoviocytes (FLSs) after Andro treatment . The mechanism underlying Andro-mediated regulation of TNFR2 distribution and nuclear factor-κB (NF-κB) expression was verified using endosome maturation inhibitor hydroxychloroquine (HCQ) through flow cytometry, immunofluorescence, and western blot analysis.

Results: Andro treatment was found to reduce synovial inflammation and OA progression . Furthermore, a decrease in pain hypersensitivity and dorsal horn neuron activation was observed after treatment. Andro also downregulated the expression of inflammatory mediators and TNFR2 in FLSs. TNFR2 is crucial for the activation of the NF-κB signaling pathway, and Andro-induced degradation of TNFR2 was associated with lysosomal function, which in turn, reduced the downstream phosphorylation of p65 in the NF-κB signaling pathway.

Conclusions: Andro could suppress synovial inflammation via regulation of TNFR2 trafficking and degradation. This also suggests it could be a potential treatment for the prevention of synovial inflammation and OA progression.

The Translational Potential Of This Article: This study provides strong evidence that Andro reduces NF-κB activation and inflammatory responses in OA FLSs via regulation of TNFR2 trafficking. The inhibition of TNFR2 and Andro could be a novel therapeutic approach for OA and pain management.
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http://dx.doi.org/10.1016/j.jot.2021.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144533PMC
July 2021

Rapid fingerprint analysis for herbal polysaccharides using direct analysis in real-time ionization mass spectrometry.

Rapid Commun Mass Spectrom 2021 Aug;35(16):e9139

Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.

Rationale: Herbal polysaccharides have various potential medicinal values. Development of reliable analytical method for the fingerprint analysis of polysaccharides is critical for their quality assessment, origin identification, and authenticity evaluation.

Methods: Mechanochemical extraction (MCE) was used to extract polysaccharide components from different herbal species. Intact polysaccharides were then directly analyzed by direct analysis in real-time mass spectrometry (DART-MS). Standard addition method with isotope-labeled internal standard was used to quantify polysaccharide amounts directly from liquid extract. Multivariate data analysis was further conducted for species classification.

Results: The intact and large polysaccharides were decomposed into small fragment ions less than m/z 350 instantaneously using DART ion source. Different polysaccharides showed distinguished fingerprint DART-MS spectra using both individual and mixed herbal species. The liquid supernatant from MCE was validated to be used as direct sample for DART-MS analysis. Quantitation was successfully achieved for polysaccharide contents in Dendrobium officinale from different locations.

Conclusions: A rapid fingerprint protocol in combination of MCE and DART-MS for herbal polysaccharides was developed. The whole process could be accomplished within a few minutes, from raw materials to final spectra, without requirements of pre-digestion and additional sample purification.
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http://dx.doi.org/10.1002/rcm.9139DOI Listing
August 2021

SUMO proteases SENP3 and SENP5 spatiotemporally regulate the kinase activity of Aurora A.

J Cell Sci 2021 Jul 8;134(13). Epub 2021 Jul 8.

Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.

Precise chromosome segregation is mediated by a well-assembled mitotic spindle, which requires balance of the kinase activity of Aurora A (AurA, also known as AURKA). However, how this kinase activity is regulated remains largely unclear. Here, using in vivo and in vitro assays, we report that conjugation of SUMO2 with AurA at K258 in early mitosis promotes the kinase activity of AurA and facilitates the binding with its activator Bora. Knockdown of the SUMO proteases SENP3 and SENP5 disrupts the deSUMOylation of AurA, leading to increased kinase activity and abnormalities in spindle assembly and chromosome segregation, which could be rescued by suppressing the kinase activity of AurA. Collectively, these results demonstrate that SENP3 and SENP5 deSUMOylate AurA to render spatiotemporal control on its kinase activity in mitosis. This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/jcs.249771DOI Listing
July 2021

Robotic 3D bio-printing technology for repairing large segmental bone defects.

J Adv Res 2021 05 25;30:75-84. Epub 2020 Nov 25.

State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital Affiliated to Medical School of Nanjing University, China.

Introduction: The traditional clinical treatment of long segmental bone defects usually requires multiple operations and depends on donor availability. The 3D bio-printing technology constitutes a great potential therapeutic tool for such an injury. However, 3D bio-printing remains a major challenge.

Objectives: In this study, we report the repair of long segmental bone defects by 3D bio-printing using a robotic manipulator 3D printer in a swine model.

Methods: We systematically optimized bio-ink gelation under physiological conditions to achieve desirable mechanical properties suitable for bone regeneration, and a D-H kinematic model was used to improve printing accuracy to 0.5 mm.

Results: These technical improvements allowed the repair of long segmental defects generated on the right tibia of pigs using 3D bio-printing within 12 min. The 3D bio-printing group showed improved treatment effects after 3 months.

Conclusion: These findings indicated that robotic 3D bio-printing is promising for direct clinical application.
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http://dx.doi.org/10.1016/j.jare.2020.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132211PMC
May 2021

The gut microbiome as non-invasive biomarkers for identifying overweight people at risk for osteoarthritis.

Microb Pathog 2021 Aug 20;157:104976. Epub 2021 May 20.

State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Macau SAR, China; Shanghai Key Laboratory of Bioactive Small Molecules & School of Pharmacy, Fudan University, Shanghai, China. Electronic address:

Objective: To evaluate the potential for identifying overweight people at risk for osteoarthritis from a gut microbiome biomarker.

Background: Osteoarthritis (OA) is the most common form of arthritis, affecting millions of people worldwide. Being overweight increases the load placed on the joints such as the knee, which increases stress and could hasten the breakdown of cartilage. Identifying overweight people at risk for osteoarthritis remains a challenge. However, emerging evidence indicates that microbial dysbiosis in the human gut might play an important role in many inflammatory diseases. Considering the role of inflammation in OA development, analysis of the gut microbiome might be a potential non-invasive tool for overweight individuals to evaluate their risk for OA.

Results: In this prospective study, we collected 182 stool samples from overweight OA patients (n = 86) and overweight normal people (n = 96) (25 kg/m
Conclusion: We present the first 16S rRNA gene sequencing profiling study of stool microbiomes in overweight people to discover and validate microbial biomarkers indicating risk for OA. Our study successfully established a 7 biomarkers prediction panel, moving towards affordable non-invasive early diagnostic biomarkers for OA in stool samples from overweight individuals.
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http://dx.doi.org/10.1016/j.micpath.2021.104976DOI Listing
August 2021

TRPV1 alleviates osteoarthritis by inhibiting M1 macrophage polarization via Ca/CaMKII/Nrf2 signaling pathway.

Cell Death Dis 2021 May 18;12(6):504. Epub 2021 May 18.

State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China.

Osteoarthritis (OA) is the major course of joint deterioration, in which M1 macrophage-driven synovitis exacerbates the pathological process. However, precise therapies for M1 macrophage to decrease synovitis and attenuate OA progression have been scarcely proposed. Transient receptor potential vanilloid 1 (TRPV1) is a cation channel that has been implicated in pain perception and inflammation. In this study, we investigated the role of TRPV1 in the M1 macrophage polarization and pathogenesis of OA. We demonstrated that TRPV1 expression and M1 macrophage infiltration were simultaneously increased in both human and rat OA synovium. More than 90% of the infiltrated M1 macrophages expressed TRPV1. In the rat OA model, intra-articular injection of capsaicin (CPS), a specific TRPV1 agonist, significantly attenuated OA phenotypes, including joint swelling, synovitis, cartilage damage, and osteophyte formation. CPS treatment markedly reduced M1 macrophage infiltration in the synovium. Further mechanistic analyses showed that TRPV1-evoked Ca influx promoted the phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) and facilitated the nuclear localization of nuclear factor-erythroid 2-related factor 2 (Nrf2), which ultimately resulted in the inhibition of M1 macrophage polarization. Taken together, our findings establish that TRPV1 attenuates the progression of OA by inhibiting M1 macrophage polarization in synovium via the Ca/CaMKII/Nrf2 signaling pathway. These results highlight the effect of targeting TRPV1 for the development of a promising therapeutic strategy for OA.
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http://dx.doi.org/10.1038/s41419-021-03792-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131608PMC
May 2021

Tissue-Specific Splicing and Dietary Interaction of a Mutant Allele Determine Muscle Metabolic Fitness in Rodents.

Diabetes 2021 May 12. Epub 2021 May 12.

MOE Key Laboratory of Model Animal for Disease Study, Department of Endocrinology, Nanjing Drum Tower Hospital, and Model Animal Research Center, School of Medicine, Nanjing University, Nanjing

Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160 mutation that causes type 2 diabetes. Whether this mutation evolutionarily confers adaptation in Inuit and how it causes metabolic disorders upon dietary changes are unknown due to limitations in human studies. Here, we develop a genetically modified rat model bearing an orthologous AS160 mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160 rats. The AS160 mutation diminishes a dominant long-variant AS160 without affecting a minor short-variant AS160 in skeletal muscle, which suppresses muscle glucose utilization but induces fatty acid oxidation. This fuel switch suggests a possible adaptation in Inuit who traditionally had lipid-rich hypoglycemic diets. Finally, induction of the short-variant AS160 restores glucose utilization in rat myocytes and a mouse model. Our findings have implications for development of precision treatments for patients bearing the AS160 mutation.
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http://dx.doi.org/10.2337/db21-0039DOI Listing
May 2021

Persistent dependent behaviour is accompanied by dynamic switching between the ventral and dorsal striatal connections in internet gaming disorder.

Addict Biol 2021 May 6:e13046. Epub 2021 May 6.

Center for Cognition and Brain Disorders, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.

Cross-sectional studies have suggested that functional heterogeneity within the striatum in individuals with addictive behaviours may involve the transition from ventral to dorsal partitions; however, due to limitations of the cross-sectional design, whether the contribution of this transition to addiction was confused by individual differences remains unclear, especially for internet gaming disorder (IGD). Longitudinal functional magnetic resonance imaging (fMRI) data from 22 IGD subjects and 18 healthy controls were collected at baseline and more than 6 months later. We examined the connectivity features of subregions within the striatum between these two scans. Based on the results, we further performed dynamic causal modelling to explore the directional effect between regions and used these key features for data classification in machine learning to test the replicability of the results. Compared with controls, IGD subjects exhibited decreased functional connectivity between the left dorsal striatum (putamen) and the left insula, whereas connectivity between the right ventral striatum (nucleus accumbens [Nacc]) and the left insula was relatively stable over time. An inhibitory effective connectivity from the left putamen to the right Nacc was found in IGD subjects during the follow-up scan. Using the above features, the classification accuracy of the training model developed with the follow-up was better than that of the model based on the initial scan. Persistent IGD status was accompanied by a switch in the locus of control within the striatum, which provided new insights into association between IGD and drug addiction.
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http://dx.doi.org/10.1111/adb.13046DOI Listing
May 2021

Safety of house dust mite subcutaneous immunotherapy in preschool children with respiratory allergic diseases.

Ital J Pediatr 2021 Apr 23;47(1):101. Epub 2021 Apr 23.

Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, 430030, Hubei, China.

Background: Allergen immunotherapy (AIT) is the only causal therapy for IgE-mediated allergy. There is less evidence about the safety and efficacy of AIT especially subcutaneous immunotherapy (SCIT) in children under 5 years old. We aimed to investigate the side effects and associated risk factors of house dust mite (HDM) SCIT in preschool children with respiratory allergic diseases.

Methods: The preschool children who had HDM-related allergic rhinitis with/without asthma were enrolled and undergone standardized HDM SCIT in our department from June 2013 to December 2019. Local reactions (LRs) and systemic reactions (SRs) were recorded and categorized according to World Allergy Organization recommendations. Demographic data and other therapeutic-related parameters were also recorded to investigate potential risk factors for these side effects.

Results: A total of 91 children (60 boys, 65.93%; 31 girls, 34.07%; mean age 4.13 years old) were included in the study. Among the 91 patients, 3109 SCIT injections were recorded, 62/91 (68.13%) experienced 186 immediate LRs, 4 /91(4.40%) experienced 6 delayed LRs, 11/91 (12.09%) children experienced 44 immediate SRs, 21/44 (47.73%) were grade 1 SRs, 21/44 (47.73%) were grade 2, 2/44 (4.55%) were grade 3, no grade 4 or 5 SRs occurred. Furthermore, 1/91 (1.10%) experienced 1 delayed SRs, manifested by urticaria 2 days later after allergen injection. 9/91 (9.89%) experienced 2 or more times SRs. Multivariable logistic regression analysis showed BMI (OR 1.506; 95%CI 1.091 to 2.079; p < 0.05) and sIgE against HDM (OR 1.497; 95%CI 1.082 to 2.071; p < 0.05) were risk factors for LRs. No variable was found to correlate with SRs (all p > 0.05).

Conclusions: HDM subcutaneous immunotherapy is considered to be safe in preschool children with respiratory allergic diseases. Higher BMI and HDM sIgE level in children are risk factors for developing LRs. The incidence of SRs and the rate of severe SRs are low in preschool children.
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http://dx.doi.org/10.1186/s13052-021-01046-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063484PMC
April 2021

Citrate-Stabilized Gold Nanorods-Directed Osteogenic Differentiation of Multiple Cells.

Int J Nanomedicine 2021 12;16:2789-2801. Epub 2021 Apr 12.

Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, People's Republic of China.

Objective: Gold nanorods (AuNRs) show great potential for versatile biomedical applications, such as stem cell therapy and bone tissue engineering. However, as an indispensable shape-directing agent for the growth of AuNRs, cetyltrimethylammonium bromide (CTAB) is not optimal for biological studies because it forms a cytotoxic bilayer on the AuNR surface, which interferes with the interactions with biological cells.

Methods: Citrate-stabilized AuNRs with various aspect-ratios (Cit-NRI, Cit-NRII, and Cit-NRIII) were prepared by the combination of end-selective etching and poly(sodium 4-styrenesulfonate)-assisted ligand exchange method. Their effects on osteogenic differentiation of the pre-osteoblastic cell line (MC3T3-E1), rat bone marrow mesenchymal stem cells (rBMSCs), and human periodontal ligament progenitor cells (PDLPs) have been investigated. Potential signaling pathway of citrate-stabilized AuNRs-induced osteogenic effects was also investigated.

Results: The experimental results showed that citrate-stabilized AuNRs have superior biocompatibility and undergo aspect-ratio-dependent osteogenic differentiation via expression of osteogenic marker genes, alkaline phosphatase (ALP) activity and formation of mineralized nodule. Furthermore, Wnt/β-catenin signaling pathway might provide a potential explanation for the citrate-stabilized AuNRs-mediated osteogenic differentiation.

Conclusion: These findings revealed that citrate-stabilized AuNRs with great biocompatibility could regulate the osteogenic differentiation of multiple cell types through Wnt/β-catenin signaling pathway, which promote innovative AuNRs in the field of tissue engineering and other biomedical applications.
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http://dx.doi.org/10.2147/IJN.S299515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052123PMC
May 2021

Steric Hindrance- and Work Function-Promoted High Performance for Electrochemical CO Methanation on Antisite Defects of MoS and WS.

ChemSusChem 2021 May 28;14(10):2255-2261. Epub 2021 Apr 28.

Key Laboratory of Automobile Materials (Jilin University), Ministry of Education, P. R. China.

CO methanation from electrochemical CO reduction reaction (CORR) is significant for sustainable environment and energy, but electrocatalysts with excellent selectivity and activity are still lacking. Selectivity is sensitive to the structure of active sites, and activity can be tailored by work function. Moreover, intrinsic active sites usually possess relatively high concentration compared to artificial ones. Here, antisite defects Mo and W , intrinsic atomic defects of MoS and WS with a transition metal atom substituting a S column, were investigated for CORR by density functional theory calculations. The steric hindrance from the special bowl structure of Mo and W ensured good selectivity towards CO methanation. Coordination environment variation of the active sites, the under-coordinated Mo or W atoms, effectively lowered the work function, making Mo and W highly active for CO methanation with the required potential of -0.47 and -0.49 V vs. reversible hydrogen electrode, respectively. Moreover, high concentration of active sites and minimal structural deformation during the catalytic process of Mo and W enhanced their attraction for future commercial application.
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http://dx.doi.org/10.1002/cssc.202100457DOI Listing
May 2021

Methylene blue prevents osteoarthritis progression and relieves pain in rats via upregulation of Nrf2/PRDX1.

Acta Pharmacol Sin 2021 Apr 8. Epub 2021 Apr 8.

State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.

Oxidative stress-related cartilage degeneration, synovitis, and joint pain play vital roles in the progress of osteoarthritis (OA). Anti-oxidative stress agents not only prevent structural damage progression but also relieve OA-related pain. In this study, we investigated the therapeutic effect of methylene blue (MB), a classical and important anti-oxidant with strong neural affinity. Experimental OA was established in rats by radial transection of medial collateral ligament and medial meniscus (MCLT + MMT) of the right knee joint. The OA rats received intra-articular injection of MB (1 mg/kg) every week starting one week after surgery. We showed that MB administration exerted significant cartilage protection, synovitis inhibition as well as pain relief in OA rats. In human chondrocytes and fibroblast-like synoviocytes, MB significantly attenuated tert-butyl hydroperoxide (TBHP)-induced inflammatory response and oxidative stress. We demonstrated that these effects of MB resulted from dual targets of important antioxidant enzymes, Nrf2 and PRDX1, which also mutually reinforcing and participated in an interaction. Furthermore, we found that calcitonin gene-related peptide (CGRP), a neural inflammatory mediator, was accumulated around the vessel in synovium and subchondral bone in OA rats and in TBHP-treated primary cortical neurons; MB administration significantly inhibited CGRP expression through upregulation of Nrf2 and PRDX1. Taken together, these results suggest that MB ameliorates oxidative stress via Nrf2/PRDX1 regulation to prevent progression and relieve pain of OA.
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http://dx.doi.org/10.1038/s41401-021-00646-zDOI Listing
April 2021

Systematic review and meta-analysis of transgluteal versus prone approach to extracorporeal shockwave lithotripsy for patients with distal ureteral stones.

Asian J Surg 2021 Mar 23. Epub 2021 Mar 23.

Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address:

To explore the effectiveness of transgluteal approach during extracorporeal shockwave lithotripsy (ESWL) for patients with distal ureteral stones compared to the prone approach. A systematic literature search was carried out by two reviewers independently on the basis of three electronic databases up to Aug. 2020. Three randomized controlled trials (RCT) and one cohort studies (CS), with a total of 516 patients, comparing transgluteal approach with prone approach during ESWL for distal ureteral stones were included. The methodological quality of RCT was evaluated by Cochrane collaboration's tools, and the quality of CS and CCS was evaluated by modified Newcatle-Ottawa scale. The weighted mean difference (WMD) and odds ratio (OR) was respectively used to describe results of continuous and dichotomous variables. Pooled data showed that transgluteal approach could significantly improve the rate of stone free after the first treatment [OR = 3.18, 95% confidence interval (CI) 2.19-4.63, p < 0.00001] and the rate of overall stone free (OR = 4.03, 95% CI 2.43-6.69, p < 0.00001). In addition, compared with the prone approach, the transgluteal one could also significantly reduce the rate of ureteroscopy (OR = 0.21, 95% CI 0.12-0.36, p < 0.00001). What's more, complications were rarely reported, which demonstrated a similar safety for two approaches. Our study suggested that, during ESWL for patients with distal ureteral stones, transgluteal approach was a safe and more effective choice than the prone position.
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http://dx.doi.org/10.1016/j.asjsur.2021.02.021DOI Listing
March 2021

Fabrication of customized Ti6AI4V heterogeneous scaffolds with selective laser melting: Optimization of the architecture for orthopedic implant applications.

Acta Biomater 2021 05 22;126:485-495. Epub 2021 Mar 22.

National Engineering Research Center for Biomaterials, Sichuan University, 610064, Chengdu, China; College of Biomedical Engineering, Sichuan University, 610064, Chengdu, China.

Orthopedic implants with heterogeneous porous structures were known as ideal bone osteointegration. This research introduced the selective laser melting (SLM), finite element analysis (FEA), and a hydrothermal process (HT) for manufacturing a three-level heterogeneous porous structure. The macroporous structure was designed via CAD and micropores were tuned via laser power regulation. A nano-size layer of hydroxyapatite crystals was coated by an HT process. The mechanical properties were reinforced via a core-shell structure with core reinforcement. The existence of micropores and nano-hydroxyapatite coating enhanced the in vitro proliferation of preosteoblasts and osteogenic cellular behaviors of rBMSCs. Thus, the three-level heterogeneous porous titanium implants could inspire researchers with potential clue of cyto-implant interaction mechanism, therefore building ideal orthopedic implants with accelerated osteointegration. STATEMENT OF SIGNIFICANCE: Porous structures of titanium implants play an important role in bone tissue regeneration; The geometrical environment influence cell behaviour and bone tissue ingrowth in all macro-/micro-/nanoscale. In this study, a novel method to fabricate heterogeneous scaffolds and its macro-/micro-/nanoscopic structures were studied. A CAD model was used to obtain the macroscopic structure and the insufficient laser power was introduced for porous microstructure. Therefore, a layer of nano hydroxyapatite was coated via hydrothermal process. Cytoproliferation and cytodifferentiation results indicated that a integrity of regular/irregular, macro-/micro-/nanoscale porous structure had advance in recruiting stem cells and promoting differentiation. This research is beneficial to the development of bone implants with better bone regeneration ability.
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http://dx.doi.org/10.1016/j.actbio.2021.03.040DOI Listing
May 2021

Which factors are associated with the prevalence of meniscal repair?

BMC Musculoskelet Disord 2021 Mar 22;22(1):295. Epub 2021 Mar 22.

Department of Orthopedics, Affiliated Taikang Xianlin Drum Tower Hospital, Medical school of Nanjing University, Nanjing, Jiangsu, P.R. China.

Purpose To investigate the potential factors associated with the prevalence of meniscal repair Methods Patients who received partial meniscectomy or meniscal repair in our institution from Jan 2015 to Dec 2019 were included in current study. The inclusion criteria were (1) meniscus tear treated using meniscectomy or repair, (2) with or without concomitant anterior cruciate ligament reconstruction, (3) not multiligamentous injury. Demographic data, including sex, age, body mass index (BMI), injury-to-surgery interval and intra-articular factors such as the location of injury, medial or lateral, ACL rupture or not and the option of procedure (partial meniscectomy or repair) were documented from medical records. Univariate analysis consisted of chi-square. Multivariate logistic regression was then performed to adjust for confounding factors. Results 592 patients including 399 males and 193 females with a mean age of 28.7 years (range from 10 to 75 years) were included in current study. In the univariate analysis, male (p = 0.002), patients aged 40 years or younger (p < 0.001), increased weight (p = 0.010), Posterior meniscus torn (0.011), concurrent ACL ruputure (p < 0.001), lateral meniscus (p = 0.039) and early surgery (p < 0.001) were all associated with the prevalence of meniscal repair. However, After adjusting for confounding factors, we found that age (OR, 0.35; 95% CI, 0.17 - 0.68, p = 0.002), ACL injury (OR, 3.76; 95% CI, 1.97 - 7.21, p < 0.001), side of menisci (OR, 3.29; 95% CI, 1.43 - 7.55, p = 0.005), site of tear (OR, 0.15; 95% CI, 0.07 - 0.32, p < 0.001), and duration of injury (OR, 0.46; 95% CI, 0.28 - 0.82, p = 0.008) were associated with the prevalence of meniscus repair. Conclusions Meniscal tear in aged patients especially those with concomitant ACL injury is likely to be repaired. Additionally, in order to increase the prevalence of repair and slow down progression of OA, the surgical procedure should be performed within two weeks after meniscus tear especially when the tear is located at lateral meniscal posterior. STUDY DESIGN: Case-control study; level of evidence, 3.
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http://dx.doi.org/10.1186/s12891-021-04107-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983264PMC
March 2021

Bone metabolic biomarker-based diagnosis of type 2 diabetes osteoporosis by support vector machine.

Ann Transl Med 2021 Feb;9(4):316

State Key Laboratory of Bioelectronics, Jiangsu Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.

Background: Diabetes has significant effects on bone metabolism. Both type 1 and type 2 diabetes can cause osteoporotic fracture. However, it remains challenging to diagnose osteoporosis in type 2 diabetes by bone mineral density which lacks regular changes. Seen another way, osteoporosis can be ascribed to the imbalance of bone metabolism, which is closely related to diabetes as well.

Methods: Here, to assist clinicians in diagnosing osteoporosis in type 2 diabetes, an efficient and simple SVM (support vector machine) model was established based on different combinations of biochemical indexes, which were collected from patients who did the test of bone turn-over markers (BTMs) from January 2016 to March 2018 in the department of endocrine, Zhongda Hospital affiliated to Southeast University. The classification was done based on a software package of machine learning in Python. The classification performance was measured by SKLearn program incorporated in the Python software package and compared with the clinical diagnostic results.

Results: The predicting accuracy rate of final model was above 88%, with feature combination of sex, age, BMI (body mass index), TP1NP (total procollagen I N-terminal propeptide) and OSTEOC (osteocalcin).

Conclusions: Experimental results show that the model showed an anticipant result for early detection and daily monitoring on type 2 diabetic osteoporosis.
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http://dx.doi.org/10.21037/atm-20-3388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944260PMC
February 2021

Nrf2 epigenetic derepression induced by running exercise protects against osteoporosis.

Bone Res 2021 Feb 26;9(1):15. Epub 2021 Feb 26.

Center for Organ Fibrosis and Remodeling Research, Jiangsu Key Lab of Molecular Medicine, Nanjing University Medical School, Nanjing, 210093, China.

Osteoporosis (OP) is a common skeletal disease involving low bone mineral density (BMD) that often leads to fragility fracture, and its development is affected by multiple cellular pathologies and associated with marked epigenetic alterations of osteogenic genes. Proper physical exercise is beneficial for bone health and OP and reportedly possesses epigenetic modulating capacities; however, whether the protective effects of exercise on OP involve epigenetic mechanisms is unclear. Here, we report that epigenetic derepression of nuclear factor erythroid derived 2-related factor-2 (Nrf2), a master regulator of oxidative stress critically involved in the pathogenesis of OP, mediates the significant osteoprotective effects of running exercise (RE) in a mouse model of OP induced by ovariectomy. We showed that Nrf2 gene knockout (Nfe2l2) ovariectomized mice displayed a worse BMD reduction than the controls, identifying Nrf2 as a critical antiosteoporotic factor. Further, femoral Nrf2 was markedly repressed with concomitant DNA methyltransferase (Dnmt) 1/Dnmt3a/Dnmt3b elevations and Nrf2 promoter hypermethylation in both patients with OP and ovariectomized mice. However, daily 1-h treadmill RE significantly corrected epigenetic alterations, recovered Nrf2 loss and improved the femur bone mass and trabecular microstructure. Consistently, RE also normalized the adverse expression of major osteogenic factors, including osteoblast/osteoclast markers, Nrf2 downstream antioxidant enzymes and proinflammatory cytokines. More importantly, the RE-conferred osteoprotective effects observed in the wild-type control mice were largely abolished in the Nfe2l2 mice. Thus, Nrf2 repression due to aberrant Dnmt elevation and subsequent Nrf2 promoter hypermethylation is likely an important epigenetic feature of the pathogenesis of OP, and Nrf2 derepression is essential for the antiosteoporotic effects of RE.
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http://dx.doi.org/10.1038/s41413-020-00128-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910611PMC
February 2021

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

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

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

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

Load-induced regulation of tendon homeostasis by SPARC, a genetic predisposition factor for tendon and ligament injuries.

Sci Transl Med 2021 02;13(582)

Institute of Tendon and Bone Regeneration, Paracelsus Medical University-Spinal Cord Injury and Tissue Regeneration Center Salzburg, 5020 Salzburg, Austria.

Tendons and tendon interfaces have a very limited regenerative capacity, rendering their injuries clinically challenging to resolve. Tendons sense muscle-mediated load; however, our knowledge on how loading affects tendon structure and functional adaption remains fragmentary. Here, we provide evidence that the matricellular protein secreted protein acidic and rich in cysteine (SPARC) is critically involved in the mechanobiology of tendons and is required for tissue maturation, homeostasis, and enthesis development. We show that tendon loading at the early postnatal stage leads to tissue hypotrophy and impaired maturation of Achilles tendon enthesis in mice. Treadmill training revealed a higher prevalence of spontaneous tendon ruptures and a net catabolic adaptation in mice. Tendon hypoplasia was attenuated in mice in response to muscle unloading with botulinum toxin A. In vitro culture of three-dimensional tendon constructs showed load-dependent impairment of ribosomal S6 kinase activation, resulting in reduced type I collagen synthesis. Further, functional calcium imaging revealed that lower stresses were required to trigger mechanically induced responses in tendon fascicles. To underscore the clinical relevance of the findings, we further demonstrate that a missense mutation (p.Cys130Gln) in the follistatin-like domain of , which causes impaired protein secretion and type I collagen fibrillogenesis, is associated with tendon and ligament injuries in patients. Together, our results demonstrate that SPARC is a key extracellular matrix protein essential for load-induced tendon tissue maturation and homeostasis.
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http://dx.doi.org/10.1126/scitranslmed.abe5738DOI Listing
February 2021

Rbbp4 Suppresses Premature Differentiation of Embryonic Stem Cells.

Stem Cell Reports 2021 03 18;16(3):566-581. Epub 2021 Feb 18.

State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, 12 Xuefu Road, Nanjing, Jiangsu 210061, China. Electronic address:

Polycomb group (PcG) proteins exist in distinct multi-protein complexes and play a central role in silencing developmental genes, yet the underlying mechanisms remain elusive. Here, we show that deficiency of retinoblastoma binding protein 4 (RBBP4), a component of the Polycomb repressive complex 2 (PRC2), in embryonic stem cells (ESCs) leads to spontaneous differentiation into mesendodermal lineages. We further show that Rbbp4 and core PRC2 share an important number of common genomic targets, encoding regulators involved in early germ layer specification. Moreover, we find that Rbbp4 is absolutely essential for genomic targeting of PRC2 to a subset of developmental genes. Interestingly, we demonstrate that Rbbp4 is necessary for sustaining the expression of Oct4 and Sox2 and that the forced co-expression of Oct4 and Sox2 fully rescues the pluripotency of Rbbp4-null ESCs. Therefore, our study indicates that Rbbp4 links maintenance of the pluripotency regulatory network with repression of mesendoderm lineages.
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http://dx.doi.org/10.1016/j.stemcr.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940252PMC
March 2021

Fused Quinoidal Dithiophene-Based Helicenes: Synthesis by Intramolecular Radical-Radical Coupling Reactions and Dynamics of Interconversion of Enantiomers.

Angew Chem Int Ed Engl 2021 Apr 17;60(18):10326-10333. Epub 2021 Mar 17.

Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543, Singapore, Singapore.

A series of fused quinoidal dithiophene-based double and triple helicenes (1-M, 2-M, 2-M-Cl, 3-M, 3-M-Cl) were synthesized by intramolecular radical-radical coupling followed by oxidative dehydrogenation reaction. These helical molecules show dynamic interconversion of enantiomers in solution as revealed by variable-temperature NMR measurements, and the energy barriers are correlated to the substituents and topological structures. Notably, dynamic high performance liquid chromatography was used to quantitatively investigate the room-temperature racemization process between the (P,P,M)- and (P,M,M)- enantiomers of the triple helical 3-M-Cl, which gave an interconversion energy barrier in consistent with density functional theory calculations. Their optical and electrochemical properties are dependent on the fusion mode. Our studies provide both new synthetic strategy and new dynamic analytical method for helicenes with unique electronic structure.
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http://dx.doi.org/10.1002/anie.202100606DOI Listing
April 2021