Publications by authors named "Jiajia Xu"

97 Publications

Depletion of hsa_circ_0000144 Suppresses Oxaliplatin Resistance of Gastric Cancer Cells by Regulating miR-502-5p/ADAM9 Axis.

Onco Targets Ther 2021 20;14:2773-2787. Epub 2021 Apr 20.

Department of Radiotherapy, Yijishan Hospital of Wannan Medical College, Wuhu City, Anhui Province, 241001, People's Republic of China.

Background: Circular RNAs (circRNAs) have been disclosed to exert important roles in human cancers, including gastric cancer (GC). CircRNA hsa_circ_0000144 was identified as an oncogene in GC development. The aim of our study was to explore the role of hsa_circ_0000144 in oxaliplatin (OXA) resistance of GC.

Methods: Expression levels of hsa_circ_0000144, microRNA-502-5p (miR-502-5p) and A disintegrin and metalloproteinase 9 (ADAM9) were examined by quantitative real-time PCR (RT-qPCR) or Western blot assay. The OXA resistance of GC cells was evaluated by Cell Counting Kit-8 (CCK-8) assay. Colony formation assay was performed to assess the colony formation capacity. Cell apoptosis was determined by flow cytometry and caspase 3 activity. And cell migration and invasion were detected by Transwell assay. Target association between miR-502-5p and hsa_circ_0000144 or ADAM9 was demonstrated by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Moreover, role of hsa_circ_0000144 in vivo was analyzed by xenograft tumor assay.

Results: Hsa_circ_0000144 and ADAM9 were highly expressed, while miR-502-5p was downregulated in OXA-resistant GC tissues and cells. Depletion of hsa_circ_0000144 could inhibit OXA resistance, proliferation and metastasis in OXA-resistant GC cells, which was attenuated by miR-502-5p inhibition. Hsa_circ_0000144 sponged miR-502-5p to positively regulate ADAM9 expression. MiR-502-5p suppressed OXA resistance, proliferation and metastasis in OXA-resistant GC cells by targeting ADAM9. Hsa_circ_0000144 knockdown could hamper tumor growth in vivo.

Conclusion: Hsa_circ_0000144 exerted inhibitory effects on OXA resistance, proliferation and metastasis of OXA-resistant GC cells by regulating miR-502-5p/ADAM9 axis, at least in part.
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http://dx.doi.org/10.2147/OTT.S281238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068497PMC
April 2021

A Sensitive and Rapid Assay for Mycoplasma hominis Detection Based on Recombinase Polymerase Amplification.

Clin Lab 2021 Apr;67(4)

Background: Mycoplasma hominis (MH) is an opportunistic pathogen, which often causes funisitis, spontaneous abortion, and low birth weight. However, current laboratory methods are time-consuming, labor-intensive, or require specialized laboratory instruments. Recombinase polymerase amplification (RPA) technology is a rapidly developing field because of the significance for clinical application and commercial value. Few studies have reported the use of RPA to detect MH. In this study, we developed the rapid MH detection assay, which may be potentially used as a sensitive point-of-care testing (POCT) in clinic.

Methods: Primers based on the MH 16SrRNA gene and gap gene were explored and screened out. The probe of RPA-LFD was designed based on the optimal primer and confirmed. The reaction conditions of temperature and time for RPA were optimized. The sensitivity and specificity of the analysis were explored. A total of 60 clinical specimens were used to verify the efficiency of the two methods.

Results: The optimal reaction conditions were determined as 15 minutes and 39°C. The sensitivity of RPA was 10-6 ng for MH, which is 100,000 times more sensitive than traditional PCR. Moreover, we observed another six non-target reproductive tract common pathogens without amplification products. Furthermore, we found that there was no significant difference between RPA and the cultivation method (p > 0.05). These two methods were in good agreement (κ = 0.938) when detecting clinical specimens.

Conclusions: A new method for sensitive and rapid detection of MH based on RPA was successfully developed, which can be applied in large-scale screening and as a supplementary method to classical methods.
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http://dx.doi.org/10.7754/Clin.Lab.2020.200826DOI Listing
April 2021

Comprehensive Machine Learning-Based Model for Predicting Compressive Strength of Ready-Mix Concrete.

Materials (Basel) 2021 Feb 25;14(5). Epub 2021 Feb 25.

Department of Chemical Engineering, Sichuan University, Chengdu 610065, China.

Considering that compressive strength (CS) is an important mechanical property parameter in many design codes, in order to ensure structural safety, concrete CS needs to be tested before application. However, conducting CS tests with multiple influencing variables is costly and time-consuming. To address this issue, a machine learning-based modeling framework is put forward in this work to evaluate the concrete CS under complex conditions. The influential factors of this process are systematically categorized into five aspects: man, machine, material, method and environment (4M1E). A genetic algorithm (GA) was applied to identify the most important influential factors for CS modeling, after which, random forest (RF) was adopted as the modeling algorithm to predict the CS from the selected influential factors. The effectiveness of the proposed model was tested on a case study, and the high Pearson correlation coefficient (0.9821) and the low mean absolute percentage error and delta (0.0394 and 0.395, respectively) indicate that the proposed model can deliver accurate and reliable results.
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http://dx.doi.org/10.3390/ma14051068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956418PMC
February 2021

Deubiquitinase USP39 and E3 ligase TRIM26 balance the level of ZEB1 ubiquitination and thereby determine the progression of hepatocellular carcinoma.

Cell Death Differ 2021 Mar 1. Epub 2021 Mar 1.

Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China.

Emerging evidence suggests that USP39 plays an important role in the development of hepatocellular carcinoma (HCC). However, the molecular mechanism by which USP39 promotes HCC progression has not been well defined, especially regarding its putative ubiquitination function. Zinc-finger E-box-binding homeobox 1 (ZEB1) is a crucial inducer of epithelial-to-mesenchymal transition (EMT) to promote tumor proliferation and metastasis, but the regulatory mechanism of ZEB1 stability in HCC remains enigmatic. Here, we reveal that USP39 is highly expressed in human HCC tissues and correlated with poor prognosis. Moreover, USP39 depletion inhibits HCC cell proliferation and metastasis by promoting ZEB1 degradation. Intriguingly, deubiquitinase USP39 has a direct interaction with the E3 ligase TRIM26 identified by co-immunoprecipitation assays and immunofluorescence staining assays. We further demonstrate that TRIM26 is lowly expressed in human HCC tissues and inhibits HCC cell proliferation and migration. TRIM26 promotes the degradation of ZEB1 protein by ubiquitination in HCC. Deubiquitinase USP39 and E3 ligase TRIM26 function in an antagonistic pattern, but not a competitive pattern, and play key roles in controlling ZEB1 stability to determine the HCC progression. In summary, our data reveal a previously unknown mechanism that USP39 and TRIM26 balance the level of ZEB1 ubiquitination and thereby determine HCC cell proliferation and migration. This novel mechanism may provide new approaches to target treatment for inhibiting HCC development by restoring TRIM26 or suppressing USP39 expression in HCC cases with high ZEB1 protein levels.
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http://dx.doi.org/10.1038/s41418-021-00754-7DOI Listing
March 2021

Comparison of MRI and CT for the Prediction of Microvascular Invasion in Solitary Hepatocellular Carcinoma Based on a Non-Radiomics and Radiomics Method: Which Imaging Modality Is Better?

J Magn Reson Imaging 2021 Feb 23. Epub 2021 Feb 23.

Department of Radiology, Jiangsu Key Laboratory of Molecular and Functional Imaging, Zhongda Hospital, Medical School of Southeast University, Nanjing, China.

Background: Computed tomography (CT) and magnetic resonance imaging (MRI) are both capable of predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). However, which modality is better is unknown.

Purpose: To intraindividually compare CT and MRI for predicting MVI in solitary HCC and investigate the added value of radiomics analyses.

Study Type: Retrospective.

Subjects: Included were 402 consecutive patients with HCC (training set:validation set = 300:102).

Field Strength/sequence: T2-weighted, diffusion-weighted, and contrast-enhanced T1-weighted imaging MRI at 3.0T and contrast-enhanced CT.

Assessment: CT- and MR-based radiomics signatures (RS) were constructed using the least absolute shrinkage and selection operator regression. CT- and MR-based radiologic (R) and radiologic-radiomics (RR) models were developed by univariate and multivariate logistic regression. The performance of the RS/models was compared between two modalities. To investigate the added value of RS, the performance of the R models was compared with the RR models in HCC of all sizes and 2-5 cm in size.

Statistical Tests: Model performance was quantified by the area under the receiver operating characteristic curve (AUC) and compared using the Delong test.

Results: Histopathologic MVI was identified in 161 patients (training set:validation set = 130:31). MRI-based RS/models tended to have a marginally higher AUC than CT-based RS/models (AUCs of CT vs. MRI, P: RS, 0.801 vs. 0.804, 0.96; R model, 0.809 vs. 0.832, 0.09; RR model, 0.835 vs. 0.872, 0.54). The improvement of RR models over R models in all sizes was not significant (P = 0.21 at CT and 0.09 at MRI), whereas the improvement in 2-5 cm was significant at MRI (P < 0.05) but not at CT (P = 0.16).

Data Conclusion: CT and MRI had a comparable predictive performance for MVI in solitary HCC. The RS of MRI only had significant added value for predicting MVI in HCC of 2-5 cm.

Level Of Evidence: 3 TECHNICAL EFFICACY: Stage 2.
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http://dx.doi.org/10.1002/jmri.27575DOI Listing
February 2021

Alleviating the nitrite stress on anaerobic ammonium oxidation by pyrolytic biochar.

Sci Total Environ 2021 Jun 12;774:145800. Epub 2021 Feb 12.

School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.

The nitrite (NO) inhibition in anaerobic ammonium oxidation (anammox) process is widely reported. Here, the effects of three pyrolytic biochars (CS300, CS550 and CS800) were investigated to alleviate NO stress on anammox process under exposure of varied NO-N concentrations (70, 200, 400 and 600 mg L). No nitrite inhibition was observed at 70 mg N L. However, the total nitrogen removal efficiency (TNREs) decreased with NO-N concentration increased, while the biochar-amended groups achieved higher TNREs than the control (CK). At 200 mg N L, the TNREs were 60.2%, 99.0%, 98.5% and 86.6% for CK, CS300, CS550 and CS800, respectively. At 400 mg N L, the TNREs were 23.3%, 56.0%, 37.1% and 29.7% for CK, CS300, CS550 and CS800, respectively. At 600 mg N L in which severe inhibition was observed, the TNREs were increased by 231% (p = 0.002), 149% (p = 0.014), and 51.0% (p = 0.166) for CS300, CS550 and CS800, respectively, as compared to CK, with the corresponding specific anammox activity increased by 3.1-, 2,0- and 1.1-folds, respectively. CS300 enriched the relative abundance of Candidatus Kuenenia and increased the gene copies of functional genes (hzsA, hdh, nirS and nirK). Besides, CS300 effectively alleviated the suppression of three membrane-associated enzyme complexes for anammox electron transport chain, indicating the possible contribution of redox-active moieties of CS300 to energy conversion metabolism for mitigating the NO-N inhibition. This study provided an effective strategy for alleviating NO-N stress by applying an environmentally compatible material (biochar) on anammox process.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145800DOI Listing
June 2021

Assessing the Bone-Forming Potential of Pericytes.

Methods Mol Biol 2021 ;2235:127-137

Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.

Human pericytes are a perivascular cell population with mesenchymal stem cell properties, present in all vascularized tissues. Human pericytes have a distinct immunoprofile, which may be leveraged for purposes of cell purification. Adipose tissue is the most commonly used cell source for human pericyte derivation. Pericytes can be isolated by FACS (fluorescence-activated cell sorting), most commonly procured from liposuction aspirates. Pericytes have clonal multilineage differentiation potential, and their potential utility for bone regeneration has been described across multiple animal models. The following review will discuss in vivo methods for assessing the bone-forming potential of purified pericytes. Potential models include (1) mouse intramuscular implantation, (2) mouse calvarial defect implantation, and (3) rat spinal fusion models. In addition, the presented surgical protocols may be used for the in vivo analysis of other osteoprogenitor cell types.
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http://dx.doi.org/10.1007/978-1-0716-1056-5_9DOI Listing
March 2021

Divergent effects of distinct perivascular cell subsets for intra-articular cell therapy in posttraumatic osteoarthritis.

J Orthop Res 2021 Jan 29. Epub 2021 Jan 29.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Intra-articular injection of mesenchymal stem cells has shown benefit for the treatment of osteoarthritis (OA). However, mesenchymal stem/stromal cells at the origin of these clinical results are heterogenous cell populations with limited cellular characterization. Here, two transgenic reporter mice were used to examine the differential effects of two precisely defined perivascular cell populations (Pdgfrα  and Pdgfrβ  cells) from white adipose tissue for alleviation of OA. Perivascular mesenchymal cells were isolated from transgenic Pdgfrα-and Pdgfrβ-CreER reporter animals and delivered as a one-time intra-articular dose to C57BL/6J mice after destabilization of the medial meniscus (DMM). Both Pdgfrα  and Pdgfrβ  cell preparations improved metrics of cartilage degradation and reduced markers of chondrocyte hypertrophy. While some similarities in cell distribution were identified within the synovial and perivascular spaces, injected Pdgfrα  cells remained in the superficial layers of articular cartilage, while Pdgfrβ  cells were more widely dispersed. Pdgfrβ  cell therapy prevented subchondral sclerosis induced by DMM, while Pdgfrα  cell therapy had no effect. In summary, while both cell therapies showed beneficial effects in the DMM model, important differences in cell incorporation, persistence, and subchondral sclerosis were identified.
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http://dx.doi.org/10.1002/jor.24997DOI Listing
January 2021

circRNA circ_102049 Implicates in Pancreatic Ductal Adenocarcinoma Progression through Activating CD80 by Targeting miR-455-3p.

Mediators Inflamm 2021 7;2021:8819990. Epub 2021 Jan 7.

Department of Medical Service, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China.

Emerging evidence has shown that circular RNAs (circRNAs) and DNA methylation play important roles in the causation and progression of cancers. However, the roles of circRNAs and abnormal methylation genes in the tumorigenesis of pancreatic ductal adenocarcinoma (PDAC) are still largely unknown. Expression profiles of circRNA, gene methylation, and mRNA were downloaded from the GEO database, and differentially expressed genes were obtained via GEO2R, and a ceRNA network was constructed based on circRNA-miRNA pairs and miRNA-mRNA pairs. Inflammation-associated genes were collected from the GeneCards database. Then, functional enrichment analysis and protein-protein interaction (PPI) networks of inflammation-associated methylated expressed genes were investigated using Metascape and STRING databases, respectively, and visualized in Cytoscape. Hub genes of PPI networks were identified using the NetworkAnalyzer plugin. Also, we analyzed the methylation, protein expression levels, and prognostic value of hub genes in PDAC patients through the UALCAN, Human Protein Atlas (HPA), and Kaplan-Meier plotter databases, respectively. The circRNA_102049/miR-455-3p/CD80 axis was identified by the ceRNA network and hub genes. In vitro and in vivo experiments were performed to evaluate the functions of circRNA_102049. The regulatory mechanisms of circRNA_102049 and miR-455-3p were explored by RT-PCR, western blot, and dual-luciferase assays. In the present study, twelve hub genes (STAT1, CCND1, KRAS, CD80, ICAM1, ESR1, RAF1, RPS6KA2, KDM6B, TNRC6A, FOSB, and DNM1) were determined from the PPI networks. Additionally, the circRNA_102049 was upregulated in PDAC cell lines. Functionally, the knockdown of circRNA_102049 by siRNAs inhibited cell growth, inflammatory factors, and migratory and invasive potential and promoted cell apoptosis. Mechanistically, circRNA_102049 functioned as a sponge of miR-455-3p and partially reversed the effect of miR-455-3p and consequently upregulated CD80 expression. Our findings showed that circRNA_102049 and methylated hub genes play an important role in the proliferation, apoptosis, migration, invasion, and inflammatory response of PDAC, which might be selected as a promising prognostic marker and therapeutic target for PDAC.
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http://dx.doi.org/10.1155/2021/8819990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811564PMC
January 2021

Systemic DKK1 neutralization enhances human adipose-derived stem cell mediated bone repair.

Stem Cells Transl Med 2021 Apr 30;10(4):610-622. Epub 2020 Dec 30.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Progenitor cells from adipose tissue are able to induce bone repair; however, inconsistent or unreliable efficacy has been reported across preclinical and clinical studies. Soluble inhibitory factors, such as the secreted Wnt signaling antagonists Dickkopf-1 (DKK1), are expressed to variable degrees in human adipose-derived stem cells (ASCs), and may represent a targetable "molecular brake" on ASC mediated bone repair. Here, anti-DKK1 neutralizing antibodies were observed to increase the osteogenic differentiation of human ASCs in vitro, accompanied by increased canonical Wnt signaling. Human ASCs were next engrafted into a femoral segmental bone defect in NOD-Scid mice, with animals subsequently treated with systemic anti-DKK1 or isotype control during the repair process. Human ASCs alone induced significant but modest bone repair. However, systemic anti-DKK1 induced an increase in human ASC engraftment and survival, an increase in vascular ingrowth, and ultimately improved bone repair outcomes. In summary, anti-DKK1 can be used as a method to augment cell-mediated bone regeneration, and could be particularly valuable in the contexts of impaired bone healing such as osteoporotic bone repair.
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http://dx.doi.org/10.1002/sctm.20-0293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980212PMC
April 2021

Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification.

Bone Res 2019 Dec 10;7(1):36. Epub 2019 Dec 10.

Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Heterotopic ossification (HO) is a debilitating condition characterized by the pathologic formation of ectopic bone. HO occurs commonly following orthopedic surgeries, burns, and neurologic injuries. While surgical excision may provide palliation, the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native bone. Based on these clinical observations, we set out to examine the role of vascular signaling in HO. Vascular endothelial growth factor A (VEGFA) has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and homeostasis. Our findings, using a validated mouse model of HO, demonstrate that HO lesions are highly vascular, and that VEGFA is critical to ectopic bone formation, despite lacking a contribution of endothelial cells within the developing anlagen.
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http://dx.doi.org/10.1038/s41413-019-0075-6DOI Listing
December 2019

Regulation of (p)ppGpp and Its Homologs on Environmental Adaptation, Survival, and Pathogenicity of Streptococci.

Front Microbiol 2020 25;11:1842. Epub 2020 Sep 25.

State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.

Most streptococci are commensals, pathogens, or opportunistic pathogens for humans and animals. Therefore, it is important for streptococci to adapt to the various challenging environments of the host during the processes of infection or colonization, as well as to conditions for transmission. Stringent response (SR) is a special class of adaptive response induced by the signal molecules (p)ppGpp, which regulate several physiological aspects, such as long-term persistence, virulence, biofilm formation, and quorum sensing in bacteria. To understand the roles of SR in streptococci, the current mini-review gives a general overview on: (1) (p)ppGpp synthetases in the genus of , (2) the effects of (p)ppGpp on the physiological phenotypes, persistence, and pathogenicity of streptococci, (3) the transcriptional regulation induced by (p)ppGpp in streptococci, and (4) the link between (p)ppGpp and another nutrient regulatory protein CodY in streptococci.
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http://dx.doi.org/10.3389/fmicb.2020.01842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545056PMC
September 2020

Lysosomal protein surface expression discriminates fat- from bone-forming human mesenchymal precursor cells.

Elife 2020 10 12;9. Epub 2020 Oct 12.

Departments of Pathology, Johns Hopkins University, Baltimore, United States.

Tissue resident mesenchymal stem/stromal cells (MSCs) occupy perivascular spaces. Profiling human adipose perivascular mesenchyme with antibody arrays identified 16 novel surface antigens, including endolysosomal protein CD107a. Surface CD107a expression segregates MSCs into functionally distinct subsets. In culture, CD107a cells demonstrate high colony formation, osteoprogenitor cell frequency, and osteogenic potential. Conversely, CD107a cells include almost exclusively adipocyte progenitor cells. Accordingly, human CD107a cells drove dramatic bone formation after intramuscular transplantation in mice, and induced spine fusion in rats, whereas CD107a cells did not. CD107a protein trafficking to the cell surface is associated with exocytosis during early adipogenic differentiation. RNA sequencing also suggested that CD107a cells are precursors of CD107a cells. These results document the molecular and functional diversity of perivascular regenerative cells, and show that relocation to cell surface of a lysosomal protein marks the transition from osteo- to adipogenic potential in native human MSCs, a population of substantial therapeutic interest.
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http://dx.doi.org/10.7554/eLife.58990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550188PMC
October 2020

Antimicrobial Effect of Hemolymph against Bovine Mastitis Pathogens.

Microorganisms 2020 Sep 28;8(10). Epub 2020 Sep 28.

Department of Veterinary Clinical Sciences, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.

Coliforms and spp. infections are the leading causes of bovine mastitis. Despite extensive research and development in antibiotics, they have remained inadequately effective in treating bovine mastitis induced by multiple pathogen infection. In the present study, we showed the protective effect of () hemolymph on bovine mammary epithelial cells against bacterial infection. hemolymph directly kills both Gram-positive and Gram-negative bacteria through membrane permeation and prevents the adhesion of or the clinically isolated strain to bovine mammary epithelial (MAC-T) cells. In addition, hemolymph downregulates the expression of nucleotide-binding oligomerization domain (NOD)-like receptor family member pyrin domain-containing protein 3 (NLRP3), caspase-1, and NLRP6, as well as inhibits the secretion of interleukin-1β (IL-1β) and IL-18, which attenuates or -induced pyroptosis. Overall, our results suggest the potential role of hemolymph as a novel therapeutic candidate for bovine mastitis.
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http://dx.doi.org/10.3390/microorganisms8101488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601528PMC
September 2020

Anammox process dosed with biochars for enhanced nitrogen removal: Role of surface functional groups.

Sci Total Environ 2020 Dec 8;748:141367. Epub 2020 Aug 8.

School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.

Biochar is an inexpensive redox-active carbon material that has been demonstrated to enhance microbial nitrogen-transforming processes. However, how redox-active biochar affects anammox remains unclear. Here, the effects of three functionally distinct biochars produced from corn stover biomass at varied pyrolysis temperatures (CS300, CS500, CS800) were evaluated as additives on the anammox performance in three reactors (R300, R550, R800) over the long term, during which nitrogen loading rate was either increased drastically (pulse strategy) or gradually (gradual strategy). Nitrogen removal was achieved at 86.5% (R300), 77.1% (Control), 59.3% (R550) and 57.7% (R800) under pulse strategy, and at 95.4% (R300), 92.3% (R550), 86.2% (Control) and 82.0% (R800) under gradual strategy, respectively. Compared with Control, addition of CS300 increased abundance of Candidatus Kuenenia with superior anammox activity. CS300 enriched with reduced functional groups (phenolic/hydroquinone) could donate electrons to support bioenergetics of anammox metabolism, whereas electron-accepting CS800 functioned inversely. Overall, this study highlights the importance of surface functional groups and redox property of biochar such that determines whether its addition impose stimulatory or suppressive effect on anammox process.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141367DOI Listing
December 2020

Reduced serum CTRP12 levels in type 2 diabetes are associated with renal dysfunction.

Int Urol Nephrol 2020 Dec 30;52(12):2321-2327. Epub 2020 Jul 30.

Department of Endocrinology and Metabolic Diseases, First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China.

Purpose: Serum C1q/TNF-related protein-12 (CTRP12) is one of the newly studied families of adipokines, which is believed to be associated with type 2 diabetes. However, the relationship between serum CTRP12 levels and diabetic nephropathy remains unclear. This study aimed to investigate the relationship between serum CTRP12 levels and renal function in patients with type 2 diabetes.

Methods: A total of 115 type 2 diabetic patients and 54 healthy subjects were enrolled in this study. 52 patients with type 2 diabetes were in the diabetes group (T2DM). The 63 patients with renal dysfunction were diabetic nephropathy group (T2DM-DN) and were divided into microalbuminuria subgroup (31 cases) and macroalbuminuria subgroup (32 cases) according to the 24-h urine protein excretion rate. The concentrations of serum CTRP12 were determined by enzyme-linked immunosorbent assay.

Results: Serum CTRP12 level in T2DM and T2DM-DN groups was significantly lower compared with the control group, while CTRP12 level in T2DM-DN group was significantly lower than that in T2DM group, and was associated with the severity of renal insufficiency. After adjusting for gender and age, serum CTRP12 level was negatively correlated with the duration of diabetes, blood urea nitrogen (BUN), uric acid (UA) and 24-h urinary albumin excretion rate (UAE) in T2DM patients. Logistic regression analysis showed that serum CTRP12 level was significantly associated with renal dysfunction in type 2 diabetes mellitus. And the duration of diabetes, total cholesterol (CHOL) and neutrophils/lymphocytes (NLR) are independent risk factors for renal dysfunction in type 2 diabetes mellitus.

Conclusion: Serum CTRP12 may be involved in the occurrence and development of diabetic nephropathy. Trial registration number and date of registration ChiCTR2000030794, March 14, 2020.
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http://dx.doi.org/10.1007/s11255-020-02591-yDOI Listing
December 2020

Human perivascular stem cells prevent bone graft resorption in osteoporotic contexts by inhibiting osteoclast formation.

Stem Cells Transl Med 2020 12 22;9(12):1617-1630. Epub 2020 Jul 22.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

The vascular wall stores mesenchymal progenitor cells which are able to induce bone regeneration, via direct and paracrine mechanisms. Although much is known regarding perivascular cell regulation of osteoblasts, their regulation of osteoclasts, and by extension utility in states of high bone resorption, is not known. Here, human perivascular stem cells (PSCs) were used as a means to prevent autograft resorption in a gonadectomy-induced osteoporotic spine fusion model. Furthermore, the paracrine regulation by PSCs of osteoclast formation was evaluated, using coculture, conditioned medium, and purified extracellular vesicles. Results showed that PSCs when mixed with autograft bone induce an increase in osteoblast:osteoclast ratio, promote bone matrix formation, and prevent bone graft resorption. The confluence of these factors resulted in high rates of fusion in an ovariectomized rat lumbar spine fusion model. Application of PSCs was superior across metrics to either the use of unpurified, culture-defined adipose-derived stromal cells or autograft bone alone. Under coculture conditions, PSCs negatively regulated osteoclast formation and did so via secreted, nonvesicular paracrine factors. Total RNA sequencing identified secreted factors overexpressed by PSCs which may explain their negative regulation of graft resorption. In summary, PSCs reduce osteoclast formation and prevent bone graft resorption in high turnover states such as gonadectomy-induced osteoporosis.
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http://dx.doi.org/10.1002/sctm.20-0152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695633PMC
December 2020

alleviates irritable bowel syndrome-related visceral hypersensitivity and microbiota dysbiosis via Paneth cell regulation.

Gut Microbes 2020 11 25;12(1):1782156. Epub 2020 Jun 25.

Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University , Shanghai, China.

Although the oral administration of () relieves the signs of irritable bowel syndrome (IBS) in clinical settings, the mechanisms underlying its effects are unclear. In this study, we evaluated the precise effects of on IBS via regulation of Paneth cell function. We confirmed the beneficial effects of on defecation habits and visceral hypersensitivity in WAS rats. Further analysis revealed that enhanced mucosal repair, promoted lysozyme production, and ameliorated dysbiosis of the microbiota in WAS rats. These processes are closely correlated with Paneth cell functions. , we incubated primary cultured enteroids with and found that promoted the proliferation of these organoids; this may be attributed to the upregulation of the stem niche factors WNT3A and TGF-β, which are secreted by Paneth cells. Based on our findings, we propose that relieves IBS by restoring the antimicrobial activity and stem niche maintenance function of Paneth cells.
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http://dx.doi.org/10.1080/19490976.2020.1782156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524277PMC
November 2020

Perivascular Fibro-Adipogenic Progenitor Tracing during Post-Traumatic Osteoarthritis.

Am J Pathol 2020 09 10;190(9):1909-1920. Epub 2020 Jun 10.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland; Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, Los Angeles, California. Electronic address:

Perivascular mural cells surround capillaries and microvessels and have diverse regenerative or fibrotic functions after tissue injury. Subsynovial fibrosis is a well-known pathologic feature of osteoarthritis, yet transgenic animals for use in visualizing perivascular cell contribution to fibrosis during arthritic changes have not been developed. Here, inducible Pdgfra-CreER reporter mice were subjected to joint-destabilization surgery to induce arthritic changes, and cell lineage was traced over an 8-week period with a focus on the joint-associated fat pad. Results showed that, at baseline, inducible Pdgfra reporter activity highlighted adventitial and, to a lesser extent, pericytic cells within the infrapatellar fat pad. Joint-destabilization surgery was associated with marked fibrosis of the infrapatellar fat pad, accompanied by an expansion of perivascular Pdgfra-expressing cellular descendants, many of which adopted α-smooth muscle actin expression. Gene expression analysis of microdissected infrapatellar fat pad confirmed enrichment in membrane-bound green fluorescent protein/Pdgfra-expressing cells, along with a gene signature that corresponded with injury-associated fibro-adipogenic progenitors. Our results highlight dynamic changes in joint-associated perivascular fibro-adipogenic progenitors during osteoarthritis.
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http://dx.doi.org/10.1016/j.ajpath.2020.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456743PMC
September 2020

Comparison of skeletal and soft tissue pericytes identifies CXCR4 bone forming mural cells in human tissues.

Bone Res 2020 22;8:22. Epub 2020 May 22.

Departments of Pathology, Johns Hopkins University, Baltimore, 21205 MD USA.

Human osteogenic progenitors are not precisely defined, being primarily studied as heterogeneous multipotent cell populations and termed mesenchymal stem cells (MSCs). Notably, select human pericytes can develop into bone-forming osteoblasts. Here, we sought to define the differentiation potential of CD146 human pericytes from skeletal and soft tissue sources, with the underlying goal of defining cell surface markers that typify an osteoblastogenic pericyte. CD146CD31CD45 pericytes were derived by fluorescence-activated cell sorting from human periosteum, adipose, or dermal tissue. Periosteal CD146CD31CD45 cells retained canonical features of pericytes/MSC. Periosteal pericytes demonstrated a striking tendency to undergo osteoblastogenesis in vitro and skeletogenesis in vivo, while soft tissue pericytes did not readily. Transcriptome analysis revealed higher CXCR4 signaling among periosteal pericytes in comparison to their soft tissue counterparts, and CXCR4 chemical inhibition abrogated ectopic ossification by periosteal pericytes. Conversely, enrichment of CXCR4 pericytes or stromal cells identified an osteoblastic/non-adipocytic precursor cell. In sum, human skeletal and soft tissue pericytes differ in their basal abilities to form bone. Diversity exists in soft tissue pericytes, however, and CXCR4 pericytes represent an osteoblastogenic, non-adipocytic cell precursor. Indeed, enrichment for CXCR4-expressing stromal cells is a potential new tactic for skeletal tissue engineering.
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http://dx.doi.org/10.1038/s41413-020-0097-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244476PMC
May 2020

Endogenous CCN family member WISP1 inhibits trauma-induced heterotopic ossification.

JCI Insight 2020 07 9;5(13). Epub 2020 Jul 9.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

Heterotopic ossification (HO) is defined as abnormal differentiation of local stromal cells of mesenchymal origin, resulting in pathologic cartilage and bone matrix deposition. Cyr61, CTGF, Nov (CCN) family members are matricellular proteins that have diverse regulatory functions on cell proliferation and differentiation, including the regulation of chondrogenesis. However, little is known regarding CCN family member expression or function in HO. Here, a combination of bulk and single-cell RNA sequencing defined the dynamic temporospatial pattern of CCN family member induction within a mouse model of trauma-induced HO. Among CCN family proteins, Wisp1 (also known as Ccn4) was most upregulated during the evolution of HO, and Wisp1 expression corresponded with chondrogenic gene profile. Immunohistochemistry confirmed WISP1 expression across traumatic and genetic HO mouse models as well as in human HO samples. Transgenic Wisp1LacZ/LacZ knockin animals showed an increase in endochondral ossification in HO after trauma. Finally, the transcriptome of Wisp1-null tenocytes revealed enrichment in signaling pathways, such as the STAT3 and PCP signaling pathways, that may explain increased HO in the context of Wisp1 deficiency. In sum, CCN family members, and in particular Wisp1, are spatiotemporally associated with and negatively regulate trauma-induced HO formation.
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http://dx.doi.org/10.1172/jci.insight.135432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406255PMC
July 2020

Preparation and biological evaluations of a collagen-like hierarchical Ti surface with superior osteogenic capabilities.

J Mater Chem B 2020 07;8(25):5472-5482

The Affiliated Stomatology Hospital, College of Medicine, Zhejiang University, Hangzhou 310006, P. R. China. and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou 310006, P. R. China.

The construction of multiscale Ti surfaces of high osteogenic ability has always attracted significant attention in the fields of oral implantology and implantable biomaterials. However, to date, the absence of a solid understanding of the correlation between the multiscale surface structure and the biological properties is the main obstacle in the development of these multiscale implants. In this study, a series of novel multiscale Ti surfaces were prepared via a three-step subtractive method. Moreover, based on the grayscale analysis of SEM images, we developed multiscale surface topography analysis methods. The typical topography characteristics at each scale of a multiscale complex surface can be analyzed according to the corresponding magnified SEM images. Thus, the evolution rule of the surface topography from a simple surface to multiscale complex surfaces can be mathematically described. Based on this, the correlation between multiscale surface structures and the corresponding biological properties was established. For the multiscale surface of superior osteogenic capacity, strict inherent regularity was found among the structures at multiple scales (i.e., multiscale order), that is, there was a balance between the construction of the 3D collagen-like network nanostructure and the preservation of the typical topographical features of the pre-existing macro- and micro-structures of the classic micro-roughened surface. Moreover, it was further found that the multiscale-ordered hierarchical Ti surface structure could modulate ROS production and enhance macrophage M2 polarization to create an osteogenesis-favorable immuno-inflammatory microenvironment and synergistically exhibit superior biological capability. Consequently, an optimized collagen-like hierarchical surface with superior osteogenic abilities was achieved.
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http://dx.doi.org/10.1039/d0tb00799dDOI Listing
July 2020

Anti-DKK1 Enhances the Early Osteogenic Differentiation of Human Adipose-Derived Stem/Stromal Cells.

Stem Cells Dev 2020 08 22;29(15):1007-1015. Epub 2020 Jun 22.

Department of Pathology and Johns Hopkins University, Baltimore, Maryland, USA.

Adipose-derived stem/stromal cells (ASCs) have been previously used for bone repair. However, significant cell heterogeneity exists within the ASC population, which has the potential to result in unreliable bone tissue formation and/or low efficacy. Although the use of cell sorting to lower cell heterogeneity is one method to improve bone formation, this is a technically sophisticated and costly process. In this study, we tried to find a simpler and more deployable solution-blocking antiosteogenic molecule Dickkopf-1 (DKK1) to improve osteogenic differentiation. Human adipose-derived stem cells were derived from = 5 samples of human lipoaspirate. In vitro, anti-DKK1 treatment, but not anti-sclerostin (SOST), promoted ASC osteogenic differentiation, assessed by alizarin red staining and real-time polymerase chain reaction (qPCR). Increased canonical Wnt signaling was confirmed after anti-DKK1 treatment. Expression levels of peaked during early osteogenic differentiation (day 3). Concordantly, anti-DKK1 supplemented early (day 3 or before), but not later (day 7) during osteogenic differentiation positively regulated osteoblast formation. Finally, anti-DKK1 led to increased transcript abundance of the Wnt inhibitor SOST, potentially representing a compensatory cellular mechanism. In sum, DKK1 represents a targetable "molecular brake" on the osteogenic differentiation of human ASC. Moreover, release of this brake by neutralizing anti-DKK1 antibody treatment at least partially rescues the poor bone-forming efficacy of ASC.
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http://dx.doi.org/10.1089/scd.2020.0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410293PMC
August 2020

A Neurotrophic Mechanism Directs Sensory Nerve Transit in Cranial Bone.

Cell Rep 2020 05;31(8):107696

Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address:

The flat bones of the skull are densely innervated during development, but little is known regarding their role during repair. We describe a neurotrophic mechanism that directs sensory nerve transit in the mouse calvaria. Patent cranial suture mesenchyme represents an NGF (nerve growth factor)-rich domain, in which sensory nerves transit. Experimental calvarial injury upregulates Ngf in an IL-1β/TNF-α-rich defect niche, with consequent axonal ingrowth. In calvarial osteoblasts, IL-1β and TNF-α stimulate Ngf and downstream NF-κB signaling. Locoregional deletion of Ngf delays defect site re-innervation and blunted repair. Genetic disruption of Ngf among LysM-expressing macrophages phenocopies these observations, whereas conditional knockout of Ngf among Pdgfra-expressing cells does not. Finally, inhibition of TrkA catalytic activity similarly delays re-innervation and repair. These results demonstrate an essential role of NGF-TrkA signaling in bone healing and implicate macrophage-derived NGF-induced ingrowth of skeletal sensory nerves as an important mediator of this repair.
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http://dx.doi.org/10.1016/j.celrep.2020.107696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335423PMC
May 2020

Ferrocene Functionalized Upconversion Nanoparticle Nanosystem with Efficient Near-Infrared-Light-Promoted Fenton-Like Reaction for Tumor Growth Suppression.

Inorg Chem 2020 Jul 24;59(13):9177-9187. Epub 2020 May 24.

Institute of Advanced Materials, Nanjing Tech University, Nanjing 210009, China.

By taking advantage of the efficient Förster resonance energy transfer (FRET) between near-infrared (NIR)-responsive lanthanide-doped upconversion nanoparticles (UCNPs) and Fenton reagent ferrocenyl compounds (), a series of -UCNPs was designed by functionalizing NaYF:Yb,Tm nanoparticles with - surface-coordination chemistry. -UCNP-Lipo nanosystems were then constructed by encapsulating -UCNP inside liposomes for efficient delivery. -UCNP can effectively release ·OH a NIR-promoted Fenton-like reaction. and studies of -UCNP-Lipo confirmed the preferential accumulation in a tumor site followed by an enhanced uptake of cancer cells. After cellular internalization, the released -UCNP can effectively promote ·OH generation for tumor growth suppression. Such a -UCNP-Lipo nanosystem exhibits advantages such as easy fabrication, low drug dosage, and no ferrous ion release.
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http://dx.doi.org/10.1021/acs.inorgchem.0c01073DOI Listing
July 2020

IL-23, but not IL-12, plays a critical role in inflammation-mediated bone disorders.

Theranostics 2020 4;10(9):3925-3938. Epub 2020 Mar 4.

Department of Orthopedic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.

Interleukin-12 (IL-12) and IL-23 are thought to have central roles in inflammation and are critical to pathologies associated with inflammation-induced bone disorders. The deletion of IL-12p40 (a common subunit of IL-12 and IL-23) can improve bone regeneration. However, the relative roles of IL-12 and IL-23 in bone disorders are largely unknown. : Ectopic bone formation and skull defect models were established to evaluate the relative roles of IL-12 and IL-23 in inflammatory bone disorders. Differences in bone mass among WT, IL-12p35, and IL-12p40 mice (young and elderly) were detected by micro-CT. Osteogenic and osteoclastic activities were explored using ELISA, qRT-PCR, and histological analysis. Moreover, the mechanisms by which IL-12 and IL-23 regulated the differentiation of BMMSCs and RAW264.7 cells were explored using Alizarin Red and tartrate-resistant acid phosphatase staining . Apilimod was used to inhibit IL-12 and IL-23 production . : Mice deficient in IL-12p40 promoted bone formation and protected against aging-related bone loss. By contrast, bone loss was aggravated in IL-12 mice, suggesting that IL-23 may play a dominant role in inflammation-related bone disorders. Mechanistically, IL-12 and IL-23 coupled osteogenesis and osteoclastic activities to regulate bone homeostasis and repair. IL-23 deficiency increased bone formation and inhibited bone resorption. Finally, apilimod treatment significantly improved bone regeneration and calvarial defect repair. : These data collectively uncover a previously unrecognized role of IL-23 in skeletal tissue engineering. Thus, IL-23 can act as a biomarker to predict diseases and treatment efficacy, and apilimod can be used as an effective therapeutic drug to combat inflammatory bone disorders.
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http://dx.doi.org/10.7150/thno.41378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086346PMC
March 2020

Effects of Nanofillers on the Hydrolytic Degradation of Polyesters.

Tissue Eng Part B Rev 2020 10 13;26(5):484-495. Epub 2020 Apr 13.

School of Mechatronics and Automation, Shanghai University, Shanghai, China.

Biopolymer matrices reinforced with nanoparticles or nanofillers have received a great deal of attention over the past decades due to their various roles such as the augmentation of thermal, electrical, mechanical, and surface properties in tissue engineering, drug delivery, and implantation. Understanding the degradation kinetics of these polyesters is very important to successful applications of them. Hydrolysis is a widely agreed mechanism for the polyester degradation. According to this mechanism, hydrolytic degradation of these polyesters can be affected by the autocatalytic action of carboxyl groups as well as other factors such as hydrophilicity, crystallinity, and glass transition temperature. In this article, the effects of nanofillers on the autocatalytic action of carboxyl groups and the foregoing factors are examined. A particular attention is paid to carbon nanotubes (CNTs), which are a favorite candidate in a wide range of applications due to their unique thermal and electrical properties. Contradictory degradation results with CNTs are reported and analyzed. Finally, a future research perspective on these polyesters is discussed. Impact statement Nanoparticles have attracted a great deal of attention over the past decades due to their various roles, such as the augmentation of thermal, electrical, mechanical, and surface properties in tissue engineering, drug delivery, and implantation. In this article, the effects of nanoparticles or nanofillers* on the degradation behavior of the polyester matrices (tissue scaffolds, drug delivery devices) are examined with a focus on the autocatalytic action of carboxyl groups, and the factors such as hydrophilicity, crystallinity, and glass transition temperature. Among many nanofillers, carbon nanotubes (CNTs), which are a favorite candidate in a wide range of applications, are found to produce some contradictory results on the degradation of the polyester matrix with CNTs incorporated, and the underlying reason for this finding is discussed for the first time in this article.
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http://dx.doi.org/10.1089/ten.TEB.2019.0260DOI Listing
October 2020

Platelet-derived growth factor receptor-β (PDGFRβ) lineage tracing highlights perivascular cell to myofibroblast transdifferentiation during post-traumatic osteoarthritis.

J Orthop Res 2020 11 9;38(11):2484-2494. Epub 2020 Mar 9.

Department of Pathology, Johns Hopkins University, Baltimore, Maryland.

Pericytes ubiquitously surround capillaries and microvessels within vascularized tissues and have diverse functions after tissue injury. In addition to regulation of angiogenesis and tissue regeneration after injury, pericytes also contribute to organ fibrosis. Destabilization of the medial meniscus (DMM) phenocopies post-traumatic osteoarthritis, yet little is known regarding the impact of DMM surgery on knee joint-associated pericytes and their cellular descendants. Here, inducible platelet-derived growth factor receptor-β (PDGFRβ)-CreER reporter mice were subjected to DMM surgery, and lineage tracing studies performed over an 8-week period. Results showed that at baseline PDGFRβ reporter activity highlights abluminal perivascular cells within synovial and infrapatellar fat pad (IFP) tissues. DMM induces a temporospatially patterned increase in vascular density within synovial and subsynovial tissues. Marked vasculogenesis within IFP was accompanied by expansion of PDGFRβ reporter perivascular cell numbers, detachment of mGFP descendants from vessel walls, and aberrant adoption of myofibroblastic markers among mGFP cells including α-SMA, ED-A, and TGF-β1. At later timepoints, fibrotic changes and vascular maturation occurred within subsynovial tissues, with the redistribution of PDGFRβ cellular descendants back to their perivascular niche. In sum, PDGFRβ lineage tracing allows for tracing of perivascular cell fate within the diarthrodial joint. Further, destabilization of the joint induces vascular and fibrogenic changes of the IFP accompanied by perivascular to myofibroblast transdifferentiation.
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http://dx.doi.org/10.1002/jor.24648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483913PMC
November 2020

Ultrafast Detection of Peroxynitrite in Parkinson's Disease Models Using a Near-Infrared Fluorescent Probe.

Anal Chem 2020 03 20;92(5):4038-4045. Epub 2020 Feb 20.

Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, P. R. China.

Parkinson's disease (PD) is a neurodegenerative disease that devastatingly affects people's lives. Numerous research studies have shown that peroxynitrite (ONOO) plays a pivotal role in the pathogenesis of PD. However, a suitable tool that could quickly and sensitively detect ONOO in various PD models is still lacking. To this end, we designed and synthesized a series of near-infrared probes that could detect ONOO within seconds by near-infrared fluorescent imaging in an ultrafast and highly selective manner. It is noteworthy that one of those developed probes, , showed excellent sensing performance and blood-brain barrier penetrating ability. was successfully applied for imaging of ONOO fluxes in multiple PD models including PC12 cell, Drosophila, , and mouse brain, indicating its great potential application not only for understanding the biological roles that ONOO played in PD but also for early PD diagnosis and treatment.
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http://dx.doi.org/10.1021/acs.analchem.9b05599DOI Listing
March 2020

Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing.

Nat Commun 2020 02 5;11(1):722. Epub 2020 Feb 5.

Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFβ levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.
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http://dx.doi.org/10.1038/s41467-019-14172-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002453PMC
February 2020