Publications by authors named "Xiujuan Zhang"

228 Publications

A vaccine inducing solely cytotoxic T lymphocytes fully prevents Zika virus infection and fetal damage.

Cell Rep 2021 May;35(6):109107

Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA. Electronic address:

As vaccine-induced non-neutralizing antibodies may cause antibody-dependent enhancement of Zika virus (ZIKV) infection, we test a vaccine that induces only specific cytotoxic T lymphocytes (CTLs) without specific antibodies. We construct a DNA vaccine expressing a ubiquitinated and rearranged ZIKV non-structural protein 3 (NS3). The protein is immediately degraded and processed in the proteasome for presentation via major histocompatibility complex (MHC) class I for CTL generation. We immunize Ifnar1 adult mice with the ubiquitin/NS3 vaccine, impregnate them, and challenge them with ZIKV. Our data show that the vaccine greatly reduces viral titers in reproductive organs and other tissues of adult mice. All mice immunized with the vaccine survived after ZIKV challenge. The vaccine remarkably reduces placenta damage and levels of pro-inflammatory cytokines, and it fully protects fetuses from damage. CD8 CTLs are essential in protection, as demonstrated via depletion experiments. Our study provides a strategy to develop safe and effective vaccines against viral infections.
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http://dx.doi.org/10.1016/j.celrep.2021.109107DOI Listing
May 2021

Costunolide suppresses melanoma growth via the AKT/mTOR pathway and .

Am J Cancer Res 2021 15;11(4):1410-1427. Epub 2021 Apr 15.

Department of Animal Science and Biotechnology, Kyungpook National University Sangju-si, Gyeongsang buk-do 37224, Republic of Korea.

Melanoma is the most common type of skin cancer and its incidence is rapidly increasing. AKT, and its related signaling pathways, are highly activated in many cancers including lung, colon, and esophageal cancers. Costunolide (CTD) is a sesquiterpene lactone that has been reported to possess neuroprotective, anti-inflammatory, and anti-cancer properties. However, the target and mechanism underlying its efficacy in melanoma have not been identified. In this study, we elucidated the mechanism behind the anti-cancer effect of CTD in melanoma and by identifying CTD as an AKT inhibitor. We first verified that p-AKT and AKT are highly expressed in melanoma patient tissues and cell lines. CTD significantly inhibited the proliferation, migration, and invasion of melanoma cells including SK-MEL-5, SK-MEL-28, and A375 that are overexpressed p-AKT and AKT proteins. We investigated the mechanism of CTD using a computational docking modeling, pull-down, and site directed mutagenesis assay. CTD directly bound to AKT thereby arresting cell cycle at the G1 phase, and inducing the apoptosis of melanoma cells. In addition, CTD regulated the G1 phase and apoptosis biomarkers, and inhibited the expression of AKT/mTOR/GSK3b/p70S6K/4EBP cascade proteins. After reducing AKT expression in melanoma cells, cell growth was significantly decreased and CTD did not showed further inhibitory effects. Furthermore, CTD administration suppressed tumor growth and weight in cell-derived xenograft mice models without body weight loss and inhibited the expression of Ki-67, p-AKT, and p70S6K in tumor tissues. In summary, our study implied that CTD inhibited melanoma progression and . In this study, we reported that CTD could affect melanoma growth by targeting AKT. Therefore, CTD has considerable potential as a drug for melanoma therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085867PMC
April 2021

Identification of key pseudogenes in nasopharyngeal carcinoma based on RNA-Seq analysis.

BMC Cancer 2021 Apr 30;21(1):483. Epub 2021 Apr 30.

Department of Otolaryngology, Eye, Ear, Nose and Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, 83 Fen Yang Road, Shanghai, 200031, China.

Background: Nasopharyngeal carcinoma (NPC) is a malignant head and neck tumor, and more than 70% of new cases are in East and Southeast Asia. However, association between NPC and pseudogenes playing important roles in genesis of multiple tumor types is still not clear and needs to be investigated.

Methods: Using RNA-Sequencing (RNA-seq) technology, we analyzed pseudogene expression in 13 primary NPC and 6 recurrent NPC samples as well as their paracancerous counterparts. Quantitative PCR was used to validate the differentially expressed pseudogenes.

Results: We found 251 differentially expressed pseudogenes including 73 up-regulated and 178 down-regulated ones between primary NPC and paracancerous tissues. Enrichment analysis of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were conducted to filter out the key pseudogenes. We reported that pseudogenes from cytochrome P450 (CYP) family, such as CYP2F2P, CYP2G1P, CYP4F24P, CYP2B7P and CYP2G2P were significantly down-regulated in NPC compared to paracancerous tissues, while IGHV1OR15-2, IGHV3-11, FCGR1CP and IGHV3-69-1 belonging to Fc gamma receptors were significantly up-regulated. CYP2B7P, CYP2F2P and CYP4F26P were enriched in arachidonic acid metabolism pathway. The qRT-PCR analysis validated the lower expression of pseudogenes CYP2F2P and CYP2B7P in NPC tissues and cell lines compared to paracancerous tissues and normal human nasopharyngeal epithelial cell line. CYP2B7P overexpression weakened migratory and invasive capacity of NPC cell line. Moreover, the expression pattern of those pseudogenes in recurrent NPC tissues was different from the primary NPC.

Conclusion: This study suggested the role of pseudogenes in tumorigenesis and progression, potentially functioning as therapeutic targets to NPC.
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http://dx.doi.org/10.1186/s12885-021-08211-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088053PMC
April 2021

Valley-Selective Topological Corner States in Sonic Crystals.

Phys Rev Lett 2021 Apr;126(15):156401

National Laboratory of Solid State Microstructures and Department of Materials Science and Engineering, Nanjing University, Nanjing 210093, China.

Higher-order topological insulators (HOTIs), a new horizon of topological phases of matter, host lower-dimensional corner or hinge states, providing important stepping stones to the realization of robust topological waveguides in higher dimensions. The nontrivial band topology that gives rise to the corner or hinge states is usually enabled by certain crystalline symmetries. As a result, higher-order topological boundary states are tied to specific corners or hinges, lacking the flexibility of switching and selecting. Here, we report the experimental realization of topologically switchable and valley-selective corner states in a two-dimensional sonic crystal. Such intriguing properties are enabled by exploiting the higher-order topology assisted with the valley degree of freedom. For this purpose, we realize a valley HOTI of second-order topology characterized by the nontrivial bulk polarization. Interestingly, the hosted corner states are found to be valley dependent and therefore enable flexible control and manipulation on the wave localization. Topological switch on or off and valley selection of the corner states are directly observed through spatial scanning of the sound field. We further design an arbitrary structure of complex patterns containing corners with various intersection angles, among which selected corners can be illuminated or darkened upon valley selection. The reported valley HOTI and the valley-selective corner states provide fundamental understanding on the interplay between higher-order topology and valley degree of freedom and pave the way for lower-dimensional valleytronics, which may find potential applications in integrated acoustics and photonics.
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http://dx.doi.org/10.1103/PhysRevLett.126.156401DOI Listing
April 2021

Relationship between plasma 12,13-diHOME level and nonalcoholic fatty liver disease in patients with type 2 diabetes and obesity.

Minerva Endocrinol (Torino) 2021 Apr 15. Epub 2021 Apr 15.

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China -

Objective: 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) was one of the newly found lipokines. The goal of this study was to investigate whether the 12,13-diHOME was associated with related metabolic markers of nonalcoholic fatty liver disease (NAFLD) in a Chinese population with type 2 diabetes (T2DM) and obesity.

Methods: This cross-sectional study enrolled 202 subjects with T2DM. Anthropometric parameters, 12,13-diHOME, serum lipids levels, fasting blood-glucose (FBG), serum glycosylated hemoglobin (HbA1c), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), liver and kidney function parameters were collected. NAFLD was diagnosed based on abdominal ultrasonography examination results. A computer-aided ultrasound quantitative method was applied to evaluate the liver fat content (LFC).

Results: The number of the patients with fatty liver was 139 (68.81%) and those with non-fatty liver was 63 (31.19%). Subjects with NAFLD had a higher body mass index (BMI), diastolic blood pressure, serum alanine aminotransferase (ALT), triglyceride (TG), HOMA-IR, LFC, p<0.05 for all. But no significant difference was found in plasma 12,13-diHOME level (p=0.967), though its level trend was higher in non-NAFLD group. Plasma 12,13-diHOME was positively correlated with aspartate aminotransferase (AST), total cholesterol (TC), high density lipoprotein cholesterol (HDLC), blood urea nitrogen (BUN), free fatty acid (FFA), C-peptide, FINS and HOMAIR. It was negatively correlated with height, body weight, glomerular filtration rate (eGFR) and HbA1c.

Conclusions: Although 12,13-diHOME was correlated with AST, TC, HDL-C, BUN, FFA, C-peptide, FINS, HOMA-IR, eGFR and HbA1c, there was no significant difference in 12,13-diHOME level between the two groups. However, more research should be carried on about this newly found lipokine.
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http://dx.doi.org/10.23736/S2724-6507.21.03424-6DOI Listing
April 2021

Clinical heterogeneity and intrafamilial variability of Joubert syndrome in two siblings with CPLANE1 variants.

Mol Genet Genomic Med 2021 Apr 6:e1682. Epub 2021 Apr 6.

National Human Genetic Resources Center, National Research Institute for Family Planning, Beijing, China.

Background: Joubert syndrome (JBTS) is a rare genetic disorder that is characterized by midbrain-hindbrain malformations. Multiple variants in genes that affect ciliary function contribute to the genetic and clinical heterogeneity of JBTS and its subtypes. However, the correlation between genotype and phenotype has not been elucidated due to the limited number of patients available.

Methods: In this study, we observed different clinical features in two siblings from the same family. The older sibling was classified as a pure JBTS patient, whereas her younger sibling displayed oral-facial-digital defects and was therefore classified as an oral-facial-digital syndrome type VI (OFD VI) patient. Next, we performed human genetic tests to identify the potential pathogenic variants in the two siblings.

Results: Genetic sequencing indicated that both siblings harbored compound heterozygous variants of a missense variant (c.1067C>T, p.S356F) and a frameshift variant (c.8377_8378del, p.E2793Lfs*24) in CPLANE1 (NM_023073.3).

Conclusion: This study reports that two novel CPLANE1 variants are associated with the occurrence of JBTS and OFD VI. These results help elucidate the intrafamilial phenotypic variability associated with CPLANE1 variants.
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http://dx.doi.org/10.1002/mgg3.1682DOI Listing
April 2021

Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo.

J Exp Clin Cancer Res 2021 Mar 30;40(1):114. Epub 2021 Mar 30.

Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, Sangju, 37224, Republic of Korea.

Background: Colorectal cancer (CRC) is a clinically challenging malignant tumor worldwide. As a natural product and sesquiterpene lactone, Costunolide (CTD) has been reported to possess anticancer activities. However, the regulation mechanism and precise target of this substance remain undiscovered in CRC. In this study, we found that CTD inhibited CRC cell proliferation in vitro and in vivo by targeting AKT.

Methods: Effects of CTD on colon cancer cell growth in vitro were evaluated in cell proliferation assays, migration and invasion, propidium iodide, and annexin V-staining analyses. Targets of CTD were identified utilizing phosphoprotein-specific antibody array; Costunolide-sepharose conjugated bead pull-down analysis and knockdown techniques. We investigated the underlying mechanisms of CTD by ubiquitination, immunofluorescence staining, and western blot assays. Cell-derived tumour xenografts (CDX) in nude mice and immunohistochemistry were used to assess anti-tumour effects of CTD in vivo.

Results: CTD suppressed the proliferation, anchorage-independent colony growth and epithelial-mesenchymal transformation (EMT) of CRC cells including HCT-15, HCT-116 and DLD1. Besides, the CTD also triggered cell apoptosis and cell cycle arrest at the G2/M phase. The CTD activates and induces p53 stability by inhibiting MDM2 ubiquitination via the suppression of AKT's phosphorylation in vitro. The CTD suppresses cell growth in a p53-independent fashion manner; p53 activation may contribute to the anticancer activity of CTD via target AKT. Finally, the CTD decreased the volume of CDX tumors without of the body weight loss and reduced the expression of AKT-MDM2-p53 signaling pathway in xenograft tumors.

Conclusions: Our project has uncovered the mechanism underlying the biological activity of CTD in colon cancer and confirmed the AKT is a directly target of CTD. All of which These results revealed that CTD might be a new AKT inhibitor in colon cancer treatment, and CTD is worthy of further exploration in preclinical and clinical trials.
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http://dx.doi.org/10.1186/s13046-021-01895-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010944PMC
March 2021

Thyroid-stimulating hormone decreases the risk of osteoporosis by regulating osteoblast proliferation and differentiation.

BMC Endocr Disord 2021 Mar 16;21(1):49. Epub 2021 Mar 16.

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.

Background: As the incidence of secretory osteoporosis has increased, bone loss, osteoporosis and their relationships with thyroid-stimulating hormone (TSH) have received increased attention. In this study, the role of TSH in bone metabolism and its possible underlying mechanisms were investigated.

Methods: We analyzed the serum levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSH and the bone mineral density (BMD) levels of 114 men with normal thyroid function. In addition, osteoblasts from rat calvarial samples were treated with different doses of TSH for different lengths of time. The related gene and protein expression levels were investigated.

Results: A comparison of the BMD between the high-level and low-level serum TSH groups showed that the TSH serum concentration was positively correlated with BMD. TSH at concentrations of 10 mU/mL and 100 mU/mL significantly increased the mRNA levels of ALP, COI1 and Runx2 compared with those of the control (P < 0.05, P < 0.01). Bone morphogenetic protein (BMP)2 activity was enhanced with both increased TSH concentration and increased time. The protein levels of Runx2 and osterix were increased in a dose-dependent manner.

Conclusions: The circulating concentrations of TSH and BMD were positively correlated with normal thyroid function in males. TSH promoted osteoblast proliferation and differentiation in rat primary osteoblasts.
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http://dx.doi.org/10.1186/s12902-021-00715-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968288PMC
March 2021

The hollow core-shell ferric oxide entrapped chitosan microcapsules as phosphate binders for phosphorus removal in vitro.

Carbohydr Polym 2021 Apr 7;257:117621. Epub 2021 Jan 7.

School of Chemical Engineering, Dalian University of Technology, Panjin, 124221, China. Electronic address:

Patients in hyperphosphatemia are orally prescribed with phosphate binders to excrete the non-metabolic phosphorus. Aiming for the bio-compatibility and binding efficacy, the Fe-based phosphate binders of low toxicity have been explored and improved. Herein, the hollow core-shell microcapsules as Fe@CH (nano ferric oxide entrapped in the polymerized chitosan) were constructed via emulsion interface polymerization, to enhance the phosphate binding from -NH group and iron complex, and limit iron leakage significantly. Via the double emulsion polymerization based on the primary Pickering emulsion stabilized by oleic acid-modified ferric oxide, Fe@CH performed as the rough polymerized-chitosan microcapsules entrapping well-distributed ferric oxide for the phosphate adsorption in vitro. At pH 3 and pH 5, Fe@CH bound phosphorus efficiently, with the capacity of 55 mg/g and 65 mg/g respectively, along with the excellent shell isolation from iron leakage and remarkable safety. Prospectively, the Fe@CH micro-sorbent is the proper candidate as the phosphate binder for hyperphosphatemia.
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http://dx.doi.org/10.1016/j.carbpol.2021.117621DOI Listing
April 2021

Age Effect on Treatment Responses to 0.05%, 0.025%, and 0.01% Atropine: Low-Concentration Atropine for Myopia Progression Study.

Ophthalmology 2021 Jan 8. Epub 2021 Jan 8.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong SAR, China; Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong SAR, China; Hong Kong Eye Hospital, Hong Kong SAR, China; Department of Ophthalmology, Hong Kong Children's Hospital, Hong Kong SAR, China. Electronic address:

Purpose: To investigate the effect of age at treatment and other factors on treatment response to atropine in the Low-Concentration Atropine for Myopia Progression (LAMP) Study.

Design: Secondary analysis from a randomized trial.

Participants: Three hundred fifty children aged 4 to 12 years who originally were assigned to receive 0.05%, 0.025%, or 0.01% atropine or placebo once daily, and who completed 2 years of the LAMP Study, were included. In the second year, the placebo group was switched to the 0.05% atropine group.

Methods: Potential predictive factors for change in spherical equivalent (SE) and axial length (AL) over 2 years were evaluated by generalized estimating equations in each treatment group. Evaluated factors included age at treatment, gender, baseline refraction, parental myopia, time outdoors, diopter hours of near work, and treatment compliance. Estimated mean values and 95% confidence intervals (CIs) of change in SE and AL over 2 years also were generated.

Main Outcome Measures: Factors associated with SE change and AL change over 2 years were the primary outcome measures. Associated factors during the first year were secondary outcome measures.

Results: In 0.05%, 0.025%, and 0.01% atropine groups, younger age was the only factor associated with SE progression (coefficient of 0.14, 0.15, and 0.20, respectively) and AL elongation (coefficient of -0.10, -0.11, and -0.12, respectively) over 2 years; the younger the age, the poorer the response. At each year of age from 4 to 12 years across the treatment groups, higher-concentration atropine showed a better treatment response, following a concentration-dependent effect (P <0.05 for each age group). In addition, the mean SE progression in 6-year-old children receiving 0.05% atropine (-0.90 diopter [D]; 95% CI, -0.99 to -0.82) was similar to that of 8-year-old children receiving 0.025% atropine (-0.89 D; 95% CI, -0.94 to -0.83) and 10-year-old children receiving 0.01% atropine (-0.92 D; 95% CI, -0.99 to -0.85). All concentrations were well tolerated in all age groups.

Conclusions: Younger age is associated with poor treatment response to low-concentration atropine at 0.05%, 0.025%, and 0.01%. Among concentrations studied, younger children required the highest 0.05% concentration to achieve similar reduction in myopic progression as older children receiving lower concentrations.
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http://dx.doi.org/10.1016/j.ophtha.2020.12.036DOI Listing
January 2021

Expansion of murine and human olfactory epithelium/mucosa colonies and generation of mature olfactory sensory neurons under chemically defined conditions.

Theranostics 2021 1;11(2):684-699. Epub 2021 Jan 1.

Department of Otolaryngology, Eye, Ear, Nose and Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, China 200031.

Olfactory dysfunctions, including hyposmia and anosmia, affect ~100 million people around the world and the underlying causes are not fully understood. Degeneration of olfactory sensory neurons and incapacity of globose basal cells to generate olfactory sensory neurons are found in elder people and patients with smell disorders. Thus, olfactory stem cell may function as a promising tool to replace inactivated globose basal cells and to generate sensory neurons. We established clonal expansion of cells from the murine olfactory epithelium as well as colony growth from human olfactory mucosa using Matrigel-based three-dimensional system. These colonies were characterized by immunostaining against olfactory epithelium cellular markers and by calcium imaging of responses to odors. Chemical addition was optimized to promote Lgr5 expression, colony growth and sensory neuron generation, tested by quantitative PCR and immunostaining against progenitor and neuronal markers. The differential transcriptomes in multiple signaling pathways between colonies under different base media and chemical cocktails were determined by RNA-Seq. In defined culture media, we found that VPA and CHIR99021 induced the highest Lgr5 expression level, while LY411575 resulted in the most abundant yield of OMP mature sensory neurons in murine colonies. Different base culture media with drug cocktails led to apparent morphological alteration from filled to cystic appearance, accompanied with massive transcriptional changes in multiple signaling pathways. Generation of sensory neurons in human colonies was affected through TGF-β signaling, while Lgr5 expression and cell proliferation was regulated by VPA. Our findings suggest that targeting expansion of olfactory epithelium/mucosa colonies potentially results in discovery of new source to cell replacement-based therapy against smell loss.
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http://dx.doi.org/10.7150/thno.46750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738855PMC
January 2021

Water-Surface Drag Coating: A New Route Toward High-Quality Conjugated Small-Molecule Thin Films with Enhanced Charge Transport Properties.

Adv Mater 2021 Feb 18;33(5):e2005915. Epub 2020 Dec 18.

Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.

Electronic properties of organic semiconductor (OSC) thin films are largely determined by their morphologies and crystallinities. However, solution-processed conjugated small-molecule OSC thin films usually exhibit abundant grain boundaries and impure grain orientations because of complex fluid dynamics during solution coating. Here, a novel methodology, water-surface drag coating, is demonstrated to fabricate high-quality OSC thin films with greatly enhanced charge transport properties. This method utilizes the water surface to alter the evaporation dynamics of solution to enlarge the grain size, and a unique drag-coating process to achieve the unidirectional growth of organic crystals. Using 2,8-difluoro-5,11-bis(triethylsilylethynyl)anthradithiophene (Dif-TES-ADT) as an example, thin films with millimeter-sized single-crystal domains and pure crystallographic orientations are achieved, revealing a significant enhancement (4.7 times) of carrier mobility. More importantly, the resulting film can be directly transferred onto any desired flexible substrates, and flexible transistors based on the Dif-TES-ADT thin films show a mobility as high as 16.1 cm V s , which represents the highest mobility value for the flexible transistors reported thus far. The method is general for the growth of various high-quality OSC thin films, thus opening up opportunities for high-performance organic flexible electronics.
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http://dx.doi.org/10.1002/adma.202005915DOI Listing
February 2021

FSH directly regulates chondrocyte dedifferentiation and cartilage development.

J Endocrinol 2021 Feb;248(2):193-206

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.

Previous studies suggest that postmenopausal osteoarthritis is linked to a decrease in estrogen levels. However, whether follicle-stimulating hormone (FSH), the upstream hormone of estrogen, affects cartilage destruction and thus contributes to the onset of osteoarthritis has never been explored. To evaluate the potential involvement of FSH in joint degeneration and to identify the molecular mechanisms through which FSH influences chondrocytes, mouse cartilage chondrocytes and the ATDC5 chondrocyte cell line were treated with FSH and inhibitors of intracellular signaling pathways. We observed that FSH induces chondrocyte dedifferentiation by decreasing type II collagen (Coll-II) synthesis. Chondrocyte cytoskeleton reorganization was also observed after FSH treatment. The FSH-induced decrease in Coll-II was rescued by ERK-1/2 inhibition but aggravated by p38 inhibition. In addition, knocking down the FSH receptor (Fshr) by using Fshr siRNA abolished chondrocyte dedifferentiation, as indicated by the increased expression of Coll-II. Inhibition of the protein Gαi by pertussis toxin (PTX) also restored FSH-inhibited Coll-II, suggesting that Gαi is downstream of FSHR in chondrocyte dedifferentiation. FSHβ antibody blockade prevented cartilage destruction and cell loss in mice. Moreover, decreased Coll-II staining due to the progression of aging could be rescued by blocking FSH. Thus, we suggest that high circulating FSH, independent of estrogen, is an important regulator in chondrocyte dedifferentiation and cartilage destruction.
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http://dx.doi.org/10.1530/JOE-20-0390DOI Listing
February 2021

Neutralizing antibodies for the treatment of COVID-19.

Nat Biomed Eng 2020 12;4(12):1134-1139

Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA.

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http://dx.doi.org/10.1038/s41551-020-00660-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891858PMC
December 2020

Graphene-Quantum-Dots-Induced Centimeter-Sized Growth of Monolayer Organic Crystals for High-Performance Transistors.

Adv Mater 2020 Sep 16;32(38):e2003315. Epub 2020 Aug 16.

Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.

Monolayer organic crystals have attracted considerable attention due to their extraordinary optoelectronic properties. Solution self-assembly on the surface of water is an effective approach to fabricate monolayer organic crystals. However, due to the difficulties in controlling the spreading of organic solution on the water surface and the weak intermolecular interaction between the organic molecules, large-area growth of monolayer organic crystals remains a great challenge. Here, a graphene quantum dots (GQDs)-induced self-assembly method for centimeter-sized growth of monolayer organic crystals on a GQDs solution surface is reported. The spreading area of the organic solution can be readily controlled by tuning the pH value of the GQDs solution. Meanwhile, the π-π stacking interaction between the GQDs and the organic molecules can effectively reduce the nucleation energy of the organic molecules and afford a cohesive force to bond the crystals, enabling large-area growth of monolayer organic crystals. Using 2,7-didecyl benzothienobenzothiopene (C-BTBT) as an examples, centimeter-sized monolayer C-BTBT crystal with uniform molecular packing and crystal orientation is attained. Organic field-effect transistors based on the monolayer C-BTBT crystals exhibit a high mobility up to 2.6 cm V s, representing the highest mobility value for solution-assembled monolayer organic crystals. This work provides a feasible route for large-scale fabrication of monolayer organic crystals toward high-performance organic devices.
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http://dx.doi.org/10.1002/adma.202003315DOI Listing
September 2020

c-Src promotes the growth and tumorigenesis of hepatocellular carcinoma via the Hippo signaling pathway.

Life Sci 2021 Jan 10;264:118711. Epub 2020 Nov 10.

Department of Oncology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, China.

We investigated the association between c-Src and the progression of hepatocellular carcinoma (HCC) and its underlying mechanisms. The relationship between c-Src expression and the occurrence and development of HCC was explored using GEPIA and further confirmed by western blotting analysis and real-time quantitative PCR. CCK-8, flow cytometry, Transwell, and wound-healing assays were conducted to analyze the effects of c-Src on the growth, cell cycle, apoptosis, migration, and infiltration of HCC cells. Mouse models of transplanted xenogeneic human tumors were constructed to explore the effects of c-Src on HCC tumor growth. Compared with that in adjacent normal liver tissues, the expression level of c-Src in HCC tissues was significantly increased and was negatively correlated with patient survival. These findings are consistent with those in the GEPIA database. Downregulation of c-Src expression can inhibit the growth, infiltration, and migration of HCC cells. c-Src impeded the translocation of YAP from the nucleus to the cytoplasm and promoted Yes-associated protein transcriptional activity. In vivo experiments showed that c-Src inhibition suppressed tumor growth in mice. We found that c-Src can promote the growth and tumorigenesis of HCC cells by activating the Hippo signaling pathway.
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http://dx.doi.org/10.1016/j.lfs.2020.118711DOI Listing
January 2021

Effect of Saxagliptin, a Dipeptidyl Peptidase 4 Inhibitor, on Non-Alcoholic Fatty Liver Disease.

Diabetes Metab Syndr Obes 2020 6;13:3507-3518. Epub 2020 Oct 6.

Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.

Background And Aim: Non-alcoholic fatty liver disease (NAFLD) represents a broad spectrum of chronic liver disease characterized by aberrant accumulation of triglycerides (TG) in hepatocytes without excessive alcohol consumption. Hepatic lipotoxicity derived from overaccumulation of free fatty acids is considered as one of the typical hallmarks of NAFLD. Insulin resistance (IR) and chronic inflammation are widely recognized as the key etiological factors associated with NAFLD. Dipeptidyl peptidase 4 inhibitor (DPP4i) is a novel pharmacological agent extensively applied in the treatment of Type 2 Diabetes Mellitus (T2DM) for decades which also have a liver protective effect.

Methods: In order to invest the therapeutic efficiency and underlying mechanism of DPP4i saxagliptin, we used high-fat diet (HFD) and streptozotocin-induced NAFLD treated with saxagliptin. Biochemical, histomorphological, genetic and protein expression of related pathways were investigated.

Results: Fasting blood glucose (FBG), TG, total cholesterol (TC), and low-density lipoprotein cholesterin significantly increased in NAFLD group, which also exhibited severe steatosis. Other remarkable findings were hyperinsulinemia, increased DPP4, and level and decreased GLP-1, , expression, concomitant with liver DPP4 expression enhancement and serum DPP4 elevation. These undesirable consequences were alleviated by saxagliptin to a certain degree.

Conclusion: DPP4i saxagliptin improves NAFLD by ameliorating IR, inflammation, downregulation of hepatic DPP4 and sDPP4, as well as subsequent steatosis. The elevation of hepatic DPP4 and sDPP4 and succedent post-treatment decrease suggested that DPP4 may involve in the development of NAFLD. The anti-lipotoxic effect of DPP4i may involve the activation of and related β-oxidation signaling pathway suppression of mediated inflammatory and . The results covered in this article showed that saxagliptin affects many aspects of the pathological characteristics of NAFLD, suggesting that DPP4i saxagliptin may offer a novel therapeutic option for NAFLD.
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http://dx.doi.org/10.2147/DMSO.S262284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547785PMC
October 2020

Diagnostic value of carbohydrate antigen 72-4 combined with carbohydrate antigen 15.3 in ovarian cancer, cervical cancer and endometrial cancer.

J BUON 2020 Jul-Aug;25(4):1918-1927

Department of Gynecology, Weifang People's Hospital, Weifang 261041, China.

Purpose: This study was designed to explore the value of carbohydrate antigen 72-4 (CA72-4) combined with carbohydrate antigen 15-3 (CA153) in diagnosing gynecologic malignancies.

Methods: 64 patients with ovarian cancer admitted to our hospital from February 2014 to February 2016 comprised the group A; 52 cases of cervical cancer were regarded as group B; 46 cases of endometrial cancer comprised the group C; and 150 cases of healthy women were considered as a control group. The CA72-4 and CA15.3 levels in serum of each group were detected, and receiver operating characteristics (ROC) curve was used to analyze the diagnostic value of CA72-4 and CA15.3 in ovarian, cervical, as well as in endometrial cancer.

Results: CA72-4 and CA15.3 increased dramatically in cancer patients (p<0.001). CA15.3 in group C was higher than in groups A and B (p<0.05). Joint diagnosis of the two had good sensitivity, specificity and area under the curve (AUC) for ovarian, cervical as well as for endometrial cancer (p<0.001). CA72-4 and CA15.3 were closely related to the occurrence of gynecologic malignancies (p<0.001). The results of follow-up revealed that CA72-4 had a higher value in predicting the death of ovarian cancer patients within 3 years, while CA15.3 had a better effect in predicting the death of ovarian and cervical cancer (p<0.05).

Conclusion: CA72-4 and CA15.3 were dramatically higher in ovarian, cervical and endometrial cancer among gynecologic malignancies. Joint detection of the two had better diagnostic value for ovarian and cervical cancer.
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October 2020

Carrier-free nanodrugs for safe and effective cancer treatment.

J Control Release 2021 Jan 9;329:805-832. Epub 2020 Oct 9.

School of Engineering, Institute for Bioengineering, The University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JL, UK. Electronic address:

Clinical applications of many anti-cancer drugs are restricted due to their hydrophobic nature, requiring use of harmful organic solvents for administration, and poor selectivity and pharmacokinetics resulting in off-target toxicity and inefficient therapies. A wide variety of carrier-based nanoparticles have been developed to tackle these issues, but such strategies often fail to encapsulate drug efficiently and require significant amounts of inorganic and/or organic nanocarriers which may cause toxicity problems in the long term. Preparation of nano-formulations for the delivery of water insoluble drugs without using carriers is thus desired, requiring elegantly designed strategies for products with high quality, stability and performance. These strategies include simple self-assembly or involving chemical modifications via coupling drugs together or conjugating them with various functional molecules such as lipids, carbohydrates and photosensitizers. During nanodrugs synthesis, insertion of redox-responsive linkers and tumor targeting ligands endows them with additional characteristics like on-target delivery, and conjugation with immunotherapeutic reagents enhances immune response alongside therapeutic efficacy. This review aims to summarize the methods of making carrier-free nanodrugs from hydrophobic drug molecules, evaluating their performance, and discussing the advantages, challenges, and future development of these strategies.
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http://dx.doi.org/10.1016/j.jconrel.2020.10.014DOI Listing
January 2021

Therapeutic antibodies and fusion inhibitors targeting the spike protein of SARS-CoV-2.

Expert Opin Ther Targets 2020 Sep 17:1-7. Epub 2020 Sep 17.

Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA.

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http://dx.doi.org/10.1080/14728222.2020.1820482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544964PMC
September 2020

Mce1C and Mce1D facilitate N. farcinica invasion of host cells and suppress immune responses by inhibiting innate signaling pathways.

Sci Rep 2020 09 10;10(1):14908. Epub 2020 Sep 10.

State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 155 Changbai Road Changping District, Beijing, 102206, China.

The mammalian cell entry (Mce) family of proteins consists of invasin-like membrane-associated proteins. The roles of Mce1C and Mce1D proteins in host-pathogen interactions have not been investigated. In this study, we demonstrate that Mce1C and Mce1D protein is localized in the cell wall fraction of N. farcinica. Both N. farcinica Mce1C and Mce1D proteins are expressed at the level of protein and mRNA and elicit antibody responses during infection. Mce1C and Mce1D facilitate the internalization of Escherichia coli expressing Mce1C protein or latex beads coated with Mce1D protein by HeLa cells, respectively. We further demonstrate that Mce1C and Mce1D can suppress the secretion of the proinflammatory factors TNF-α and IL-6 in macrophages infected with Mycobacterium smegmatis expressing Mce1C or Mce1D and promote the survival of M. smegmatis expressing Mce1C or Mce1D in macrophages. In addition, Mce1C and Mce1D supress the activation of the NF-κB and MAPK signaling pathways by blocking the phosphorylation of AKT, P65, ERK1/2, JNK, or P38 in macrophages. These findings suggest that Mce1C and Mce1D proteins facilitate N. farcinica invasion of HeLa cells and suppress host innate immune responses by manipulating NF-κB and MAPK signaling pathways, which may provide a target for N. farcinica treatment.
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http://dx.doi.org/10.1038/s41598-020-71860-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484815PMC
September 2020

Prevalence and predictors of myopic macular degeneration among Asian adults: pooled analysis from the Asian Eye Epidemiology Consortium.

Br J Ophthalmol 2020 Sep 2. Epub 2020 Sep 2.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

Aims: To determine the prevalence and predictors of myopic macular degeneration (MMD) in a consortium of Asian studies.

Methods: Individual-level data from 19 885 participants from four population-based studies, and 1379 highly myopic participants (defined as axial length (AL) >26.0 mm) from three clinic-based/school-based studies of the Asian Eye Epidemiology Consortium were pooled. MMD was graded from fundus photographs following the meta-analysis for pathologic myopia classification and defined as the presence of diffuse choroidal atrophy, patchy chorioretinal atrophy, macular atrophy, with or without 'plus' lesion (lacquer crack, choroidal neovascularisation or Fuchs' spot). Area under the curve (AUC) evaluation for predictors was performed for the population-based studies.

Results: The prevalence of MMD was 0.4%, 0.5%, 1.5% and 5.2% among Asians in rural India, Beijing, Russia and Singapore, respectively. In the population-based studies, older age (per year; OR=1.13), female (OR=2.0), spherical equivalent (SE; per negative diopter; OR=1.7), longer AL (per mm; OR=3.1) and lower education (OR=1.9) were associated with MMD after multivariable adjustment (all p<0.001). Similarly, in the clinic-based/school-based studies, older age (OR=1.07; p<0.001), female (OR=2.1; p<0.001), longer AL (OR=2.1; p<0.001) and lower education (OR=1.7; p=0.005) were associated with MMD after multivariable adjustment. SE had the highest AUC of 0.92, followed by AL (AUC=0.87). The combination of SE, age, education and gender had a marginally higher AUC (0.94).

Conclusion: In this pooled analysis of multiple Asian studies, older age, female, lower education, greater myopia severity and longer AL were risk factors of MMD, and myopic SE was the strongest single predictor of MMD.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316648DOI Listing
September 2020

Study of Adipose-Derived Mesenchymal Stem Cells Transduced with Lentiviral Vector Carrying the Brain-Derived Neurotrophic Factor Gene.

Int J Stem Cells 2020 Nov;13(3):386-393

State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Panjin Campus, Dalian University of Technology, Panjin, China.

Brain-derived neurotrophic factor (BDNF) exerts its survival-promoting effects on photoreceptors and retinal ganglion cells, however, delivery systems with little-to-no side effect are needed to sustain its controlled release and long-term efficacy. Our previous studies demonstrated that adipose-derived stem cells (ADSCs) are ideal delivery systems for gene therapy; moreover, ADSCs present unique properties like migration to damaged tissue sites, immunomodulation and anti-inflammation. Herein, we propose to employ ADSCs as the BDNF gene delivery vehicle. Different Analyses like flow cytometry, differentiation and cell proliferation assays etc demonstrated that BDNF were successfully transduced into ADSCs and the stemness of ADSCs was maintained even with the transduction. Real Time PCR and Western blot were used to measure mRNA and protein expressions of the BDNF-transduced ADSCs. The results demonstrated that the BDNF expression level of the lentiviral-BDNF transduced ADSCs is significantly increased and, moreover, enhanced the expression of other neurotrophic and downstream signaling factors. The data suggest that ADSCs are a reliable delivery vehicle for BDNF and could be used for the treatment of various diseases.
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http://dx.doi.org/10.15283/ijsc20038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691859PMC
November 2020

Chitosan-hydrophobic alginate nanocomposites stabilized pH-triggered Pickering emulsion for drug controlled-release.

Int J Biol Macromol 2020 Nov 12;162:1888-1896. Epub 2020 Aug 12.

School of Chemical Engineering, Dalian University of Technology, Panjin 124221, China. Electronic address:

Alginate or chitosan microparticles as drug loading system performed pH-responsiveness and biocompatibility, yet with the burst-release and limited encapsulation. In order to improve the performance, herein, Pickering emulsion of chitosan-hydrophobic alginate nanocomposite (HSA-CS NCs) as the bio-stabilizer, was proposed as the drug-loading vehicle. Integrating the merits of HSA-CS and Pickering emulsion, such drug carrier of emulsion performed pH-response and biocompatibility from HSA-CS, and high loading capacity and rigid layer from Pickering emulsion, so as for the manipulated release behavior. With thorough investigation, via the various pH-response of HSA-CS nanocomposite in the continuous simulated gastrointestinal fluid, Pickering emulsion gradually released the loading drug (ibuprofen) out, performing the pH-triggered controlled-release behavior. Ibuprofen-loaded Pickering emulsions (30 mg/mL) released nearly none in SGF for 3 h, whereas in SIF, performed constant release in initial 5 h and continuous-release of 88.37% ibuprofen in 24 h with no drug-burst and high loading capacity, promisingly as the pH-responsive vehicle for drug delivery in oral route.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.08.092DOI Listing
November 2020

SpyGlass-guided laser lithotripsy versus laparoscopic common bile duct exploration for large common bile duct stones: a non-inferiority trial.

Surg Endosc 2020 Aug 11. Epub 2020 Aug 11.

Department of Endoscopy, the First Affiliated Hospital of Shandong First Medical, University, 250014, Jinan, China.

Background: Laparoscopic common bile duct exploration (LCBDE) is the first choice of treatment for large common bile duct (CBD) stones. Recently, single-operator cholangioscopy (SpyGlass system) has been introduced widely in referral and large medical centers. Several studies have reported favorable results for treatment of large CBD stones guided by SpyGlass. We evaluated the clinical efficacy and safety of SpyGlass-guided laser lithotripsy LCBDE for treatment of large CBD stones.

Methods: From August 2015 to August 2018, 157 patients with large bile duct stones who met the inclusion criteria were randomly divided into two groups: SpyGlass-guided laser lithotripsy (Group A) and LCBDE (Group B). The efficacy and complications were compared between the groups.

Results: Although the first-session stone removal rate in Group A was significantly lower than that in Group B, Group A was not inferior to Group B in terms of total stone removal rate. Compared with Group B, Group A had shorter hospital stay and enhanced recovery. The short-term complication rates were also similar between the two groups.

Conclusions: The clinical efficacy of SpyGlass-guided laser lithotripsy for the treatment of large CBD stones is not inferior to that of LCBDE, and it is less invasive. SpyGlass-guided laser lithotripsy is an important option for treatment of large CBD stones.
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http://dx.doi.org/10.1007/s00464-020-07862-4DOI Listing
August 2020

Lgr5 maintains stemness and regulates cell property in nasopharyngeal carcinoma through Wnt/β-catenin signaling pathway.

Stem Cell Res 2020 Jul 18;47:101916. Epub 2020 Jul 18.

School of Life Sciences, Shanghai University, Shanghai 200444 China; Department of Otolaryngology, Eye, Ear, Nose and Throat Hospital, Shanghai Key Clinical, Disciplines of Otorhinolaryngology, Fudan University, Shanghai 200031 China. Electronic address:

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in Southern China and Southeast Asia. In this study, we found that Leucine rich repeat containing G protein-coupled receptor 5 (Lgr5) was highly expressed in NPC tissues and marked NPC stem cells. Lgr5 tumors showed differential transcriptional landscape compared to Lgr5 tumors. Lgr5 expression was associated with the clinicopathologic features in NPC and was able to regulate the stemness and viability of NPC cell line CNE1 and HNE1. Meanwhile, the migration, invasion and epithelial-mesenchymal transition (EMT) was modulated by Lgr5 via Wnt/β-catenin signaling pathway. Furthermore, Lgr5 could regulate the sensitivity of NPC cells to chemotherapy drugs. Xenografted tumors from Lgr5-overexpressed CNE1 cells showed stronger tumor forming capacity and higher expression level of stem cell markers. Thus, we characterized previously unidentified role of Lgr5 in NPC cells, potential serving as a NPC stem cell biomarker and a therapeutic target against NPC.
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http://dx.doi.org/10.1016/j.scr.2020.101916DOI Listing
July 2020

High fat diet impairs spermatogenesis by regulating glucose and lipid metabolism in Sertoli cells.

Life Sci 2020 Sep 29;257:118028. Epub 2020 Jun 29.

Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, China; Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China. Electronic address:

Aims: Sertoli cells (SCs) play an important role in the process of spermatogenesis. SCs provide energy for germ cells (GCs) and themselves through glycolysis and fatty acid oxidation (FAO) respectively. High fat diet (HFD) impairs spermatogenesis by damaging function of SCs, however whether HFD disrupts energy metabolism in SCs remains unclear.

Main Methods: To explore this hypothesis, we built male Wistar rat model fed on HFD and cultured rats' primary SCs with palmitic acid (PA). Rats' fertility and sperm quality were evaluated in vivo. Glycolysis, lactate production and mitochondrial respiration were assessed by using extracellular flux analyzer, and the expression of enzymes involved in glucose and FAO was analyzed by Real-Time PCR or Western Blotting.

Key Findings: The showed that the sperm concentration and pups per litter significantly decreased in rats fed on HFD compared to those rats fed on normal diet. There was an elevation of lactate levels in testicular tissue of rats fed on HFD and primary SCs exposed to PA. In vitro, PA increased glycolytic flux, and lactate production, and the levels of carnitine palmitoyltransferase I (CPT1) and long chain acyl-CoA dehydrogenase (LCAD) which were two key enzymes for fatty acid β oxidation. Further analysis showed that mitochondrial respiration was impaired by PA, followed by the decrease in ATP turnover, maximal respiration and the increase in proton leak.

Significance: Taken together, the elevated lactate level, lipid metabolism disorder and mitochondrial dysfunction caused by HFD lead to SCs dysfunction, which ultimately leads to decreased sperm quality.
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http://dx.doi.org/10.1016/j.lfs.2020.118028DOI Listing
September 2020

Age-related taste cell generation in circumvallate papillae organoids via regulation of multiple signaling pathways.

Exp Cell Res 2020 09 22;394(2):112150. Epub 2020 Jun 22.

Department of Otolaryngology, Eye, Ear, Nose and Throat Hospital, Shanghai Key Clinical Disciplines of Otorhinolaryngology, Fudan University, Shanghai, 200031, China. Electronic address:

Sense of taste is central to evaluate food before digestion. Taste stem cells undergo constant differentiation throughout the life. However, the mechanism underlying the generation of taste receptor cells is still not clear. Here, we cultured taste organoids from either Lgr5+ or Lgr5-cells, and found the preferential generation of Car4+ and Gustducin + taste receptor cells in organoids derived from Lgr5+ cells in circumvallate, foliate or fungiform papillae. Taste organoids derived from Lgr5+ cells in circumvallate papillae of neonatal mice showed stronger capacity to generate taste receptor cells compared to the organoids from Lgr5+ cells of the adult circumvallate papillae. Massive transcriptional differences were found in multiple signaling pathways including taste transduction between organoids derived from circumvallate papillae of adult and neonatal mice. Inhibiting the Notch signaling pathway by LY411575 enhanced taste receptor cell generation in organoids from circumvallate papillae and modulated multiple signaling pathways. Thus, we concluded that receptor cell generation in taste organoids was age-related and regulated via multiple signaling pathways.
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http://dx.doi.org/10.1016/j.yexcr.2020.112150DOI Listing
September 2020

Correction: Successful Management of Recurrent Subacute Thyroiditis by Adding Colchicine to Glucocorticoid Treatment: A Case Series Study.

Horm Metab Res 2020 May 19. Epub 2020 May 19.

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

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http://dx.doi.org/10.1055/a-1175-6502DOI Listing
May 2020