Publications by authors named "Jun Tian"

455 Publications

Apolipoprotein E Genotype Contributes to Motor Progression in Parkinson's Disease.

Mov Disord 2021 Oct 6. Epub 2021 Oct 6.

Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Background: Emerging evidence indicates that the apolipoprotein E (APOE) ε4 exacerbates α-synuclein pathology.

Objective: To determine whether APOE ε4 contributes to motor progression in early Parkinson's disease (PD).

Methods: Longitudinal data were obtained from 384 patients with PD divided into APOE ε4 carriers (n = 85) and noncarriers (n = 299) in the Parkinson's Progression Marker Initiative. Participants underwent yearly motor assessments over a mean follow-up period of 78.9 months. Repeated measures and linear mixed models were used to test the effects of APOE ε4.

Results: The motor progression was significantly more rapid in patients with PD carrying APOE ε4 than in noncarriers (β = 0.283, P = 0.026, 95% confidence interval: 0.033-0.532). Through subgroup analysis, we found that the effect of APOE ε4 was significant only in patients with high amyloid β burden (β = 0.761, P < 0.001, 95% confidence interval: 0.0356-1.167).

Conclusions: APOE ε4 may be associated with rapid motor progression in PD. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28805DOI Listing
October 2021

Juxtaglomerular Cell Tumor: A Rare Cause of Hypertension.

Urology 2021 Sep 15. Epub 2021 Sep 15.

Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address:

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http://dx.doi.org/10.1016/j.urology.2021.08.039DOI Listing
September 2021

Prognostic Value and Immunological Characteristics of a Novel RNA Binding Protein Signature in Cutaneous Melanoma.

Front Genet 2021 31;12:723796. Epub 2021 Aug 31.

Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, China.

Background: The existing studies indicate that RNA binding proteins (RBPs) are closely correlated with the genesis and development of cancers. However, the role of RBPs in cutaneous melanoma remains largely unknown. Therefore, the present study aims to establish a reliable prognostic signature based on RBPs to distinguish cutaneous melanoma patients with different prognoses and investigate the immune infiltration of patients.

Methods: After screening RBPs from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, Cox and least absolute shrinkage and selection operator (LASSO) regression analysis were then used to establish a prediction model. The relationship between the signature and the abundance of immune cell types, the tumor microenvironment (TME), immune-related pathways, and immune checkpoints were also analyzed.

Results: In total, 7 RBPs were selected to establish the prognostic signature. Patients categorized as a high-risk group demonstrated worse overall survival (OS) rates compared to those of patients categorized as a low-risk group. The signature was validated in an independent external cohort and indicated a promising prognostic ability. Further analysis indicated that the signature wasan independent prognostic indicator in cutaneous melanoma. A nomogram combining risk score and clinicopathological features was then established to evaluate the 3- and 5-year OS in cutaneous melanoma patients. Analyses of immune infiltrating, the TME, immune checkpoint, and drug susceptibility revealed significant differences between the two groups. GSEA analysis revealed that basal cell carcinoma, notch signaling pathway, melanogenesis pathways were enriched in the high-risk group, resulting in poor OS.

Conclusion: We established and validated a robust 7-RBP signature that could be a potential biomarker to predict the prognosis and immunotherapy response of cutaneous melanoma patients, which provides new insights into cutaneous melanoma immunotherapeutic strategies.
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http://dx.doi.org/10.3389/fgene.2021.723796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438157PMC
August 2021

Exosomes derived from ADSCs containing miR-378 promotes wound healing by targeting caspase-3.

J Biochem Mol Toxicol 2021 Oct 15;35(10):e22881. Epub 2021 Aug 15.

Department of Dermatology, Shaanxi Provincial People's Hospital, Xi'an, China.

Pathological scars and chronic wounds caused by injury, aging, or surgery have always been important public health problems, and there is an urgent need to study the driving forces to find more effective treatments. In this study, we extracted and identified ADSCs exosomes and found that they have the ability to protect HaCat cells from oxidative damage, including promoting proliferation and migration and reducing apoptosis. Further studies determined that the expression of miR-378 was significantly enriched in exosomes. Studies have found that miR-378 mimic can produce protection similar to ADSCs-exo. However, when miR-378 inhibitors are used on ADSCs, the damage protection of the secreted exosomes disappears. This proves that miR-378 enriched in exosomes can improve HaCat's oxidative stress damage. Luciferase experiments show that this effect is achieved by targeting caspase-3. These results indicate that ADSCs play a protective role in wound healing by secreting miR-378-rich exosomes.
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http://dx.doi.org/10.1002/jbt.22881DOI Listing
October 2021

The effect of the PARK16 rs11240572 variant on brain structure in Parkinson's disease.

Brain Struct Funct 2021 Nov 9;226(8):2665-2673. Epub 2021 Aug 9.

Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, People's Republic of China.

Increasing evidence suggests that genetic factors play a key role in the development of Parkinson's disease (PD). The variant rs11240572 in the PARK16 gene locus is strongly associated with PD. However, its effect on the pathogenesis of PD is yet to be clarified. The objective of the study was to explore the effect of the PARK16 rs11240572 variant on brain structure in PD patients. A total of 51 PD patients were enrolled in the study and genotyped for the rs11240572 variant. Clinical assessments and MRI scans were conducted across all participants. Voxel-based morphometry (VBM) was used to investigate gray matter volume (GMV) of the whole brain between these two groups. Correlation analysis was performed to identify the relationships between GMV and clinical features. There were 17 rs11240572-A variant carriers and 34 non-carriers, with no significant demographic differences between these two groups. Compared with non-carriers, rs11240572-A carriers showed increased GMV in the left caudate nucleus and putamen, but decreased GMV in the left superior temporal gyrus and supramarginal gyrus. In non-carriers, left basal ganglia GMV was positively correlated with UPDRS III (r = 0.365, p = 0.034) and bradykinesia (r = 0.352, p = 0.042), but negatively correlated with MMSE (r =  - 0.344, p = 0.047), while in carriers negative correlation between basal ganglia GMV and MMSE was also observed (r =  - 0.666, p = 0.004). Moreover, the GMV of left temporoparietal cortex was positively associated with cognitive function in both groups (carriers, r = 0.692, p = 0.002; non-carriers, r = 0.879, p < 0.001). When reducing the sample size of non-carriers to the level of the carrier sample, similar correlations were observed in both groups. Our study showed that the PARK16 rs11240572 variant affects the brain structure of patients with PD, especially in the basal ganglia and temporoparietal cortex. This indicated that this variant might play an important role in the pathogenesis of PD.
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http://dx.doi.org/10.1007/s00429-021-02359-9DOI Listing
November 2021

Association analysis and polygenic risk score evaluation of 38 GWAS-identified Loci in a Chinese population with Parkinson's disease.

Neurosci Lett 2021 09 2;762:136150. Epub 2021 Aug 2.

Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China. Electronic address:

Objective: Recently, a meta-analysis of genome-wide association studies (GWASs) has identified 38 novel independent loci associated with risk of Parkinson's disease (PD) in European populations. We sought to investigate whether these genetic susceptibility variants could be replicated in the Chinese Han population.

Methods: We genotyped 38 independent loci in 495 Chinese sporadic PD patients and 470 unrelated controls and performed allelic and genotypic association test using chi-square tests or Armitage test for trend. Polygenic risk score (PRS) models were built to evaluate the cumulative effects of the selected SNPs.

Results: We found that the rs11610045 of FBRSL1 (p = 0.02, OR = 0.63, allele model), rs76116224 of KCNS3 (p < 0.01, OR = 0.09, allele model), and the rs2248244 of DYRK1A (p = 0.02, OR = 1.35, allele model) were significantly associated with PD. The PRS model of cumulative effects of the SNPs associated with PD in our study had the area under the curve (AUC) of 0.61.

Conclusions: Our study revealed that rs11610045 of FBRSL1, rs76116224 of KCNS3 and rs2248244 of DYRK1A showed an impact on the risk of PD, and the GWAS-derived PRS models we built had predictive value for PD risk in the Chinese population. Further studies are needed to explore the pathogenesis of these potentially risk-associated variants.
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http://dx.doi.org/10.1016/j.neulet.2021.136150DOI Listing
September 2021

LPS-induced autophagy in human dental pulp cells is associated with p38.

J Mol Histol 2021 Oct 26;52(5):919-928. Epub 2021 Jul 26.

Department of Operative Dentistry and Endodontics, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, 56 Ling yuan Road West, Guangzhou, 510055, China.

Lipopolysaccharides (LPS), which are components of the cell wall of Gram-negative bacteria, are among the important factors that induce inflammation, including pulpitis. Autophagy in human dental pulp cells (hDPCs) acts as a protective mechanism that promotes cell survival under adverse conditions through different signaling pathways. In this study, we examined whether LPS increases autophagy in hDPCs and investigated the role of mitogen-activated protein kinases signaling and nuclear factor κB (NF-κB) in this process. We found that stimulation of hDPCs with 0.1 µg/mL LPS increased the protein and mRNA levels of autophagy markers, beclin1 and microtubule associated protein light chain 3II (LC3II). In addition, acridine orange staining and transmission electron microscopy demonstrated the induction of autophagy upon the treatment of LPS. Furthermore, LPS affected phosphorylation of p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), and the nuclear translocation of NF-κB. While p38 inhibitor suppressed the LPS-induced increase in protein levels of beclin1 and LC3-II. Our results suggest that LPS induced autophagy in hDPCs and affected the phosphorylation of p38, ERK, and JNK, as well as the nuclear translocation of NF-κB. Phosphorylation of p38 may be involved in LPS-induced autophagy in hDPCs.
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http://dx.doi.org/10.1007/s10735-021-10004-2DOI Listing
October 2021

Melatonin Attenuates Neuroinflammation by Down-Regulating NLRP3 Inflammasome via a SIRT1-Dependent Pathway in MPTP-Induced Models of Parkinson's Disease.

J Inflamm Res 2021 8;14:3063-3075. Epub 2021 Jul 8.

Department of Neurology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, 310009, People's Republic of China.

Background: Inflammasome-induced neuroinflammation is a key contributor to the pathology of Parkinson's disease (PD). NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation has been implicated in PD in postmortem human PD brains, indicating it as a potential target for PD treatment. Melatonin, a multitasking molecule, has been found to have anti-inflammatory activities, mediated by silence information regulator 1 (SIRT1). However, whether and how melatonin is involved in inflammasome-induced neuroinflammation in PD pathogenesis remains unclear.

Methods: We investigated the potential anti-inflammatory effects of melatonin in vitro and in vivo, using 1-methyl-4-phenylpyridinium (MPP)-simulated BV2 and primary microglia cell models, and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine PD model, with or without melatonin treatment. Rotarod, grip strength, and open-field tests were performed to measure the effects of melatonin on MPTP-induced motor disorders. Degeneration of dopaminergic neurons was evaluated by immunofluorescence. Changes in microglia were examined by immunofluorescence and Western blotting, and the expression levels of the involved signaling molecules were assessed by Western blotting and enzyme-linked immunosorbent assay (ELISA). Intracellular reactive oxygen species (ROS) was detected using fluorescent probes via flow cytometry.

Results: We found that melatonin significantly alleviated motor dysfunction and prevented MPTP-induced neurotoxicity in dopaminergic neurons. Additionally, melatonin reduced MPTP-induced microglial activation and suppressed NLRP3 inflammasome activity, and also inhibited IL-1β secretion. Moreover, in MPP-primed BV2 cells, melatonin markedly restored the downregulation of SIRT1 and attenuated the activation of the NLRP3 inflammasome. This was reversed by SIRT1 inhibitor treatment.

Conclusion: In conclusion, our data demonstrated that melatonin attenuates neuroinflammation by negatively regulating NLRP3 inflammasome activation via a SIRT1-dependent pathway in MPTP-induced PD models. These findings provide novel insights into the mechanism underlying the anti-inflammatory effects of melatonin in PD.
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http://dx.doi.org/10.2147/JIR.S317672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275196PMC
July 2021

Effects of Paired Associative Stimulation on Metabolites in Ischemia Stroke Rats Model as Studied by Nuclear Magnetic Resonance Spectrum.

Neurochem Res 2021 Sep 7;46(9):2495-2504. Epub 2021 Jul 7.

Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, No. 1095, Jiefang Avenue, Qiaokou District, Wuhan City, 430000, Hubei Province, China.

Paired associated stimulation (PAS) has been confirmed to play a role in motor recovery after stroke, but the underlying mechanism has not been fully elucidated. In this study, we employed a comprehensive battery of measurements, including behavioral test, electrophysiology and H-NMR approaches, to investigate the therapeutic effects of PAS in rat model of cerebral ischemia and its underlying mechanism. Rats were randomly divided into a transient middle cerebral artery occlusion group (tMCAO group), a tMCAO + PAS group (PAS group), and a sham group. PAS was applied over 7 consecutive days in PAS group. The behavioral function of rats was evaluated by modified Garcia Scores and Rota-rod test. Electrophysiological changes were measured by motor evoked potentials (MEP). Metabolic changes of ischemic penumbra were detected by H-NMR. After PAS intervention, the performances on Rota-rod test and Garcia test improved and the amplitude of MEP increased significantly. The gamma-aminobutyric acid (GABA) in penumbra cortex was decreased significantly, whereas the glutamate showed the opposite changes. The results suggested that post-stroke recovery promoted by PAS may be related to the metabolites alteration in ischemic penumbra and also regulate the excitability of motor cortex.
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http://dx.doi.org/10.1007/s11064-021-03388-wDOI Listing
September 2021

Anxiety and depression status prior to radiotherapy in patients with nasopharyngeal carcinoma and its effect on acute radiation toxicities.

Eur J Cancer Care (Engl) 2021 Jul 5:e13487. Epub 2021 Jul 5.

Department of Radiotherapy, Cancer Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.

Objective: The objective of this work is to explore anxiety and depression status prior to radiotherapy in patients with nasopharyngeal carcinoma (NPC) and its effect on acute radiation toxicities.

Methods: A total of 267 NPC patients were enrolled between August 2013 and September 2016. The anxiety and depression status of the patients prior to radiotherapy was evaluated using the Hospital Anxiety and Depression Scale. Acute radiation toxicities were assessed weekly and recorded according to the Common Terminology Criteria for Adverse Events version 4.0. Logistic regression analysis was used to identify the predictive factors for acute radiation toxicities.

Results: The rates of anxiety and depression status prior to radiotherapy were 35.2% and 25.5%, respectively. Anxiety was a significant predictor of vomiting (P = 0.001, OR = 2.874) and dysphagia (P = 0.029, OR = 2.080). Depression was a significant predictor of dysgeusia (P = 0.030, OR = 2.957). In addition, age was a significant predictor of dysphagia (P = 0.001, OR = 1.131).

Conclusions: Anxiety and depression status prior to radiotherapy aggravate acute radiation toxicities in patients with NPC. Assessment of the anxiety and depression status and appropriate interventions should be an integral part of treatment to relieve radiation injury during intensity-modulated radiotherapy.
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http://dx.doi.org/10.1111/ecc.13487DOI Listing
July 2021

Semiquantitative Visual Chiral Assay with a Pseudoenantiomeric Fluorescent Sensor Pair.

J Org Chem 2021 07 24;86(14):9603-9609. Epub 2021 Jun 24.

Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States.

A new red-light-emitting fluorescent probe ()- was synthesized. In the presence of Zn, this compound was found to exhibit good enantioselective fluorescence enhancement at λ = 655 nm when treated with a variety of amino acids in aqueous solution. This probe in combination with a green-light-emitting probe ()- that has enantioselective fluorescence enhancement at λ = 505 nm has formed a pseudoenantiomeric sensor pair because of their opposite enantioselectivities. This sensor pair can simultaneously detect both enantiomers of a chiral amino acid at two very different wavelengths (Δ = 150 nm). It was used to visually and semiquantitatively determine the enantiomeric compositions of amino acids. For example, when a 1:1 mixture of ()- and ()- was treated with Zn(OAc) and histidine samples of 0-100% [d-His], the color of the mixtures changed from green to yellow, orange, and red under a UV lamp (365 nm), which allowed a quick quantification of [d-His]%. This is the first example of using fluorescence to visually quantify the enantiomeric composition of chiral compounds.
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http://dx.doi.org/10.1021/acs.joc.1c00875DOI Listing
July 2021

The psychological status in patients with nasopharyngeal carcinoma during radiotherapy.

Eur Arch Otorhinolaryngol 2021 Jun 10. Epub 2021 Jun 10.

Department of Radiotherapy, Cancer Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.

Purpose: The psychological status of nasopharyngeal carcinoma (NPC) patients cannot be ignored. Few studies have studied the dynamic changes and influencing factors of psychological status in NPC patients during radiotherapy. The purpose of this study was to investigate the changing trends and risk factors of anxiety and depression in NPC patients during radiotherapy.

Methods: Demographic and clinical data of 232 newly treated NPC patients were collected. Before radiotherapy, the fourth week, and the end of radiotherapy were observational timepoints. Anxiety and depression states were evaluated by the hospital anxiety and depression scale.

Results: Scores of anxiety before radiotherapy, in the fourth week and at the end of radiotherapy were 6.32 ± 3.19, 7.87 ± 3.49, and 9.08 ± 3.69, respectively (P < 0.001). Incidence rates of anxiety were 34.0%, 55.1%, and 64.0% (P < 0.001). Depression scores were 5.31 ± 3.19, 7.07 ± 3.63, and 8.32 ± 3.89 (P < 0.001). Incidence rates of depression were 25.0%, 43.9%, and 56.0% (P < 0.001). Gender, age, education level, smoking, and treatment-related toxicity scores (P < 0.05) were independent risk factors for anxiety in patients with NPC during radiotherapy, while age, education level, and treatment-related toxicity scores (P < 0.05) were independent risk factors for depression in these patients.

Conclusion: The incidence and degree of anxiety and depression in NPC patients increased during radiotherapy. Age, education level, and treatment-related side effects influenced anxiety and depression. More psychological nursing should be given to the NPC patients who are more likely to suffer from psychological distress.
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http://dx.doi.org/10.1007/s00405-021-06892-5DOI Listing
June 2021

Toll-Like Receptor 2 Antagonist Ameliorates Type 2 Diabetes Mellitus Associated Neuropathic Pain by Repolarizing Pro-inflammatory Macrophages.

Neurochem Res 2021 Sep 3;46(9):2276-2284. Epub 2021 Jun 3.

Department of Gynecology, Shijiazhuang First Hospital, Shijiazhuang, China.

Diabetic neuropathy is one of the common complications of type 2 diabetes mellitus (T2DM) with severe outcomes. The mechanisms of physiopathology of diabetic neuropathy are not well elucidated. Inflammation and inflammatory macrophages are recognized to be crucial in diabetic neuropathy. Toll-like receptor 2 (TLR2) is an important factor in innate immune response which could promote the polarization of inflammatory macrophages. In present study, we evaluated the effects of a TLR2 antagonist CU-CPT22 on diabetic neuropathy. We induced T2DM in mice by feeding with high fat diet (HFD). We measured the body weight, blood glucose level, paw withdrawal threshold, inflammatory cytokine production, and macrophages infiltration in T2DM mice. We evaluated the effects of CU-CPT22 on pro-inflammatory cytokines production, macrophage marker expression in lipopolysaccharides (LPS)-treated BMDMs. We administrated CU-CPT22 in T2DM mice and measured the pro-inflammatory cytokines levels, expression of macrophages markers in sciatic nerve (SCN), and paw withdrawal threshold. T2DM mice had significantly increased body weight and blood glucose, and had significantly decreased paw withdrawal threshold. Obvious increased pro-inflammatory cytokine level and infiltration of M1 phenotype macrophages was observed in SCN from T2DM mice. CU-CPT22 prevented pro-inflammatory cytokine production in LPS-treated BMDMs and re-polarized them to M2 phenotype. CU-CPT22 suppressed the inflammation and induced M2 macrophages in SCN from T2DM mice, and ameliorated the paw withdrawal threshold in T2DM mice. CU-CPT22 ameliorates neuropathic pain in T2DM by promoting M2 phenotype macrophages.
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http://dx.doi.org/10.1007/s11064-021-03365-3DOI Listing
September 2021

Study of the collagen type VI alpha 3 (COL6A3) gene in Parkinson's disease.

BMC Neurol 2021 May 8;21(1):187. Epub 2021 May 8.

Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, People's Republic of China.

Background: To date, the genetic contribution to Parkinson's disease (PD) remains unclear. Mutations in the collagen type VI alpha 3 (COL6A3) gene were recently identified as a cause of isolated dystonia. Since PD and dystonia are closely related disorders with shared clinical and genetic characteristics, we explored the association between COL6A3 and PD in a Chinese cohort.

Methods: We performed genetic screening of COL6A3 in a Chinese cohort of 173 patients with sporadic PD and 200 healthy controls. We identified variants that are likely to have pathogenic effects based on: 1) a minor allele frequency of < 0.01; and 2) the variant being recognized as deleterious by at least 15 different in silico predicting tools. Finally, we tested the aggregate burden of COL6A3 on PD via SKAT-O analysis.

Results: First, we found compound heterozygous COL6A3 gene mutations in one early-onset PD patients. Then, we explored whether COL6A3 variants contributed to increased risk of developing PD in a Chinese population. We detected 21 rare non-synonymous variants. Pathogenicity predictions identified 7 novel non-synonymous variants as likely to be pathogenic. SKAT-O analysis further revealed that an aggregate burden of variants in COL6A3 contributes to PD (p = 0.038).

Conclusion: An increased aggregate burden of the COL6A3 gene was detected in patients with PD.
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http://dx.doi.org/10.1186/s12883-021-02215-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106155PMC
May 2021

From MonoBINOL to BisBINOL: Expanded Enantioselective Fluorescent Recognition of Amino Acids.

J Org Chem 2021 05 26;86(9):6780-6786. Epub 2021 Apr 26.

Department of Chemistry, University of Virginia, McCormick Road, Charlottesville, Virginia 22904, United States.

Condensation of the methoxymethyl-protected ()-3,3'-diformyl-1,1'-bi-2-naphthol (BINOL) with (pyridine-2,6-diylbis(methylene))bis(triphenyl phosphonium)dibromide in the presence of a base followed by deprotection gave a new bisBINOL-based fluorescent probe (,)-. This compound showed expanded substrate scope in the recognition of amino acids with good enantioselective fluorescence responses toward 17 common amino acids. Two diastereomeric imines were synthesized from the condensation of (,)- with l- and d-valine, and the reactions of these imines with Zn(OAc) were investigated by various spectroscopic methods for a better understanding of the enantioselective fluorescent recognition process.
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http://dx.doi.org/10.1021/acs.joc.1c00507DOI Listing
May 2021

The comparison of ketamine with tramadol for postoperative pain relief on children following adenotonsillectomy or tonsillectomy: A meta-analysis of randomized controlled trials.

Medicine (Baltimore) 2021 Apr;100(14):e22541

Department of Pediatrics, The First People's Hospital of Xiaoshan, Hangzhou, Zhejiang Province, P.R. China.

Introduction: The comparison of ketamine with tramadol for pain control remains controversial in pediatric adenotonsillectomy or tonsillectomy. We conduct a systematic review and meta-analysis to explore the efficacy of ketamine vs tramadol for pain relief in children following adenotonsillectomy or tonsillectomy.

Methods: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through October 2019 for randomized controlled trials (RCTs) assessing the effect of ketamine vs tramadol for pediatric adenotonsillectomy or tonsillectomy. This meta-analysis is performed using the random-effects model.

Results: Six RCTs are included in the meta-analysis. Overall, compared to ketamine group for pediatric adenotonsillectomy or tonsillectomy, tramadol is associated with substantially lower CHEOPS at 1 h (SMD = 1.56; 95% CI = 0.20-2.92; P = .02; low quality) and longer first time of additional pain medication (SMD = -0.47; 95% CI = -0.74 to -0.19; P = .0008; low quality), but demonstrates no obvious effect on CHEOPS at 6 h (SMD = 0.51; 95% CI = -1.17 to 2.19; P = .55; low quality), sedation scale at 1 h (SMD = -0.80; 95% CI = -3.07 to 1.48; P = .49; low quality) or additional pain medication (RR = 1.31; 95% CI = 0.85-2.02; P = .23; moderate quality).

Conclusions: Tramadol may be better to alleviate the postoperative pain after pediatric adenotonsillectomy or tonsillectomy.
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http://dx.doi.org/10.1097/MD.0000000000022541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036051PMC
April 2021

The Effects of Different Modes of Delivery on the Structure and Predicted Function of Intestinal Microbiota in Neonates and Early Infants.

Pol J Microbiol 2021 Mar 9;70(1):45-55. Epub 2021 Mar 9.

Department of Paediatrics, The First People's Hospital of Xiaoshan District, Hangzhou, China.

Several studies have shown that an increased risk of metabolic and immune disorders associated with cesarean section mode of delivery may exist. However, such studies have not been conducted in the Chinese population. Stool sample sequencing of the gene encoding the 16S rRNA of 82 prospectively enrolled 3- and 30-42-day-old vaginal and cesarean section delivered newborns was performed to study the composition and predicted function of the intestinal microbiota. In the samples from the 3-day-old neonates, the levels of in the two groups were similar. The genera , and were more prominent in the vaginal delivery than in the cesarean section group, which showed a predominance of , and . The differences between the two groups were statistically significant ( < 0.05). In the samples from 30- to 42-day-old infants, , and were the main genera present in the vaginal delivery group, while in the cesarean section delivery group; the predominant genera were , and . Predicted functions of the vaginal delivery group revealed higher metabolic and biodegradation rates of carbohydrates, vitamins, and xenobiotics than those in the cesarean section group, which contributed to the stability of the microbiota in the former. The abundance of probiotic bacteria such as and , and the negative correlation between obesity and presence were higher in vaginally delivered infants than in cesarean-delivered infants at both studied time points.
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http://dx.doi.org/10.33073/pjm-2021-002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008759PMC
March 2021

Impact of Various Microbial-Fermented Methods on the Chemical Profile of Dark Tea Using a Single Raw Tea Material.

J Agric Food Chem 2021 Apr 1;69(14):4210-4222. Epub 2021 Apr 1.

Key Laboratory of Tea Biology and Resource Utilization of Ministry of Agriculture, Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310008, China.

In the present study, we produced Pu-erh, Liubao, Qingzhuan, and Fuzhuan teas using a single raw tea material and applied widely targeted metabolomics to study the impact of various microbial-fermented methods on the chemical profile of dark tea. The contents of catechins and free amino acids decreased drastically, whereas the contents of gallic acid and theabrownins increased significantly during microbial fermentation. Pu-erh tea had the highest content of theabrownins (11.82 ± 0.49%). Moreover, MS-based metabolomics analysis revealed that the different types of dark teas were significantly different from their raw material. A total of 85 differential metabolites were screened among 569 metabolites identified referring to self-compiled database. Glycosylated, hydroxylated, methylated, and condensed and oxidated products originating from microbial bioconversion of their corresponding primitive forms were significantly increased in dark teas. These results suggest that various microbial-fermented methods greatly affect the metabolic profile of dark tea, which can provide useful information for dark tea biochemistry research.
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http://dx.doi.org/10.1021/acs.jafc.1c00598DOI Listing
April 2021

The effect of psychological condition before radiotherapy on prognosis in 390 patients initially treated for nasopharyngeal carcinoma.

Support Care Cancer 2021 Oct 25;29(10):5967-5972. Epub 2021 Mar 25.

The Department of Radiation Oncology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.

Purpose: To explore whether anxiety and depression are prognostic indexes for overall survival in patients with nasopharyngeal carcinoma (NPC) who underwent intensity-modulated radiotherapy (IMRT).

Methods: Clinical data were collected for NPC patients who underwent IMRT. Anxiety and depression were investigated before radiotherapy by using the Hospital Anxiety and Depression Scale (HADS). The survival rate was calculated by the Kaplan-Meier method, and survival curves were compared among patients with different levels of anxiety and depression. The Cox risk regression model was used to screen the factors affecting survival.

Results: A total of 390 initially treated NPC patients were included in the study. Among them, 166 patients suffered from anxiety, and 95 patients suffered from depression before radiotherapy. The 5-year overall survival rates for patients with and without anxiety before radiotherapy were 71.6% and 81.8% (χ = 5.31, P = 0.021), respectively. The 5-year overall survival rates for patients with and without depression before radiotherapy were 74.3% and 78.1% (χ = 0.05, P = 0.82), respectively. Cox regression analysis indicated clinical stages (HR = 3.982, 95% CI: 2.365~6.705), anxiety (HR = 1.832, 95% CI: 1.140~2.944), and gender (HR = 0.555, 95% CI: 0.313~0.984) as independent prognostic factors.

Conclusion: Anxiety before radiotherapy is associated with poor prognosis in NPC patients.
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http://dx.doi.org/10.1007/s00520-021-06130-yDOI Listing
October 2021

Recent development in biological activities and safety concerns of perillaldehyde from perilla plants: A review.

Crit Rev Food Sci Nutr 2021 Mar 22:1-13. Epub 2021 Mar 22.

School of Life Sciences, Jiangsu Normal University, Xuzhou, Jiangsu Province, PR China.

Monoterpene Perillaldehyde (PAE) is a major component of the essential oil extracted from perilla plants (), which has been used as a leafy vegetable and a medicinal agent. PAE has gained a lot of attention in recent years because of its antifungal and other microbial activities and, human health benefits. PAE has also been used as food additives, perfume ingredients, and traditional medicine concoctions. Biological analyses of PAE have revealed that it has good antioxidant activities and can serve as organic fruit and food preservative. Animal studies indicated potent anticancer, anti-depressant, and anti-inflammatory effects of PAE. Also, PAE is certified "generally recognized as safe" (GRAS) and not mutagenic. However, moderation during usage is advisable, as minor adverse effects are associated with a very high dosage. Despite the newly reported findings, its properties have not been thoroughly summarized and reviewed. Also, clinical trials and official large-scale field applications of PAE in the agricultural sectors are yet to be reported. In this review, updated PAE research progress was provided, focusing on its antifungal and other antimicrobial properties and the mechanisms behind it, phytochemical profile, pharmacological effects, and safety concerns.HighlightsIsolation and recovery techniques of PAE from perilla plants have been developed and improved in recent years.PAE is a potential anti-oxidant and antifungal agent that can be widely used in the food industry.PAE can be developed into drug ingredients for pharmaceutical industries due to its anti-inflammatory, anti-cancer and anti-depressant activities.PAE can be safely used in human when low and moderate dosage is used.
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http://dx.doi.org/10.1080/10408398.2021.1900060DOI Listing
March 2021

Deubiquitylation and stabilization of Acf7 by ubiquitin carboxylterminal hydrolase 14 (USP14) is critical for NSCLC migration.

J Biosci 2021 ;46

Department of Laboratory, The Second People's Hospital of Jiaozuo, The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo, China.

The ubiquitin-proteasome system is an essential regulator of Acf7, which serves as a key effector for the maintenance of the EMT program and migration. However, the precise mechanism for the deubiquitination of Acf7 is still not fully understood. Using a proteomic approach, we identified ubiquitin-specific peptidase 14 (USP14) as an Acf7-associated deubiquitinase. Our findings show that there was an interaction between USP14 and Acf7. The expression of USP14 and Acf7 were elevated in lung cancer tissues compared to adjacent normal cells. Employing the overexpression of USP14 and the knockdown assay indicated that USP14 can greatly increase the steady-state levels of Acf7 by inhibiting the degradation of Acf7 through the ubiquitin- proteasome pathway. Here we identified USP14 as a deubiquitinating enzyme that regulated Acf7 ubiquitination and protein levels. Moreover, knockdown of USP14 inhibited cell migration, however, overexpression of wild-type USP14 but not USP14 mutants promoted cell migration. Together, these results suggest that USP14 plays an important role in the NSCLC migration through modulating Acf7 stability.
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January 2021

Factors Affecting College Students' Continuous Intention to Use Online Course Platform.

SN Comput Sci 2021 25;2(2):114. Epub 2021 Feb 25.

Co-Innovation Center of Informatization and Balanced Development of Basic Education, Central China Normal University, Wuhan, China.

In recent years, online learning model has become the mainstream in higher education. The cooperation between universities and Internet education platforms provides a good learning environment and abundant online elective courses for college students, but the practical teaching effect is not ideal. Therefore, based on the Universal Theory of Acceptance and Use of Technology (UTAUT), this study introduced the perceived cost and content quality to build a model of college students' continuous intention to use online course platforms, and used structural equation model to study the relationship among the variables. The results showed that effort expectancy and social influence affected continuous intention indirectly via performance expectancy; content quality indirectly affected continuous intention through effort expectancy, performance expectancy and effort expectancy-performance expectancy; perceived cost had a significant negative effect on continuous intention. These research results provide new ideas for the design and development of online course platform.
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http://dx.doi.org/10.1007/s42979-021-00498-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905762PMC
February 2021

A comparative study of dentinal tubule penetration and the retreatability of EndoSequence BC Sealer HiFlow, iRoot SP, and AH Plus with different obturation techniques.

Clin Oral Investig 2021 Jun 26;25(6):4163-4173. Epub 2021 Feb 26.

Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Hospital of Stomatology Sun Yat-sen University, 56 Ling Yuan Xi Road, Guangzhou, 510055, Guangdong, China.

Objectives: This study aimed to evaluate dentinal tubule penetration and the retreatability of EndoSequence BC Sealer HiFlow (HiFlow), iRoot SP, and AH Plus when using the single-cone (SC) or continuous wave condensation (CWC) technique.

Materials And Methods: Sixty-five single-rooted teeth were instrumented and randomly divided into 5 groups: group 1, AH Plus/CWC; group 2, iRoot SP/CWC; group 3, iRoot SP/SC; group 4, HiFlow/CWC; and group 5, HiFlow/SC. The ability to re-establish patency during endodontic retreatment was recorded, as was the time taken to reach the working length. Dentinal tubule penetration and remaining debris after retreatment were evaluated by confocal microscopy and scanning electron microscopy. Data were analyzed by Kruskal-Wallis test and Dunn's multiple comparisons test (α = 0.05).

Results: The HiFlow/CWC and iRoot SP/CWC groups required more time to reach the working length than groups that underwent the SC technique regardless of the sealer used (P < .05). The HiFlow/CWC group showed a significantly higher percentage of sealer penetration area than that of the iRoot SP/SC at 4 mm from the apex (P < .05) and penetrated deeper into dentinal tubules than iRoot SP/SC at both 8-mm and 12-mm levels (P < .05). Moreover, the HiFlow/CWC and HiFlow/SC groups demonstrated less remaining sealer along the canal wall than AH Plus/CWC group at 4-mm level (P < .05).

Conclusions: HiFlow/CWC technique showed better performance in dentinal tubule penetration than that of iRoot SP/SC. Both HiFlow and iRoot SP combined with CWC technique groups required more retreatment time than the other groups. Furthermore, using HiFlow with either the CWC or SC technique left less remaining sealer at 4-mm level than using AH Plus with the CWC technique during retreatment.

Clinical Relevance: With favorable performance in dentinal tubule penetration and retreatability in endodontic retreatment, the combined use of EndoSequence BC Sealer HiFlow with the recommended continuous wave condensation technique may be a worthwhile choice in root canal treatment.
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http://dx.doi.org/10.1007/s00784-020-03747-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137581PMC
June 2021

Neoadjuvant Chemotherapy-Guided Bladder-Sparing Treatment for Muscle-Invasive Bladder Cancer: Results of a Pilot Phase II Study.

Cancer Res Treat 2021 Oct 10;53(4):1156-1165. Epub 2021 Feb 10.

Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Purpose: Reduced quality of life after cystectomy has made bladder preservation a popular research topic for muscle-invasive bladder cancer (MIBC). Previous research has indicated significant tumor downstaging after neoadjuvant chemotherapy (NAC). However, maximal transurethral resection of bladder tumor (TURBT) was performed before NAC to define the pathology, impacting the real evaluation of NAC. This research aimed to assess real NAC efficacy without interference from TURBT and apply combined modality therapies guided by NAC efficacy.

Materials And Methods: Patients with cT2-4aN0M0 MIBC were confirmed by cystoscopic biopsy and imaging. NAC efficacy was assessed by imaging, urine cytology, and cystoscopy with multidisciplinary team discussion. Definite responders (≤ T1) underwent TURBT plus concurrent chemoradiotherapy. Incomplete responders underwent radical cystectomy or partial cystectomy if feasible. The primary endpoint was the bladder preservation rate.

Results: Fifty-nine patients were enrolled, and the median age was 63 years. Patients with cT3-4 accounted for 75%. The median number of NAC cycles was three. Definite responders were 52.5%. The complete response (CR) was 10.2%, and 59.3% of patients received bladder-sparing treatments. With a median follow-up of 44.6 months, the 3-year overall survival (OS) was 72.8%. Three-year OS and relapse-free survival were 88.4% and 60.0% in the bladder-sparing group but only 74.3% and 37.5% in the cystectomy group. The evaluations of preserved bladder function were satisfactory.

Conclusion: After stratifying MIBC patients by NAC efficacy, definite responders achieved a satisfactory bladder-sparing rate, prognosis, and bladder function. The CR rate reflected the real NAC efficacy for MIBC. This therapy is worth verifying through multicenter research.
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http://dx.doi.org/10.4143/crt.2020.1356DOI Listing
October 2021

The novel circular RNA circ-PGAP3 retards cervical cancer growth by regulating the miR-769-5p/p53 axis.

Hum Cell 2021 May 16;34(3):878-888. Epub 2021 Feb 16.

Department of Gynecology, HuaiHe Hosipital of Henan University, Kaifeng, 475001, Henan, China.

Cervical cancer (CC) is still an intractable disease that seriously affects women's health. Elucidating its pathogenesis will bring new targets for clinical treatment. Circular RNA (circRNA) is an endogenous RNA that has recently been reported to be closely related to cancer progression and development. In the current study, by performing in silico analysis and qRT-PCR assay, we found a circRNA derived from PGAP3, referred as circ-PGAP3 (hsa_circ_0106800, chr17:37843549-37844086), which was significantly downregulated in CC tissues. Low circ-PGAP3 was closely linked to poor prognosis. And overexpression of circ-PGAP3 significantly reduced CC cell proliferation in vitro and tumor growth in vivo. In terms of mechanism, circ-PGAP3 was transcriptionally elevated by p53, a well-recognized tumor suppressor, and circ-PGAP3 was located in the cytoplasm where sponged miR-769-5p to increase the levels of p53 and its downstream targets. Importantly, the regulatory feedback loop of circ-PGAP3/p53 was also confirmed in vivo. Overall, our data clearly expounded the tumor-inhibiting role of circ-PGAP3 in CC, circ-PGAP3 repressed CC tumorigenesis via regulating the miR-769-5p/p53 axis. Therefore, restoration of circ-PGAP3 may be a promising therapeutic target for this thorny disease.
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http://dx.doi.org/10.1007/s13577-021-00493-4DOI Listing
May 2021

Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition.

Breast Cancer Res 2021 02 15;23(1):23. Epub 2021 Feb 15.

Department of Medicine, McGill University Health Center, Cancer Research Program, 1001 Decarie Blvd, Bloc E, Suite E02.6224, Montreal, QC, H4A 3J1, Canada.

Background: Cyclooxygenase 2 (COX-2) promotes stemness in triple negative breast cancer (TNBC), highlighting COX-2 as a promising therapeutic target in these tumors. However, to date, clinical trials using COX-2 inhibitors in breast cancer only showed variable patient responses with no clear significant clinical benefits, suggesting underlying molecular mechanisms contributing to resistance to COX-2 inhibitors.

Methods: By combining in silico analysis of human breast cancer RNA-seq data with interrogation of public patient databases and their associated transcriptomic, genomic, and clinical profiles, we identified COX-2 associated genes whose expression correlate with aggressive TNBC features and resistance to COX-2 inhibitors. We then assessed their individual contributions to TNBC metastasis and resistance to COX-2 inhibitors, using CRISPR gene knockout approaches in both in vitro and in vivo preclinical models of TNBC.

Results: We identified multiple COX-2 associated genes (TPM4, RGS2, LAMC2, SERPINB5, KLK7, MFGE8, KLK5, ID4, RBP1, SLC2A1) that regulate tumor lung colonization in TNBC. Furthermore, we found that silencing MFGE8 and KLK5/7 gene expression in TNBC cells markedly restored sensitivity to COX-2 selective inhibitor both in vitro and in vivo.

Conclusions: Together, our study supports the establishment and use of novel COX-2 inhibitor-based combination therapies as future strategies for TNBC treatment.
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http://dx.doi.org/10.1186/s13058-021-01401-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885389PMC
February 2021

Retraction Note: Eficacy of pentoxifylline treatment for neonatal sepsis: a meta-analysis of randomized controlled studies.

Ital J Pediatr 2021 Feb 12;47(1):30. Epub 2021 Feb 12.

Department of pediatrics, Children's Hospital of Hangzhou, No 318 Chaowang Road, Hangzhou, 310005, Zhejiang Province, People's Republic of China.

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http://dx.doi.org/10.1186/s13052-021-00979-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881532PMC
February 2021

Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice.

Alzheimers Res Ther 2021 02 9;13(1):40. Epub 2021 Feb 9.

Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.

Background: The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aβ deposition precedes the aggregation of tau pathology and Aβ pathology precipitates tau pathology. Evidence also indicates the reciprocal interactions between amyloid and tau pathology. However, the detailed relationship between amyloid and tau pathology in AD remains elusive. Metformin might have a positive effect on cognitive impairments. However, whether metformin can reduce AD-related pathologies is still unconclusive.

Methods: Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of 9-month-old APPswe/PS1DE9 (APP/PS1) mice and age-matched wild-type (WT) mice. Metformin was administrated in the drinking water for 2 months. Aβ pathology, tau pathology, plaque-associated microgliosis, and autophagy marker were analyzed by immunohistochemical staining and immunofluorescence analysis 2 months after injection of proteopathic tau seeds. The effects of metformin on both pathologies were explored.

Results: We observed tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. Aβ plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated Aβ deposits and decreased the number of microglia around Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around Aβ plaques, promoted the phagocytosis of NP tau, and reduced Aβ load and NP tau pathology in APP/PS1 mice.

Conclusion: These findings indicate the existence of the crosstalk between amyloid and NP tau pathology. Metformin promoted the phagocytosis of pathological Aβ and tau proteins by enhancing microglial autophagy capability. It reduced Aβ deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies.
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http://dx.doi.org/10.1186/s13195-020-00761-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871393PMC
February 2021

The role of brain perivascular space burden in early-stage Parkinson's disease.

NPJ Parkinsons Dis 2021 Feb 5;7(1):12. Epub 2021 Feb 5.

Department of Neurology of the Second Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.

Perivascular space (PVS) is associated with neurodegenerative diseases, while its effect on Parkinson's disease (PD) remains unclear. We aimed to investigate the clinical and neuroimaging significance of PVS in basal ganglia (BG) and midbrain in early-stage PD. We recruited 40 early-stage PD patients and 41 healthy controls (HCs). Both PVS number and volume were calculated to evaluate PVS burden on 7 T magnetic resonance imaging images. We compared PVS burden between PD and HC, and conducted partial correlation analysis between PVS burden and clinical and imaging features. PD patients had a significantly more serious PVS burden in BG and midbrain, and the PVS number in BG was significantly correlated to the PD disease severity and L-dopa equivalent dosage. The fractional anisotropy and mean diffusivity values of certain subcortical nuclei and white matter fibers within or nearby the BG and midbrain were significantly correlated with the ipsilateral PVS burden indexes. Regarding to the midbrain, the difference between bilateral PVS burden was, respectively, correlated to the difference between fiber counts of white fiber tract passing through bilateral substantia nigra in PD. Our study suggests that PVS burden indexes in BG are candidate biomarkers to evaluate PD motor symptom severity and aid in predicting medication dosage. And our findings also highlight the potential correlations between PVS burden and both grey and white matter microstructures.
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http://dx.doi.org/10.1038/s41531-021-00155-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864928PMC
February 2021

Deubiquitylation and stabilization of ARMC5 by ubiquitin-specific processing protease 7 (USP7) are critical for RCC proliferation.

J Cell Mol Med 2021 03 5;25(6):3149-3159. Epub 2021 Feb 5.

Henan Polytechnic University, Jiaozuo, China.

The ubiquitin-proteasome system is an essential regulator of ARMC5, which serves as a new tumour suppressor protein for inhibiting meningiomas and hereditary adrenocortical tumorigenesis. However, the precise mechanism for the deubiquitination of ARMC5 is still not fully understood. A Western blot analysis of ARMC5 was performed and showed that the expression of ARMC5 was decreased in the renal cancer cell tissues and lines. By screening a deubiquitinase library, we identified USP7 as a potential ARMC5 associated deubiquitinase. In this paper, we demonstrated that there was an interaction between USP7 and ARMC5 in vivo and in vitro. Employing the overexpression and knockdown assay indicated that USP7 could greatly increase the steady state of ARMC5 through the ubiquitin-proteasome pathway and regulate ARMC5 ubiquitination. Moreover, USP7 altered cell cycle G1/S phases and regulated renal cancer cell proliferation by targeting ARMC5. Together, these results suggest that USP7 plays an important role in the RCC proliferation through modulating ARMC5 stability.
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http://dx.doi.org/10.1111/jcmm.16306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957176PMC
March 2021
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