Publications by authors named "Yali Zhou"

69 Publications

The role of mediator complex subunit 19 in human diseases.

Exp Biol Med (Maywood) 2021 May 26:15353702211011701. Epub 2021 May 26.

Department of Microbiology, Guilin Medical University, Guilin 541004, China.

Mediator is an evolutionarily conserved multi-protein complex that mediates the interaction between different proteins as a basic linker in the transcription mechanism of eukaryotes. It interacts with RNA polymerase II and participates in the process of gene expression. Mediator complex subunit 19 or regulation by oxygen 3, or lung cancer metastasis-related protein 1 is located at the head of the mediator complex; it is a multi-protein co-activator that induces the transcription of RNA polymerase II by DNA transcription factors. It is a tumor-related gene that plays an important role in transcriptional regulation, cell proliferation, and apoptosis and is closely related to the occurrence and development of the cancers of the lung, bladder, skin, etc. Here, we used the structure of mediator complex subunit 19 to review its role in tumor progression, fat metabolism, drug therapy, as well as the novel coronavirus, which has attracted much attention at present, suggesting that mediator complex subunit 19 has broad application in the occurrence and development of clinical diseases. As a tumor-related gene, the role and mechanism of mediator complex subunit 19 in the regulation of tumor growth could be of great significance for the diagnosis, prognosis, and treatment of mediator complex subunit 19 -related tumors.
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http://dx.doi.org/10.1177/15353702211011701DOI Listing
May 2021

Changes in bone mineral density, 25-hydroxyvitamin D and inflammatory factors in patients with hyperthyroidism.

Exp Ther Med 2021 Jun 14;21(6):617. Epub 2021 Apr 14.

Department of Anesthesiology, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China.

The present study aimed to evaluate changes in bone mineral density, 25-hydroxyvitamin D [25-(OH)D] and inflammatory factors in patients with hyperthyroidism, in order to determine the correlations with the pathogenesis of hyperthyroidism. A total of 55 patients with hyperthyroidism (observation group) and 53 healthy patients (control group) enrolled at Weifang People's Hospital from March 2017 to February 2018 were randomly enrolled. The thyroid function, bone mineral density, 25-(OH)D and inflammatory factors were measured and compared between the two groups. The measurement data are presented as mean ± standard deviation (SD), and Student t-test was performed for the comparison between two groups. Chi-square test was used for enumeration data regarding sex. Pearson correlation analysis was performed for two-variable analysis on L1, 25-(OH)D, interleukin (IL)-2, IL-6 with FT3, respectively. In regards to the results, no difference in sex, age and body mass index (BMI) between the two groups were found but the thyroid function was markedly enhanced in the observation group compared to the control group. Bone mineral density index and 25-(OH)D in the observation group were significantly lower than those in the control group (P<0.05). There were significant differences in the inflammatory factors between the two groups (P<0.05). The L1, 25-(OH)D and IL-2 levels were significantly negatively correlated with thyroid function index and free triiodothyronine (FT3) while a statistically positive correlation was found between IL-6 and FT3 (P<0.05). In conclusion, abnormal levels of bone mineral density, 25-(OH)D and inflammatory factors are observed in patients with hyperthyroidism, and there are correlations between L1, 25-(OH)D, IL-2, IL-6 and FT3 in the pathogenesis of hyperthyroidism, which provides new insight for the diagnosis of hyperthyroidism.
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http://dx.doi.org/10.3892/etm.2021.10049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082602PMC
June 2021

Long-Term Stability of Different Kinds of Gas Nanobubbles in Deionized and Salt Water.

Materials (Basel) 2021 Apr 6;14(7). Epub 2021 Apr 6.

College of Resources, Environment and Materials, Guangxi University, Nanning 530004, China.

Nanobubbles have many potential applications depending on their types. The long-term stability of different gas nanobubbles is necessary to be studied considering their applications. In the present study, five kinds of nanobubbles (N, O, Ar + 8%H, air and CO) in deionized water and a salt aqueous solution were prepared by the hydrodynamic cavitation method. The mean size and zeta potential of the nanobubbles were measured by a light scattering system, while the pH and Eh of the nanobubble suspensions were measured as a function of time. The nanobubble stability was predicted and discussed by the total potential energies between two bubbles by the extended Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. The nanobubbles, except CO, in deionized water showed a long-term stability for 60 days, while they were not stable in the 1 mM (milli mol/L) salt aqueous solution. During the 60 days, the bubble size gradually increased and decreased in deionized water. This size change was discussed by the Ostwald ripening effect coupled with the bubble interaction evaluated by the extended DLVO theory. On the other hand, CO nanobubbles in deionized water were not stable and disappeared after 5 days, while the CO nanobubbles in 1 mM of NaCl and CaCl aqueous solution became stable for 2 weeks. The floating and disappearing phenomena of nanobubbles were estimated and discussed by calculating the relationship between the terminal velocity of the floating bubble and bubble size.
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http://dx.doi.org/10.3390/ma14071808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038778PMC
April 2021

Role of Human Mesangial-Tubular Crosstalk in Secretory IgA-Induced IgA Nephropathy.

Kidney Blood Press Res 2021 Apr 16:1-12. Epub 2021 Apr 16.

Department of Renal Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: IgA nephropathy (IgAN) is characterized by the mesangial deposition of pathogenic IgA. We previously detected the deposition of pathogenic secretory IgA (SIgA) in the mesangium of about one-third of IgAN patients. Tubulointerstitial injury has an important role in the development of IgAN. However, the relationship between SIgA and tubulointerstitial damage is currently unclear. In this work, the role of the mesangial-tubular crosstalk was explored in the tubulointerstitial damage in SIgA-induced IgAN.

Methods: SIgA deposition in renal tissues of IgAN patients was detected by immunofluorescence. Flow cytometry was used to assess the binding of SIgA to human renal mesangial cells (HRMC) and human proximal tubule epithelial (HK-2) cells. HK-2 was co-cultured with HRMC added with SIgA isolated from patients or normal volunteers. Protein synthesis and gene expressions of TNF-α, TGF-β1, and MCP-1 were determined by ELISA and PCR, respectively. The expressions of the above cytokines in renal tissues of patients and normal controls were detected by immunohistochemistry.

Results: Twenty-nine of 96 patients had SIgA deposition in the mesangium, but SIgA was rarely detected in the tubulointerstitium. The binding rate of SIgA to HK-2 (2.79%) was significantly lower than that of HRMC (81.6%) (p < 0.001). The expressions of TNF-α, TGF-β1, and MCP-1 in HRMC were significantly higher than in SIgA-stimulated HK-2 (p < 0.05), and their expressions were significantly higher in the SIgA-stimulated co-culture group compared with SIgA-stimulated HRMC (p < 0.05). The expressions of the above cytokines were mainly detected in tubulointerstitium of IgAN patients with positive and negative SIgA deposition, without significant difference between the 2 groups, but to a significantly higher level than that in normal controls, and their expressions positively correlated with tubulointerstitial injury.

Conclusion: Inflammatory factors released from the mesangium after SIgA deposition might mediate tubulointerstitial damage via mesangial-tubular crosstalk in IgAN.
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http://dx.doi.org/10.1159/000514183DOI Listing
April 2021

Development of highly efficient platinum catalysts for hydroalkoxylation and hydroamination of unactivated alkenes.

Nat Commun 2021 03 29;12(1):1953. Epub 2021 Mar 29.

Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, Guangdong, China.

Hydrofunctionalization, the direct addition of an X-H (e.g., X=O, N) bond across an alkene, is a desirable strategy to make heterocycles that are important structural components of naturally occurring molecules. Described here is the design and discovery of "donor-acceptor"-type platinum catalysts that are highly effective in both hydroalkoxylation and hydroamination of unactivated alkenes over a broad range of substrates under mild conditions. A number of alkene substitution patterns are accommodated, including tri-substituted, 1,1-disubstituted, (E)-disubstituted, (Z)-disubstituted and even mono-substituted double bonds. Detailed mechanistic investigations suggest a plausible pathway that includes an unexpected dissociation/re-association of the electron-deficient ligand to form an alkene-bound "donor-acceptor"-type intermediate. These mechanistic studies help understand the origins of the high reactivity exhibited by the catalytic system, and provide a foundation for the rational design of chiral catalysts towards asymmetric hydrofunctionalization reactions.
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http://dx.doi.org/10.1038/s41467-021-22287-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007598PMC
March 2021

Integrated Protein-Protein Interaction and Weighted Gene Co-expression Network Analysis Uncover Three Key Genes in Hepatoblastoma.

Front Cell Dev Biol 2021 26;9:631982. Epub 2021 Feb 26.

Department of Microbiology, Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, China.

Hepatoblastoma (HB) is the most common liver tumor in the pediatric population, with typically poor outcomes for advanced-stage or chemotherapy-refractory HB patients. The objective of this study was to identify genes involved in HB pathogenesis via microarray analysis and subsequent experimental validation. We identified 856 differentially expressed genes (DEGs) between HB and normal liver tissue based on two publicly available microarray datasets (GSE131329 and GSE75271) after data merging and batch effect correction. Protein-protein interaction (PPI) analysis and weighted gene co-expression network analysis (WGCNA) were conducted to explore HB-related critical modules and hub genes. Subsequently, Gene Ontology (GO) analysis was used to reveal critical biological functions in the initiation and progression of HB. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that genes involved in cell cycle phase transition and the PI3K/AKT signaling were associated with HB. The intersection of hub genes identified by both PPI and WGCNA analyses revealed five potential candidate genes. Based on receiver operating characteristic (ROC) curve analysis and reports in the literature, we selected CCNA2, CDK1, and CDC20 as key genes of interest to validate experimentally. CCNA2, CDK1, or CDC20 small interfering RNA (siRNA) knockdown inhibited aggressive biological properties of both HepG2 and HuH-6 cell lines . In conclusion, we identified CCNA2, CDK1, and CDC20 as new potential therapeutic biomarkers for HB, providing novel insights into important and viable targets in future HB treatment.
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http://dx.doi.org/10.3389/fcell.2021.631982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953069PMC
February 2021

CRISPR/Cas9-Engineered Universal CD19/CD22 Dual-Targeted CAR-T Cell Therapy for Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia.

Clin Cancer Res 2021 May 24;27(10):2764-2772. Epub 2021 Feb 24.

Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.

Purpose: Autologous chimeric antigen receptor T (CAR-T) cell therapy is an effective treatment for relapsed/refractory acute lymphoblastic leukemia (r/r ALL). However, certain characteristics of autologous CAR-T cells can delay treatment availability. Relapse caused by antigen escape after single-targeted CAR-T therapy is another issue. Therefore, we aim to develop CRISPR-edited universal off-the-shelf CD19/CD22 dual-targeted CAR-T cells as a novel therapy for r/r ALL.

Patients And Methods: In this open-label dose-escalation phase I study, universal CD19/CD22-targeting CAR-T cells (CTA101) with a CRISPR/Cas9-disrupted region and gene to avoid host immune-mediated rejection were infused in patients with r/r ALL. Safety, efficacy, and CTA101 cellular kinetics were evaluated.

Results: CRISPR/Cas9 technology mediated highly efficient, high-fidelity gene editing and production of universal CAR-T cells. No gene editing-associated genotoxicity or chromosomal translocation was observed. Six patients received CTA101 infusions at doses of 1 (3 patients) and 3 (3 patients) × 10 CAR T cells/kg body weight. Cytokine release syndrome occurred in all patients. No dose-limiting toxicity, GvHD, neurotoxicity, or genome editing-associated adverse events have occurred to date. The complete remission (CR) rate was 83.3% on day 28 after CTA101 infusion. With a median follow-up of 4.3 months, 3 of the 5 patients who achieved CR or CR with incomplete hematologic recovery (CR/CRi) remained minimal residual disease (MRD) negative.

Conclusions: CRISPR/Cas9-engineered universal CD19/CD22 CAR-T cells exhibited a manageable safety profile and prominent antileukemia activity. Universal dual-targeted CAR-T cell therapy may offer an alternative therapy for patients with r/r ALL.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3863DOI Listing
May 2021

Comparison of the analgesic effect of quadratus lumborum block and epidural block in open uterine surgery: a randomized controlled trial.

Minerva Anestesiol 2021 04 16;87(4):414-422. Epub 2021 Feb 16.

Department of Anesthesiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China -

Background: Effective regional analgesia during open surgery could reduce opioid consumption and enhance early recovery. We compared the effects of the newly developed quadratus lumborum block (QLB) and the traditional epidural block (EB) in open uterine surgery.

Methods: In this randomized controlled trial, we included patients scheduled for elective open uterine surgery during May - September 30, 2019. Patients received QLB or EB for perioperative pain relief before general anesthesia. Perioperative opioid consumption, and numeric rating scale (NRS: 0-10) pain scores after surgery, heart rate (HR), mean arterial pressure (MAP), ephedrine and urapidil use during surgery, lower limb muscle strength, timing of first flatus and defecation, nausea, vomiting, and other complications within 24 h post-surgery, were the primary and secondary outcomes, respectively.

Results: Data of 72 (86%; 36/group) of 83 eligible patients were analyzed. Remifentanil consumption during surgery was higher in the QLB than in the EB group, while cumulative sufentanil consumption within 24 h post-surgery was similar between both groups. NRS pain scores at rest and during activity were higher at 1 h post-surgery, and MAP was higher at 5-, 15-, and 30-min postincision in the QLB than in the EB group; HR was similar between groups. Lower ephedrine requirements, higher lower limb muscle strength at 1 h post-surgery, and lower nausea incidence were observed in the QLB group.

Conclusions: QLB produces a less intense but longer block and fewer side effects in the first 24 h after open uterine surgery than those produced by EB.
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http://dx.doi.org/10.23736/S0375-9393.21.14800-XDOI Listing
April 2021

microRNA-125a targets MAVS and TRAF6 to modulate interferon signaling and promote HCV infection.

Virus Res 2021 Apr 9;296:198336. Epub 2021 Feb 9.

Department of Microbiology, Guilin Medical University, Guilin, 541004, Guangxi, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541004, Guangxi, China. Electronic address:

Hepatitis C virus (HCV) can cause chronic lifelong infections in humans, resulting in sustained hepatic inflammation, liver cirrhosis, and hepatocellular carcinoma. The clearance of HCV infections is dependent upon effective and coordinated innate and adaptive antiviral immune responses. However, HCV has evolved a range of strategies that enable it to evade or overcome the host immune response, enabling the virus to persist in susceptible hosts through mechanisms that remain to be fully clarified. Herein, we describe a novel mechanism whereby HCV can evade immune surveillance by activating microRNA (miR)-125a. Hepatocytes upregulate miR-125a following HCV infection, and serum from HCV-infected patients similarly exhibits the upregulation of this miRNA. We found that miR-125a is able to target and suppress the expression of two key genes associated with the interferon (IFN) signaling pathway - mitochondrial antiviral signaling (MAVS) and TNF receptor-associated factor 6 (TRAF6). Disrupting the expression of these genes can in turn compromise type I IFN responses to HCV. Together, our data reveal that HCV infection results in the upregulation of miR-125a, which negatively regulates IFN signaling via inhibiting the expression of MAVS and TRAF6, thereby enabling the virus to evade innate antiviral immunity. Targeting this pathway may thus represent an efficient approach to treating HCV and bolstering antiviral immune responses in infected patients.
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http://dx.doi.org/10.1016/j.virusres.2021.198336DOI Listing
April 2021

Free radical degradation in aqueous solution by blowing hydrogen and carbon dioxide nanobubbles.

Sci Rep 2021 Feb 4;11(1):3068. Epub 2021 Feb 4.

College of Resources, Environment and Materials, Guangxi University, Nanning, 530004, China.

The main findings are the hydroxyl radical scavenging and the superoxide anion diminishing by mixing the carbon dioxide (CO) nanobubbles after hydrogen nanobubble blowing in water and alcohol aqueous solution. The nanobubbles produce the hydroxyl radical by ultrasonic waves, changing the pH and catalyst and so on, while the nanobubble is very reactive to scavenge free radicals. In this research especially hydrogen (4% H in argon) and CO nanobubbles have been blown into hydrogen peroxide (HO) added pure water, ethanol, and ethylene glycol aqueous solution through a porous ceramic sparger from the gas cylinder. The aqueous solutions with HO are irradiated by ultraviolet (UV) light and the produced hydroxyl radical amount is measured with spin trapping reagent and electron spin resonance (ESR). The CO nanobubble blowing extremely has reduced the hydroxyl radical in water, ethanol, and ethylene glycol aqueous solution. On the other hand, when H nanobubbles are brown after CO nanobubble blowing, the hydroxyl radical amount has increased. For the disinfection test, the increase of hydroxyl radicals is useful to reduce the bacteria by the observation in the agar medium. Next, when the superoxide anion solution is mixed with nanobubble containing water, ethanol, and ethylene glycol aqueous solution, H nanobubble has reduced the superoxide anion slightly. The water containing both CO and H nanobubble reduces the superoxide anion. The less than 20% ethanol and the 30% ethylene glycol aqueous solution containing CO nanobubbles generated after H nanobubble blowing can diminish the superoxide anion much more. While the H nanobubble blowing after CO nanobubble blowing scavenges the superoxide anion slightly. The experimental results have been considered using a chemical reaction formula.
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http://dx.doi.org/10.1038/s41598-021-82717-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862495PMC
February 2021

Incidence and risk factors predicting deep venous thrombosis of lower extremity following spinal fractures.

Sci Rep 2021 Jan 28;11(1):2441. Epub 2021 Jan 28.

Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People's Republic of China.

The aim of this study was to investigate the presence of preoperative DVT following spinal fracture and the association between the presence of DVT and risk factors. Ultrasonography and blood analyses were performed preoperatively in patients diagnosed with spinal fracture between October 2014 and December 2018. Univariate analyses were performed on the data of demographics, comorbidities, location of injury, spinal cord injury (SCI) grading and laboratory biomarkers. The receiver operating characteristic (ROC) curve analysis was employed to obtain the optimal D-dimer cut-off value for diagnosis. In total, 2432 patients with spinal fractures were included, among whom 108 (4.4%) patients had preoperative DVTs. The average interval between fracture and initial diagnosis of DVT was 4.7 days (median, 2 days), ranging from 0 to 20 days; 78 (72.2%) were diagnosed within 7 days after injury and 67 (62.0%) within 3 days; 19 (17.5%) patients had proximal vein involved and 89 (82.4%) presented in distal veins. Multivariate logistic regression suggested six risk factors independently correlated to DVT, including delay to DUS (in each day) (odds ratio [OR] = 1.11), ASA class III-IV (OR = 2.36), ASIA grade (A/B) (OR = 2.36), ALB < 3.5 g/dL (OR = 2.08), HDL-C < 1.1 mmol/L (OR = 1.68) and D-Dimer > 1.08 µg/ml (OR = 2.49).
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http://dx.doi.org/10.1038/s41598-021-82147-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843965PMC
January 2021

Extracellular vesicles-released parathyroid hormone-related protein from Lewis lung carcinoma induces lipolysis and adipose tissue browning in cancer cachexia.

Cell Death Dis 2021 01 28;12(1):134. Epub 2021 Jan 28.

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

Cancer cachexia is a metabolic disorder characterized by skeletal muscle wasting and white adipose tissue browning. Specific functions of several hormones, growth factors, and cytokines derived from tumors can trigger cachexia. Moreover, adipose tissue lipolysis might explain weight loss that occurs owing to cachexia. Extracellular vesicles (EVs) are involved in intercellular communication. However, whether EVs participate in lipolysis induced by cancer cachexia has not been thoroughly investigated. Using Lewis lung carcinoma (LLC) cell culture, we tested whether LLC cell-derived EVs can induce lipolysis in 3T3-L1 adipocytes. EVs derived from LLC cells were isolated and characterized biochemically and biophysically. Western blotting and glycerol assay were used to study lipolysis. LLC cell-derived EVs induced lipolysis in vivo and vitro. EVs fused directly with target 3T3-L1 adipocytes and transferred parathyroid hormone-related protein (PTHrP), activating the PKA signaling pathway in 3T3-L1 adipocytes. Blocking PTHrP activity in LLC-EVs using a neutralizing antibody and by knocking down PTHR expression prevented lipolysis in adipocytes. Inhibiting the PKA signaling pathway also prevents the lipolytic effects of EVs. In vivo, suppression of LLC-EVs release by knocking down Rab27A alleviated white adipose tissue browning and lipolysis. Our data showed that LLC cell-derived EVs induced adipocyte lipolysis via the extracellular PTHrP-mediated PKA pathway. Our data demonstrate that LLC-EVs induce lipolysis in vitro and vivo by delivering PTHrP, which interacts with PTHR. The lipolytic effect of LLC-EVs was abrogated by PTHR knockdown and treatment with a neutralizing anti-PTHrP antibody. Together, these data show that LLC-EV-induced lipolysis is mediated by extracellular PTHrP. These findings suggest a novel mechanism of lipid droplet loss and identify a potential therapeutic strategy for cancer cachexia.
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http://dx.doi.org/10.1038/s41419-020-03382-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843996PMC
January 2021

Correlation between C9ORF72 mutation and neurodegenerative diseases: A comprehensive review of the literature.

Int J Med Sci 2021 1;18(2):378-386. Epub 2021 Jan 1.

Faculty of Basic Medical Sciences, Guilin Medical University, Guilin, 541004, Guangxi, China.

Chromosome 9 open reading frame 72 (C9ORF72) encodes a 54-kDa protein with unknown function that is expressed at high levels in the central nervous system. The C9ORF72 hexanucleotide amplification is one of the most recently discovered repetitive amplification diseases related to neurodegeneration. Its association with amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum diseases has been fully established, although a causative role for C9ORF72 in Alzheimer's disease (AD) and Parkinson's disease (PD) remains to be established. Therefore, in this article, we will review the evidence for C9ORF72 as a causative factor in neurodegenerative diseases, the underlying mechanisms, and the potential for targeting C9ORF72 as a strategy to alleviate neurodegenerative disease progression.
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http://dx.doi.org/10.7150/ijms.53550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757155PMC
January 2021

Association between thrombotic microangiopathy and activated alternative complement pathway in malignant nephrosclerosis.

Nephrol Dial Transplant 2020 Dec 26. Epub 2020 Dec 26.

Department of Nephrology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: Malignant nephrosclerosis, defined as renal microangiopathy in the setting of severe hypertension, remains a critical renal emergency leading to end-stage renal disease despite aggressive anti-hypertensive treatment. Recently, activation of the complement alternative pathway (AP) has been reported to play a prominent role in the pathogenesis of malignant nephrosclerosis. However, subsequent study failed to recapitulate the findings of genetic complement abnormalities in the disease. This study aimed to determine the presence of AP activation and genetic complement defects and establish their correlations to renal microangiopathy lesions, clinical features and prognosis in patients with malignant nephrosclerosis.

Methods: Fifty patients with malignant hypertension and concomitant thrombotic microangiopathy (TMA) proven by renal biopsy were investigated; 25 cases of kidney donors who received zero-hour allograft biopsies were used as normal controls. Various renal TMA lesions in patients with malignant nephrosclerosis were reviewed and evaluated using a semi-quantitative scoring system. Deposition of C5b-9, C3a, C5a, C4d and mannose-binding lectin was assessed by immunohistochemistry. Co-localization of C5b-9 and CD34 was detected by confocal microscopy. Complement factor B (FB), factor P (FP; properdin), factor D (FD), factor H (FH), C3a and C5a levels were quantified by enzyme-linked immonosorbent assay in plasma and urine samples of patients with malignant nephrosclerosis and controls. Genetic abnormalities of complement components were analysed by whole-exome sequencing.

Results: Renal biopsies of malignant nephrosclerosis showed identical histopathological and ultrastructural features to atypical haemolytic uraemic syndrome. C5b-9, C3a and C5a deposits were found along the walls of arteries/arterioles and glomerular capillaries and localized in the endothelial cells. Elevated plasma and urinary levels of FB, FP, FD, C3a and C5a as well as decreased FH levels were observed in patients with malignant nephrosclerosis compared with normal controls. The urinary levels of complement AP components, but not the plasma levels, were correlated with renal functions, prognosis and active TMA lesions except for arteriolar thrombi. Finally, mutations of the MCP, CFB, CFH and CFHR5 genes were identified in 8 of 20 patients with malignant nephrosclerosis.

Conclusions: Aberrant complement AP dysregulation was demonstrated and associated with the activity, severity and renal outcomes of malignant nephrosclerosis. This observation warrants screening for complement defects in patients with malignant nephrosclerosis for the potential use of complement regulators and also highlights the need for further investigation of the precise role of AP in the pathogenesis of the disease.
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http://dx.doi.org/10.1093/ndt/gfaa280DOI Listing
December 2020

Effects of icariin on the proliferation and osteogenic differentiation of human amniotic mesenchymal stem cells.

J Orthop Surg Res 2020 Dec 2;15(1):578. Epub 2020 Dec 2.

Oral Maxillofacia Trauma and Orthognathic Surgery, Hospital of Stomatology, Zunyi Medical University, Zunyi, Guizhou, China.

Background: Tissue engineering technology has been applied extensively for clinical research and human amnion mesenchymal stem cells (hAMSCs) could cause mesenchymal stem cells to differentiate into the bone tissue. However, it is necessary to develop and identify the safer appropriate amount of osteogenic inducer. The objective of this study is to investigate the effect of icariin (ICA) on the proliferation and osteogenic differentiation of hAMSCs.

Methods: The morphology and phenotype of hAMSCs were discovered by flow cytometry and immunocytochemical staining. The osteogenic differentiation of hAMSCs under the influence of different concentrations of ICA were assessed by alkaline phosphatase (ALP) activity substrate assay and alizarin red staining.

Results: MTT assay revealed that the hAMSCs pretreated with ICA exhibited increased proliferation when compared with the control group, and the most optimum concentration of ICA was 1 × 10 mol/L. The combined analysis of ALP activity and ARS staining showed that ICA could significantly promote the osteogenic differentiation of hAMSCs, and the effect was most significant when the concentration of ICA was 1 × 10 mol/L.

Conclusion: All the above results implied that ICA could significantly increase proliferation and enhance the osteogenic differentiation of hAMSCs, especially when the concentration of ICA was 1 × 10 mol/L.
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http://dx.doi.org/10.1186/s13018-020-02076-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709318PMC
December 2020

Incidence and risk factors of preoperative deep venous thrombosis in closed tibial shaft fracture: a prospective cohort study.

Arch Orthop Trauma Surg 2020 Nov 21. Epub 2020 Nov 21.

Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, Hebei, People's Republic of China.

Objective: To investigate the preoperative morbidity of deep venous thrombosis (DVT) and predictive risk factors associated with DVT after closed tibial shaft fracture.

Methods: Ultrasonography and blood analyses were performed preoperatively in patients who sustained tibial shaft fracture between October 2014 and December 2018. Univariate analyses were used in the data of demographics, comorbidities, mechanism of injury, concomitant fractures and laboratory biomarkers. Multivariate logistic regression analyses were conducted to determine the independent risk factors associated with DVT.

Results: In total, 918 patients with an operatively treated tibial shaft fracture were included, among whom 122 patients had preoperative DVTs, indicating a crude morbidity of 13.3%. Ninety-two of 758 (12.1%) patients with isolated tibial shaft fracture developed DVT, while 30 of 160 (18.8%) patients with concurrent fracture presented with DVT. The average interval between fracture and initial diagnosis of DVT was 3.1 days (median, 2 days), ranging from 0 to 33 days. Among DVT-positive patients, 16 (13.1%) patients presented with proximal DVT and 106 (86.9%) patients had distal DVT. Multivariate logistic regression analysis showed four independent risk factors were significantly correlated to the development of DVT, including increased age (OR = 1.17, p = 0.003), diabetes (OR = 1.99, p = 0.009), serum hydroxybutyrate dehydrogenase > 182 U/L (OR = 1.83, p = 0.008), and delay to DUS (in each day) (OR = 1.13, p < 0.001).

Conclusion: In the present cohort study, the incidence of DVT was 12.1% in patients with isolated tibial shaft fracture. We suggest individualized risk stratification and early anticoagulation for patients with high risk factors including pre-existing diabetes, HBDH > 182 U/L, delay to DUS and older age.

Level Of Evidence: Level III, a prospective cohort study.
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http://dx.doi.org/10.1007/s00402-020-03685-zDOI Listing
November 2020

Incidence and Hematological Biomarkers Associated With Preoperative Deep Venous Thrombosis Following Foot Fractures.

Foot Ankle Int 2020 Dec 18;41(12):1563-1570. Epub 2020 Aug 18.

Department of Orthopaedic Surgery, the 3rd Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.

Background: This study was designed to investigate the incidence and hematological biomarker levels that are associated with deep venous thrombosis (DVT) following closed foot fractures (except calcaneal fractures).

Methods: A retrospective analysis of data on patients presenting with closed foot fractures (excluding the calcaneus) between October 2014 and December 2018 was conducted. Duplex ultrasonography was used to screen preoperative DVT of bilateral lower extremities. Data on demographics, comorbidities, types of fracture, and laboratory biomarkers at admission were collected. Univariate analyses and multivariate logistic regression analyses were carried out to determine the independent risk factors associated with DVT.

Results: A total of 537 patients were included, among whom 28 patients had preoperative DVTs, indicating a crude incidence rate of 5.2%. In isolated closed foot fractures, DVT occurred in 12 (2.9%) out of 410 patients, while in patients with concurrent fracture in other locations, 16 (12.6%) out of 127 patients developed DVT. The average interval between fracture occurrence and diagnosis of DVT was 4.2 days (median, 2 days), ranging from 0 to 17 days. Twenty-four patients (85.7%) developed DVT in the injured extremity, 3 (10.7%) in the uninjured extremity, and 1 (3.5%) in bilateral extremities. Seven risk factors were identified to be associated with DVT, including alcohol consumption, concomitant other fractures, platelet distribution width (PDW) <12%, high-density lipoprotein cholesterol (HDL-C) <1.1mmol/L, serum alkaline phosphatase (ALP) >100 U/L, serum sodium concentration (Na) <135 mmol/L, and D-dimer >0.5 mg/L.

Conclusion: Being aware of the prevalence of DVT in closed foot fractures can help physicians to carry out the overall assessment, risk stratification, and individual prevention programs.

Level Of Evidence: Level III, a prospective cohort study.
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http://dx.doi.org/10.1177/1071100720943844DOI Listing
December 2020

Spectrum of biopsy proven renal diseases in Central China: a 10-year retrospective study based on 34,630 cases.

Sci Rep 2020 07 3;10(1):10994. Epub 2020 Jul 3.

Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.

Chronic kidney diseases have become a major issue worldwide. The spectrum of biopsy proven renal diseases differs between locations and changes over time. It is therefore essential to describe the local epidemiological trends and the prevalence of renal biopsy in various regions to shine new light on the pathogenesis of various renal diseases and provide a basis for further hypothesis-driven research. We retrospectively analyzed 34,630 hospitalized patients undergoing native renal biopsy between January 1, 2009 and December 31, 2018. Indications for renal biopsy and histological diagnosis were analyzed to describe the prevalence of renal biopsy, and changing prevalence between period 1 (2009-2013) and period 2 (2014-2018) were further analyzed. Nephrotic syndrome (NS) was the most common indication for biopsy. Membranous nephropathy (MN, 24.96%) and IgA nephropathy (IgAN, 24.09%) were the most common primary glomerulonephritis (PGN). MN was most common in adults, with IgAN more prevalent in children. Lupus nephritis (LN) was the most common secondary glomerulonephritis (SGN) in adults, while Henöch-Schönlein purpura nephritis (HSPN) in children. The prevalence of MN increased significantly and nearly doubled from period 1 (15.98%) to period 2 (30.81%) (P = 0.0004). The same trend appeared with membranoproliferative glomerulonephritis (MPGN), diabetic nephropathy (DN) and obesity-related glomerulopathy (ORG), while the frequencies of minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), LN and hepatitis B associated glomerulonephritis (HBV-GN) significantly decreased between the two intervals. NS was the most common indication for biopsy across all age groups and genders. MN has overtaken IgAN to become the most common PGN in adults, while IgAN was the most common PGN in children. LN was the most common SGN in adults, and HSPN the most common in children.
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http://dx.doi.org/10.1038/s41598-020-67910-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335090PMC
July 2020

RNA-binding proteins tristetraprolin and human antigen R are novel modulators of podocyte injury in diabetic kidney disease.

Cell Death Dis 2020 06 2;11(6):413. Epub 2020 Jun 2.

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

Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and the most common cause of end-stage renal disease, for which no effective therapies are yet available. RNA-binding proteins (RBPs) play a pivotal role in epigenetic regulation; tristetraprolin (TTP) and human antigen R (HuR) competitively bind cytokine mRNAs, exert contrasting effects on RNA stability, and drive inflammation. However, RBPs' roles in diabetes-related glomerulopathy are poorly understood. Herein, we investigated whether TTP and HuR are involved in post-transcriptional regulation of podocytopathic molecules and inflammatory cytokines in DKD. In DKD patients and db/db mice, TTP expression was significantly decreased and HuR expression was increased in glomerular podocytes, concurrent with podocyte injury, histological signs of DKD, and augmented glomerular expression of interleukin (IL)-17 and claudin-1, which are targets of TTP and HuR, as evidenced by RNA immunoprecipitation. In cultured podocytes, exposure to high ambient glucose amplified HuR expression and repressed TTP expression, upregulated IL-17 and claudin-1, and promoted podocyte injury. Thus, TTP hypoactivity or HuR hyperactivity is sufficient and essential to diabetic podocytopathy. Moreover, in silico analysis revealed that several kinases govern phosphorylation and activation of TTP and HuR, and glycogen synthase kinase (GSK)-3β activated both TTP and HuR, which harbor putative GSK-3β consensus phosphorylation motifs. Treatment of db/db mice with a small molecule inhibitor of GSK-3β abrogated the changes in TTP and HuR in glomeruli and mitigated the overexpression of their target genes (IL-17, claudin-1, B7-1, and MCP-1) thus also mitigating proteinuria and DKD pathology. Our study indicates that TTP and HuR are dysregulated in DKD via a GSK-3β-mediated mechanism and play crucial roles in podocyte injury through post-transcriptional regulation of diverse genes. It also provides novel insights into DKD's pathophysiology and identifies potential therapeutic targets.
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http://dx.doi.org/10.1038/s41419-020-2630-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265504PMC
June 2020

Thalidomide for Patients with β-Thalassemia: A Multicenter Experience.

Mediterr J Hematol Infect Dis 2020 1;12(1):e2020021. Epub 2020 May 1.

Department of Hematology, The 923 Hospital of the Joint Logistics Support Force of the Peoples Liberation Army, Nanning, China.

Objective: This study focused on the efficacy and safety of thalidomide for patients with β-thalassemia in a multicenter trial.

Methods: Patients with non-transfusion-dependent thalassemia (NTDT) or transfusion-dependent thalassemia (TDT), who were unable to pursue conventional therapy with transfusion and chelation, were recruited over 3 years in three centers in southern China. We evaluated the efficacy and safety of thalidomide in the short-term (three months) and long-term follow-up (12 and 24 months). Response to thalidomide was defined as follows: Main Responder (MaR) showing an increase in hemoglobin (Hb) level of >2.0 g/dl or free from blood transfusion and Minor Responder (MiR) achieving elevated Hb level of 1.0-2.0 g/dl or ≥50% reduction in blood transfusion frequency.

Results: The overall response rate (ORR) was 93.5%, with MaR and MiR rates accounting for 62.9% and 30.6% in short-term follow-up. For patients with NTDT, the Hb level increased from a baseline mean of 6.8±1.1 g/dl to 9.7±1.9 g/dl (<0.001). Elevated Hb was mainly attributable to increased fetal hemoglobin (HbF) levels. Among patients with TDT, while an increase in the average Hb concentration was observed, there was a significant drop in yearly transfusions from 20.7±7.7 to 5.8±6.8 blood units per year (<0.001). The response of patients in both categories was sustained even after an average follow up of 14.6±9.6 months (3-37 months). Minimal side-effects were documented throughout, except peripheral neurotoxicity in one patient. Logistic regression analysis identified the ratio of HbF at baseline (=0.038, OR=1.111, 95% CI: 1.006-1.226) as an independent risk factor for the primary response to thalidomide.

Conclusion: Thalidomide had significant therapeutic effects on patients with β-thalassemia with a sustained response. Peripheral neuropathy is one of the most feared complications. While these preliminary results support the potential long-term efficacy of thalidomide as a therapeutic agent for β-thalassemia, several issues need to be addressed before its application in the clinic.
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http://dx.doi.org/10.4084/MJHID.2020.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202343PMC
May 2020

The TLR4-MyD88-NF-κB pathway is involved in sIgA-mediated IgA nephropathy.

J Nephrol 2020 Dec 9;33(6):1251-1261. Epub 2020 May 9.

Department of Renal Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.

Previous studies have shown that secretory IgA (sIgA) was critically involved in IgA nephropathy (IgAN) immune responses. Toll-like receptors (TLRs), especially TLR4 which participates in mucosal immunity, may be involved in the pathogenesis of IgAN. The purpose of this study was to investigate whether sIgA and TLR4 interact to mediate kidney damage in IgAN patients. IgAN patients with positive sIgA deposition in renal tissues were screened by immunofluorescence assay. Patient salivary sIgA (P-sIgA) was collected and purified by jacalin affinity chromatography. Salivary sIgA from healthy volunteers was used as a control (N-sIgA). Expression of TLR4, MyD88, NF-κB, TNF-α, IL-6, and MCP-1 were detected in the mesangial area of IgAN patients by immunohistochemistry, the expression levels in patients with positive sIgA deposition were higher than that with negative sIgA deposition. Human renal mesangial cells (HRMCs) were cultured in vitro, flow cytometry showed that P-sIgA bound HRMCs significantly better than N-sIgA. HRMCs were cultured in the presence of sIgA (400 μg/mL) for 24 h, compared with cells cultured with N-sIgA, HRMCs cultured in vitro with P-sIgA showed enhanced expression of TLR4, increased secretion of TNF-α, IL-6, and MCP-1, and increased expression of MyD88/NF-κB. TLR4 shRNA silencing and NF-κB inhibition both reduced the ability of HRMCs to synthesize TNF-α, IL-6, and MCP-1. Our results indicate that sIgA may induce high expression of TLR4 in HRMCs and further activate downstream signalling pathways, prompting HRMCs to secrete multiple cytokines and thereby mediating kidney damage in IgAN patients.
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http://dx.doi.org/10.1007/s40620-020-00722-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701070PMC
December 2020

The association of HBG2, BCL11A, and HBS1L-MYB polymorphisms to thalidomide response in Chinese β-thalassemia patients.

Blood Cells Mol Dis 2020 09 26;84:102442. Epub 2020 Apr 26.

Department of Hematology, The 923(rd) Hospital of the Joint Logistics Support Force of the People's Liberation Army, Nanning, China. Electronic address:

Thalidomide has been shown to reactivate fetal hemoglobin (HbF) production and reduce the need for blood transfusions in β-thalassemia patients. However, some patients show a minor response or no response to thalidomide. In view of its potential side effects, targeted prescription of thalidomide is imperative. We initially aimed to explore the relevance of HBG2 (rs7482144), BCL11A (rs11886868, rs4671393, rs766432 and rs1427407) and HBS1L-MYB (rs9399137, rs4895440 and rs4895441) single nucleotide polymorphisms (SNPs) in thalidomide response. Eight SNPs were investigated by PCR and DNA sequencing, and their roles in thalidomide response in Chinese β-thalassemia patients were assessed. Results demonstrated that minor alleles of four SNPs were associated with an increased main response risk (rs7482144: P = 0.015; rs9399137: OR = 4.911, P = 0.029; rs4895440: OR = 4.522, P = 0.040; and rs4895441: OR = 4.522, P = 0.040). For patients with non-transfusion-dependent thalassemia (NTDT), with an increase in the minor allele numbers of rs7482144 (P = 0.011), rs9399137 (P = 0.013), rs4895440 (P = 0.011) and rs4895441 (P = 0.011), Hb increments after treatment were increased significantly as well. The cumulative effects of patients carrying any combination of one or three significant minor alleles included a gradually increased main response risk compared to those without the significant minor alleles (P = 0.040-0.018, OR = 8.556-11.000). Furthermore, Hb increments after treatment correlated with cumulative numbers of minor alleles in the four significant SNPs among patients with NTDT (P = 0.001). It was demonstrated that SNPs in HBG2 and HBS1L-MYB contributed significantly to thalidomide response in Chinese patients with β-thalassemia and that the cumulative number of minor SNP alleles may serve as good predictors of treatment response in this population.
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http://dx.doi.org/10.1016/j.bcmd.2020.102442DOI Listing
September 2020

Quantitative proteomic, physiological and biochemical analysis of cotyledon, embryo, leaf and pod reveals the effects of high temperature and humidity stress on seed vigor formation in soybean.

BMC Plant Biol 2020 Mar 26;20(1):127. Epub 2020 Mar 26.

State Key Laboratory of Crop Genetics and Germplasm Enhancement, Nanjing Agricultural University, Nanjing, 210095, China.

Background: Soybean developing seed is susceptible to high temperature and humidity (HTH) stress in the field, resulting in vigor reduction. Actually, the HTH in the field during soybean seed growth and development would also stress the whole plant, especially on leaf and pod, which in turn affect seed growth and development as well as vigor formation through nutrient supply and protection.

Results: In the present study, using a pair of pre-harvest seed deterioration-sensitive and -resistant cultivars Ningzhen No. 1 and Xiangdou No. 3, the comprehensive effects of HTH stress on seed vigor formation during physiological maturity were investigated by analyzing cotyledon, embryo, leaf, and pod at the levels of protein, ultrastructure, and physiology and biochemistry. There were 247, 179, and 517 differentially abundant proteins (DAPs) identified in cotyledon, embryo, and leaf of cv. Xiangdou No. 3 under HTH stress, while 235, 366, and 479 DAPs were identified in cotyledon, embryo, and leaf of cv. Ningzhen No. 1. Moreover, 120, 144, and 438 DAPs between the two cultivars were identified in cotyledon, embryo, and leaf under HTH stress, respectively. Moreover, 120, 144, and 438 DAPs between the two cultivars were identified in cotyledon, embryo, and leaf under HTH stress, respectively. Most of the DAPs identified were found to be involved in major metabolic pathways and cellular processes, including signal transduction, tricarboxylic acid cycle, fatty acid metabolism, photosynthesis, protein processing, folding and assembly, protein biosynthesis or degradation, plant-pathogen interaction, starch and sucrose metabolism, and oxidative stress response. The HTH stress had less negative effects on metabolic pathways, cell ultrastructure, and physiology and biochemistry in the four organs of Xiangdou No. 3 than in those of Ningzhen No. 1, leading to produce higher vigor seeds in the former.

Conclusion: High seed vigor formation is enhanced by increasing protein biosynthesis and nutrient storage in cotyledon, stronger stability and viability in embryo, more powerful photosynthetic capacity and nutrient supply in leaf, and stronger protection in pod under HTH stress. These results provide comprehensive characteristics of leaf, pod and seed (cotyledon and embryo) under HTH stress, and some of them can be used as selection index in high seed vigor breeding program in soybean.
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http://dx.doi.org/10.1186/s12870-020-02335-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098090PMC
March 2020

Critical transitions in Chinese dunes during the past 12,000 years.

Sci Adv 2020 Feb 26;6(9):eaay8020. Epub 2020 Feb 26.

School of Geography and Ocean Science, Nanjing University, Nanjing 210023, China.

Dune systems can have alternative stable states that coexist under certain environmental conditions: a vegetated, stabilized state and a bare active state. This behavior implies the possibility of abrupt transitions from one state to another in response to gradual environmental change. Here, we synthesize stratigraphic records covering 12,000 years of dynamics of this system at 144 localities across three dune fields in northern China. We find side-by-side coexistence of active and stabilized states, and occasional sharp shifts in time between those contrasting states. Those shifts occur asynchronously despite the fact that the entire landscape has been subject to the same gradual changes in monsoon rainfall and other conditions. At larger scale, the spatial heterogeneity in dune dynamics averages out to produce relatively smooth change. However, our results do show different paths of recovery and collapse of vegetation at system-wide scales, implying that hysteretic behavior occurs in spatially extended systems.
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http://dx.doi.org/10.1126/sciadv.aay8020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043910PMC
February 2020

A Case of Hereditary Spherocytosis Caused by a Novel Homozygous Mutation in the Gene Misdiagnosed as β-Thalassemia Intermedia Due to a Gene Mutation.

Hemoglobin 2019 Mar 13;43(2):140-144. Epub 2019 Jun 13.

b Department of Hematology , The 923rd Hospital of the Peoples Liberation Army , Nanning , Guangxi Zhuang Autonomous Region , People's Republic of China.

We report a rare case of hereditary spherocytosis (HS) and hereditary persistence of fetal hemoglobin (Hb) (HPFH) complicated with a β-thalassemia (β-thal) trait and a () gene mutation misdiagnosed as β-thal intermedia (β-TI) due to a high percentage of Hb F. The proband presented with pale skin, jaundice and splenomegaly. Analysis of the thalassemia gene indicated β/β (: c.52A>T), while Hb analysis showed significantly increased Hb F levels. The proband was diagnosed to carry β-TI, and a blood transfusion regimen together with iron chelation treatment was recommended. Due to the difference between the phenotype and genotype, next generation sequencing (NGS) was performed and the proband was found to carry a homozygous mutation on the gene combined with a heterozygous mutation in . An eosin-5-maleimide binding test (EMA-BT) showed that the mean fluorescence intensity decreased by 47.1%. The proband was finally diagnosed with HS and HPFH complicated with a β-thal trait and the high percentage of Hb F was believed to be ascribed to the gene mutation, which is frequent in areas where thalassemia is prevalent. For patients with a β gene mutation accompanying significantly high percentage of Hb F, the diagnosis of β-TI could be warranted, and the influence of the gene mutation should be carefully excluded to avoid misdiagnosis of other types of hereditary hemolytic diseases.
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http://dx.doi.org/10.1080/03630269.2019.1620764DOI Listing
March 2019

Lung cancer-derived extracellular vesicles induced myotube atrophy and adipocyte lipolysis via the extracellular IL-6-mediated STAT3 pathway.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 08 17;1864(8):1091-1102. Epub 2019 Apr 17.

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

Cancer-associated cachexia (CAC) constitutes a metabolic dysfunction characterized by systemic inflammation and body weight loss. Muscle atrophy and adipose tissue lipolysis might explain weight loss in CAC. Specific functions of numerous hormones and cytokines derived from tumours can provoke cachexia. Extracellular vesicles (EVs) can be involved in intercellular communication. However, whether EVs participate in this process has not been investigated thoroughly. Using Lewis lung carcinoma (LLC) cell cultures, we tested whether LLC-derived EVs induced C2C12 myotube atrophy and 3T3-L1 adipocyte lipolysis. EVs derived from LLC cells and serum from patients with lung cancer, non-lung cancer controls, tumour-bearing mice, and non-tumour-bearing control mice were isolated and characterized biochemically and biophysically. LLC cell-derived EVs induced dose-dependent effects of atrophy in C2C12 myotubes and lipolysis in 3T3-L1 adipocytes. Mechanistically, EVs directly fused with target C2C12 myotubes and 3T3-L1 adipocytes, and transferred interleukin-6 (IL-6) activates the STAT3 signalling pathway in C2C12 myotubes and 3T3-L1 adipocytes. Neutralization of extracellular IL-6 prevented the atrophy and lipolysis effects of EVs. Inhibiting the STAT3 signalling pathway also prevented the atrophy and lipolysis effects of EVs. PKH67-labelled (PKH 67 is a lipid dye that can be used to label extracellular vesicles) LLC-EVs were readily internalized into myotubes and adipocytes. Our data showed that LLC cell-derived EVs induced myotube atrophy and adipocyte lipolysis via the extracellular IL-6-mediated STAT3 pathway in target cells. These findings represent a potentially novel basis for further research in this field towards identifying targets and developing strategies for maintaining weight in CAC.
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http://dx.doi.org/10.1016/j.bbalip.2019.04.006DOI Listing
August 2019

Baicalin suppresses proliferation, migration, and invasion in human glioblastoma cells via Ca-dependent pathway.

Drug Des Devel Ther 2018 2;12:3247-3261. Epub 2018 Oct 2.

Department of Neurosurgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China,

Objective: Baicalin, a kind of flavonoid extracted from the dry root of Scutellaria, possesses potent anticancer bioactivities in various tumor cell lines. Accumulating evidences show that baicalin induces autophagy and apoptosis to suppress the cancer growth. Moreover, the antineoplastic role of baicalin in human glioblastoma cells remains to be uncovered.

Methods: Both U87 and U251 human glioblastoma cell lines were employed in the present study. Cell viability was tested by Cell Counting Kit-8 and colony-forming assay; Flow cytometry was employed to analyze cell apoptosis, cell cycle, and Ca content. Cell immunofluorescence assays were used for analyzing terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), light chain 3 beta (LC3B), 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanineiodide (JC-1), and Ca content. The protein levels were tested by Western blot. The SPSS software was used for statistical analysis.

Results: Baicalin suppressed the proliferation, migration, and invasion ability of human glioblastoma cells in a dose-dependent manner. Baicalin induced the loss of mitochondrial membrane potential and led to mitochondrial apoptosis. The maturation of microtubule-associated protein 1A/1B-LC3B indicated the activation of autophagy potentially through PI3K/Akt/mTOR pathway, and inhibition of autophagy by 3-methyladenine decreased the apoptotic cell ratio. Besides, baicalin increased the intercellular Ca content; meanwhile, chelation of free Ca by 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid inhibited both apoptotic and autophagy. Finally, baicalin suppressed tumor growth in vivo.

Conclusion: Our observations suggest that baicalin exerts cytotoxic effects on human glioblastoma cells by the autophagy-related apoptosis through Ca movement to the cytosol. Furthermore, baicalin has the potential as a candidate for the treatment of glioblastoma.
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http://dx.doi.org/10.2147/DDDT.S176403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173175PMC
February 2019

The therapeutic effect of tanshinone IIA on Propionibacterium acnes-induced inflammation in vitro.

Authors:
Yifan Li Yali Zhou

Dermatol Ther 2018 11 24;31(6):e12716. Epub 2018 Sep 24.

Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, China.

Acne vulgaris, a chronic inflammatory skin disease, affects many adolescents. New therapeutic agents for acne allow for a higher therapeutic activity, but fewer side effects. Tanshinone IIA, a natural product, has been proved to exhibit antibacterial and anti-inflammatory abilities in many diseases. However, its antibacterial and anti-inflammatory activities against Propionibacterium acnes have not been described. In the present study, the broth microdilution method was used to evaluate the antibacterial activity of tanshinone IIA and it had an inhibitory effect on the growth of P. acnes. Enzyme-linked immunosorbent assay and quantitative real-time PCR were used to investigate the effect of tanshinone IIA on IL-1β, IL-8, and TNF-α expression, and western blot was used to examine TLR2, NF-κB, and intercellular cell adhesion molecule-1 (ICAM-1) protein level induced by P. acnes in THP-1 cells. Results showed that the expression of inflammatory cytokines and TLR2, NF-κB, ICAM-1 protein levels were inhibited by Tanshinone IIA, suggesting that tanshinone IIA appeared to suppress P. acnes-induced inflammation by blockade of TLR2/NF-κB signaling pathway. In conclusion, the present study revealed the inhibitory effect of tanshinone IIA on P. acnes-induced inflammation, providing an evidence to support the mechanism of anti-acne properties of tanshinone IIA.
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http://dx.doi.org/10.1111/dth.12716DOI Listing
November 2018

Fisetin alleviates oxidative stress after traumatic brain injury via the Nrf2-ARE pathway.

Neurochem Int 2018 09 22;118:304-313. Epub 2018 May 22.

Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.

Fisetin, a natural flavonoid, has neuroprotection properties in many brain injury models. However, its role in traumatic brain injury (TBI) has not been fully explained. In the present study, we aimed to explore the neuroprotective effects of fisetin in a mouse model of TBI. We found that fisetin improved neurological function, reduced cerebral edema, attenuated brain lesion and ameliorated blood-brain barrier (BBB) disruption after TBI. Moreover, the up-regulation of malondialdehyde (MDA) and the activity of glutathione peroxidase (GPx) were reversed by fisetin treatment. Furthermore, administration of fisetin suppressed neuron cell death and apoptosis, increased the expression of B-cell lymphoma 2 (Bcl-2), while decreased the expression of Bcl-2-associated X protein (Bax) and caspase-3 after TBI. In addition, fisetin activated the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway following TBI. However, fisetin only failed to suppress oxidative stress in Nrf2 mice. In conclusion, our data provided the first evidence that fisetin played a critical role in neuroprotection after TBI partly through the activation of the Nrf2-ARE pathway.
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http://dx.doi.org/10.1016/j.neuint.2018.05.011DOI Listing
September 2018

Cascade double isocyanide insertion and C-N coupling of 2-iodo-2'-isocyano-1,1'-biphenyls.

Org Biomol Chem 2018 05;16(21):3893-3896

State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P. R. China.

A palladium-catalyzed double isocyanide insertion using 2-iodo-2'-isocyano-1,1'-biphenyls followed by copper-catalyzed intramolecular C-N coupling, delivering a unique heterocyclic structure containing both phenanthridine and carbazole scaffolds, has been developed. In this cascade process, four chemical bonds, including two C-C, one C-O, and one C-N bonds are formed consecutively without isolating an intermediate. The strategy of using a functionalized isocyanide in double insertion provides a quick approach for constructing heterocyclic systems with high bond-forming efficiency.
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http://dx.doi.org/10.1039/c8ob00956bDOI Listing
May 2018