Publications by authors named "Zifeng Huang"

19 Publications

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Super-enhancer-driven Sorting Nexin 5 expression promotes dopaminergic neuronal ferroptosis in Parkinson's disease models.

Biochem Biophys Res Commun 2021 Aug 13;567:35-41. Epub 2021 Jun 13.

Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China. Electronic address:

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide. Recent studies revealed that the ferroptosis pathway is involved in the death process of dopaminergic neurons in PD. The aberrant endosomal sorting pathway, which results in aberrant iron level in eukaryotic cells, may serve a role in the ferroptosis pathway in PD condition. However, its specific molecular mechanisms remained unclear. In the present study, we performed chromatin immunoprecipitation (ChIP) assay, the rank ordering of super-enhancers (ROSE) algorithm, and RNA interference (RNAi) to explore the regulatory mechanism of PD-specific super-enhancer (SE) in the endosomal sorting pathway and ferroptosis pathway of 6-OHDA-lesioned rats and cells. The ChIP assay and ROSE algorithm results showed that there are specific SEs expression in 6-OHDA-lesioned SNc of PD rats, and the most significant expression gene is Sorting Nexin 5 (SNX5). SNX5 silencing by RNAi experiments significantly decreased the level of ferroptosis in 6-OHDA-lesioned PC12 cells, suggesting the correlation between the SNX5, ferroptosis, and PD. In conclusion, this study investigated the mechanism by which PD-specific SE driven SNX5 promoted the ferroptosis level in PD models. This study further improved the understanding of the mechanism of ferroptosis during PD injury and provided potential therapeutic targets and clinical diagnostic markers in PD condition.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.024DOI Listing
August 2021

Niujiaodihuang Detoxify Decoction inhibits ferroptosis by enhancing glutathione synthesis in acute liver failure models.

J Ethnopharmacol 2021 Jun 12;279:114305. Epub 2021 Jun 12.

School of Pharmacy, Guangdong Medical University, Dongguan, 524023, China. Electronic address:

Ethnopharmacological Relevance: Niujiaodihuang Detoxify Decoction (NDD) is an integrated traditional Chinese medicine prescription that has been used as a therapeutic agent for the treatment of acute liver failure (ALF). However, the mechanisms underlying its action remain unclear.

Aim Of The Study: To determine the protective effect of NDD on D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced ALF and explore the underlying mechanisms.

Materials And Methods: We characterized the NDD fingerprint by HPLC and established D-GalN/LPS-induced ALF models in Sprague-Dawley rats and LO2 cells. Next, we measured the protective and antiferroptotic effects of NDD in vivo and in vitro. To further investigate the molecular mechanisms underlying the effects of NDD, we performed metabolomic analysis of the liver tissue using LC-MS/MS.

Results: Results of serum biochemical analysis, liver histopathology, and cell viability showed that NDD effectively relieved the liver injury. It reduced the accumulation of labile iron and alleviated lipid peroxidation by enhancing GPX4 activity. The mitochondrial morphology indicated that NDD exerted its hepatoprotective effect through an antiferroptotic activity. Metabolomic analysis showed that NDD treatment increased the levels of cysteine, decreased those of glutamate, and ameliorated the D-GalN/LPS-induced reduction in the levels of glutathione (GSH). The results for intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione were consistent with those of metabolomic analysis.

Conclusion: Our findings indicate that NDD exerts hepatoprotective activity by evoking the reprogramming of GSH metabolism, and thereby, inhibiting ferroptosis.
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http://dx.doi.org/10.1016/j.jep.2021.114305DOI Listing
June 2021

Moxibustion Protects Dopaminergic Neurons in Parkinson's Disease through Antiferroptosis.

Evid Based Complement Alternat Med 2021 16;2021:6668249. Epub 2021 Apr 16.

Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong 518104, China.

Ferroptosis is associated with neural degeneration of dopaminergic neurons in Parkinson's disease (PD). However, how to control the level of ferroptosis in PD remains unclear. Clinically, moxibustion has been used to treat PD and has an apparent therapeutic effect on improving the motor symptoms of PD. In the present study, the PD rat model was constructed by two-point stereotactic 6-hydroxydopamine injection. Then, moxibustion was used to treat the PD rats. The expression of glutathione peroxidase 4 (GPX4) and Ferritin Heavy Chain 1 (FTH1), the level of reactive oxygen species (ROS), and the morphology of mitochondrial were detected to evaluate the level of ferroptosis. The results showed that moxibustion treatment of Shi's moxa sticks could reduce the behavioral score, alleviate the level of ferroptosis, decrease mitochondrial damage, and improve dopaminergic neuron survival. In conclusion, the present study results indicated that Shi's moxa sticks could effectively suppress the level of ferroptosis, thereby improving the survival of dopaminergic neurons in the SNpc of PD rats, which may provide a promising complementary and alternative therapy for PD patients.
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http://dx.doi.org/10.1155/2021/6668249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191581PMC
April 2021

Two heterozygous progranulin mutations in progressive supranuclear palsy.

Brain 2021 Apr;144(3):e27

Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P. R. China.

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http://dx.doi.org/10.1093/brain/awaa428DOI Listing
April 2021

miR‑335 promotes ferroptosis by targeting ferritin heavy chain 1 in and models of Parkinson's disease.

Int J Mol Med 2021 04 2;47(4). Epub 2021 Mar 2.

Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong 518104, P.R. China.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). In a previous study, the authors demonstrated that ferritin heavy chain 1 (FTH1) inhibited ferroptosis in a model of 6‑hydroxydopamine (6‑OHDA)‑induced PD. However, whether and how microRNAs (miRNAs/miRs) modulate FTH1 in PD ferroptosis is not yet well understood. In the present study, and models of PD induced by 6‑OHDA were established. The results and revealed that the levels of the ferroptosis marker protein, glutathione peroxidase 4 (GPX4), and the PD marker protein, tyrosine hydroxylase (TH), were decreased in the model group, associated with a decreased FTH1 expression and the upregulation of miR‑335. In both the and models, miR‑335 mimic led to a lower FTH1 expression, exacerbated ferroptosis and an enhanced PD pathology. The luciferase 3'‑untranslated region reporter results identified FTH1 as the direct target of miR‑335. The silencing of FTH1 in 6‑OHDA‑stimulated cells enhanced the effects of miR‑335 on ferroptosis and promoted PD pathology. Mechanistically, miR‑335 enhanced ferroptosis through the degradation of FTH1 to increase iron release, lipid peroxidation and reactive oxygen species (ROS) accumulation, and to decrease mitochondrial membrane potential (MMP). On the whole, the findings of the present study reveal that miR‑335 promotes ferroptosis by targeting FTH1 in and models of PD, providing a potential therapeutic target for the treatment of PD.
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http://dx.doi.org/10.3892/ijmm.2021.4894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910012PMC
April 2021

"Hot cross bun" is a potential imaging marker for the severity of cerebellar ataxia in MSA-C.

NPJ Parkinsons Dis 2021 Feb 15;7(1):15. Epub 2021 Feb 15.

Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, P.R. China.

To evaluate the correlation between "hot cross bun" sign (HCBs) and disease severity in multiple system atrophy (MSA). We recruited patients with probable and possible MSA with parkinsonism (MSA-P) or the cerebellar ataxia (MSA-C) subtypes. Clinical and imaging characteristics were collected and comparison was performed between MSA-C and MSA-P cases. Spearman test was used to evaluate the correlation between HCBs and other variables. Curve estimate and general linear regression was performed to evaluate the relationship between HCBs and the Scale for Assessment and Rating of Ataxia (SARA). Unified Multiple System Atrophy Rating Scale (UMSARS) IV was used to assess the severity of disease. Multinomial ordered logistic regression was used to confirm the increased likelihood of disability for the disease. Eighty-one MSA with HCBs comprising of 50 MSA-C and 31 MSA-P were recruited. We demonstrated that the severity of HCBs showed a positive linear correlation with SARA scores in MSA-C. Multinomial ordered logistic regression test revealed that the increase in the HCBs grade may be associated with an increased likelihood of disability for the disease severity in MSA, especially in those with cerebellar ataxia subtype. We demonstrated that HCBs is a potential imaging marker for the severity of cerebellar ataxia. The increase in the HCBs grade may be associated with an increased likelihood of disability in MSA-C, but not MSA-P cases, suggesting that it may be a useful imaging indicator for disease progression in Chinese patients with MSA-C.
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http://dx.doi.org/10.1038/s41531-021-00159-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884406PMC
February 2021

Various Diseases and Clinical Heterogeneity Are Associated With "Hot Cross Bun".

Front Aging Neurosci 2020 20;12:592212. Epub 2020 Nov 20.

Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China.

To characterize the clinical phenotypes associated with the "hot cross bun" sign (HCBs) on MRI and identify correlations between neuroimaging and clinical characteristics. Firstly, we screened a cohort of patients with HCBs from our radiologic information system (RIS) in our center. Secondly, we systematically reviewed published cases on HCBs and classified all these cases according to their etiologies. Finally, we characterized all HCBs cases in detail and classified the disease spectra and their clinical heterogeneity. : Out of a total of 3,546 patients who were screened, we identified 40 patients with HCBs imaging sign in our cohort; systemic literature review identified 39 cases, which were associated with 14 diseases. In our cohort, inflammation [neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS), and acute disseminated encephalomyelitis (ADEM)] and toxicants [toxic encephalopathy caused by phenytoin sodium (TEPS)] were some of the underlying etiologies. Published cases by systemic literature review were linked to metabolic abnormality, degeneration, neoplasm, infection, and stroke. We demonstrated that the clinical phenotype, neuroimaging characteristics, and HCBs response to therapy varied greatly depending on underlying etiologies. : This is the first to report HCBs spectra in inflammatory and toxication diseases. Our study and systemic literature review demonstrated that the underpinning disease spectrum may be broader than previously recognized.
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http://dx.doi.org/10.3389/fnagi.2020.592212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714952PMC
November 2020

Cystatin C is a potential predictor of unfavorable outcomes for cerebral ischemia with intravenous tissue plasminogen activator treatment: A multicenter prospective nested case-control study.

Eur J Neurol 2021 Apr 26;28(4):1265-1274. Epub 2020 Dec 26.

Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China.

Background And Purpose: The aim of this study was to explore whether cystatin C (CysC) could be used as a potential predictor of clinical outcomes in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (IV-tPA).

Methods: We performed an observational study including a retrospective analysis of data from 125 AIS patients with intravenous thrombolysis. General linear models were applied to compare CysC levels between groups with different outcomes; logistic regression analysis and receiver-operating characteristic curves were adopted to identify the association between CysC and the therapeutic effects.

Results: Compared with the "good and sustained benefit" (GSB) outcome group (defined as ≥4-point reduction in National Institutes of Health Stroke Scale or a score of 0-1 at 24 h and 7 days) and the "good functional outcome" (GFO) group (modified Rankin Scale score 0-2 at 90 days), serum CysC baseline levels were increased in the non-GSB and non-GFO groups. Logistic regression analysis found that CysC was an independent negative prognostic factor for GSB (odds ratio [OR] 0.010; p = 0.005) and GFO (OR 0.011; p = 0.021) after adjustment for potential influencing factors. Receiver-operating characteristic curves showed the CysC-involved combined models provided credible efficacy for predicting post-90-day favorable clinical outcome (area under the curve 0.86; p < 0.001).

Conclusions: Elevated serum CysC is independently associated with unfavorable clinical outcomes after IV-tPA therapy in AIS. Our findings provide new insights into discovering potential mediators for neuropathological process or treatment in stroke.
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http://dx.doi.org/10.1111/ene.14663DOI Listing
April 2021

Multimodal analysis of gene expression from postmortem brains and blood identifies synaptic vesicle trafficking genes to be associated with Parkinson's disease.

Brief Bioinform 2021 Jul;22(4)

Head of Department of Neurology, Zhujiang Hospital, Southern Medical University, China.

Objective: We aimed to identify key susceptibility gene targets in multiple datasets generated from postmortem brains and blood of Parkinson's disease (PD) patients and healthy controls (HC).

Methods: We performed a multitiered analysis to integrate the gene expression data using multiple-gene chips from 244 human postmortem tissues. We identified hub node genes in the highly PD-related consensus module by constructing protein-protein interaction (PPI) networks. Next, we validated the top four interacting genes in 238 subjects (90 sporadic PD, 125 HC and 23 Parkinson's Plus Syndrome (PPS)). Utilizing multinomial logistic regression analysis (MLRA) and receiver operating characteristic (ROC), we analyzed the risk factors and diagnostic power for discriminating PD from HC and PPS.

Results: We identified 1333 genes that were significantly different between PD and HCs based on seven microarray datasets. The identified MEturquoise module is related to synaptic vesicle trafficking (SVT) dysfunction in PD (P < 0.05), and PPI analysis revealed that SVT genes PPP2CA, SYNJ1, NSF and PPP3CB were the top four hub node genes in MEturquoise (P < 0.001). The levels of these four genes in PD postmortem brains were lower than those in HC brains. We found lower blood levels of PPP2CA, SYNJ1 and NSF in PD compared with HC, and lower SYNJ1 in PD compared with PPS (P < 0.05). SYNJ1, negatively correlated to PD severity, displayed an excellent power to discriminating PD from HC and PPS.

Conclusions: This study highlights that SVT genes, especially SYNJ1, may be promising markers in discriminating PD from HCs and PPS.
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http://dx.doi.org/10.1093/bib/bbaa244DOI Listing
July 2021

RNA Binding Protein Motif 3 Inhibits Oxygen-Glucose Deprivation/Reoxygenation-Induced Apoptosis Through Promoting Stress Granules Formation in PC12 Cells and Rat Primary Cortical Neurons.

Front Cell Neurosci 2020 2;14:559384. Epub 2020 Sep 2.

Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China.

As a sensitive cold-shock protein, RNA binding protein motif 3 (RBM3) exhibits a neuroprotective function in the condition of brain injury. However, how RBM3 is involved in acute ischemic stroke by affecting stress granules (SGs) remains unclear. Here, we established an oxygen-glucose deprivation/reperfusion (OGD/R) model in rat primary cortical neurons and PC12 cells to explore the potential mechanism between RBM3 and SG formation in acute ischemic/reperfusion (I/R) condition. The immunofluorescence results showed that the SG formation significantly decreased in rat primary cortical neurons and PC12 cells during the reperfusion period after 6 h of OGD stimulation. The western blot results, flow cytometry analysis, and cell viability assessment showed that the RBM3 expression and ratio of cell viability significantly decreased, while the rate of apoptosis increased in PC12 cells during the reperfusion period after 6 h of OGD stimulation. Co-immunoprecipitation (Co-IP) and immunofluorescence indicated that RBM3 and GTPase-activating protein-binding protein 1 (G3BP1) colocalized cytoplasm of PC12 cells after 6 h of OGD stimulation when the SGs formation reached the highest level. Besides, overexpression and knockdown of the RBM3 were achieved via plasmid transfection and CRISPR-Cas9 technology, respectively. The results of overexpression and knockdown of RBM3 gene illustrated the pivotal role of RBM3 in affecting SG formation and apoptosis level in OGD-treated PC12 cells. In conclusion, RBM3 could combine with G3BP1 resulted in increasing stress granules generation in rat primary cortical neurons and PC12 cells after 6 h of oxygen-glucose deprivation (OGD) injury, which ultimately reduced the apoptosis in OGD-induced cells. Our study may enable a new promising target for alleviating ischemia-reperfusion injury in cells.
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http://dx.doi.org/10.3389/fncel.2020.559384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492797PMC
September 2020

Clinical efficacy and safety of drug interventions for primary and secondary prevention of osteoporotic fractures in postmenopausal women: Network meta-analysis followed by factor and cluster analysis.

PLoS One 2020 3;15(6):e0234123. Epub 2020 Jun 3.

Department of Orthopedics, The Gaoxin District People's Hospital, Chongqing, China.

We aimed to evaluate the comparative efficacy and safety of drugs respectively for primary prevention and secondary prevention of osteoporotic fractures in postmenopausal women (PMW), and to further identify the optimal intervention(s) respectively for the two groups when efficacy and safety both considered. We searched three databases. Bayesian network meta-analyses were conducted for two efficacy outcomes (vertebral fractures and nonvertebral fractures) and two safety outcomes (tolerability and acceptability) respectively in primary prevention group and secondary prevention group. We synthesized hazard ratios (HRs) and 95% confidence intervals (CIs) for nonvertebral fractures, and risk ratios (RRs) for three others. Factor and cluster analyses on surface under the cumulative ranking curve (SUCRA) values were conducted to identify the best intervention(s) with efficacy and safety both considered. The study protocol has been registered in PROSPERO. We included 57 randomized trials involving fifteen anti-osteoporotic interventions and 106320 PMW. For primary prevention, only zoledronate (once per 18 months) reduced both vertebral (RR 0.46, 95% CI 0.28-0.74) and nonvertebral (HR 0.66, 95% CI 0.51-0.85) fractures. For secondary prevention, abaloparatide, alendronate, denosumab, lasofoxifene, risedronate, romosozumab, teriparatide, and zoledronate (once per 12 months) reduced both vertebral (RRs: from 0.17 to 0.62) and nonvertebral (HRs: from 0.54 to 0.81) fractures. PTH (1-84) and abaloparatide increased withdrawal risk. Romosozumab, teriparatide, denosumab and risedronate, with the greatest composite scores, constituted the optimal cluster having both superior efficacy and superior safety. Zoledronate used at 5 mg per 18 months, with the similar safety as placebo, is the only drug intervention which has been shown to significantly reduce both vertebral and nonvertebral fractures for primary prevention of osteoporotic fractures in PMW; while romosozumab, teriparatide, denosumab, and risedronate are the optimal treatments for secondary prevention when efficacy and safety both considered. A limitation is that safety outcomes failed to consider the severity of adverse effects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234123PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269244PMC
August 2020

Contra-Directional Expression of Plasma Superoxide Dismutase with Lipoprotein Cholesterol and High-Sensitivity C-reactive Protein as Important Markers of Parkinson's Disease Severity.

Front Aging Neurosci 2020 6;12:53. Epub 2020 Mar 6.

Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China.

: Oxidative stress and inflammation play critical roles in the neuropathogenesis of PD. We aimed to evaluate oxidative stress and inflammation status by measuring serum superoxide dismutase (SOD) with lipoprotein cholesterol and high-sensitivity C-reactive protein (hsCRP) respectively in PD patients, and explore their correlation with the disease severity. : We performed a cross-sectional study that included 204 PD patients and 204 age-matched healthy controls (HCs). Plasma levels of SOD, hsCRP, total cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured. A series of neuropsychological assessments were performed to rate the severity of PD. : The plasma levels of SOD (135.7 ± 20.14 vs. 147.2 ± 24.34, < 0.0001), total cholesterol, HDL-C and LDL-C in PD were significantly lower than those in HCs; the hsCRP level was remarkably increased in PD compared to HC (2.766 ± 3.242 vs. 1.637 ± 1.597, < 0.0001). The plasma SOD was negatively correlated with the hsCRP, while positively correlated with total cholesterol, HDL-C, and LDL-C in PD patients. The plasma SOD were negatively correlated with H&Y, total UPDRS, UPDRS (I), UPDRS (II), and UPDRS (III) scores, but positively correlated with MoCA and MMSE scores. Besides, hsCRP was negatively correlated with MoCA; while total cholesterol, HDL-C and LDL-C were positively correlated with the MoCA, respectively. : Our findings suggest that lower SOD along with cholesterol, HDL-C and LDL-C, and higher hsCRP levels might be important markers to assess the PD severity. A better understanding of SOD and hsCRP may yield insights into the pathogenesis of PD.
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http://dx.doi.org/10.3389/fnagi.2020.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068795PMC
March 2020

Inhibition of Nwd1 activity attenuates neuronal hyperexcitability and GluN2B phosphorylation in the hippocampus.

EBioMedicine 2019 Sep 29;47:470-483. Epub 2019 Aug 29.

Department of Neurology, Zhujiang Hospital of Southern Medical University, Gongye Road 253, Guangzhou, Guangdong Province 510282, PR China. Electronic address:

Background: NACHT and WD repeat domain-containing protein 1 (Nwd1) is a member of the innate immune protein subfamily. Nwd1 contributes to the androgen receptor signaling pathway and is involved in axonal growth. However, the mechanisms that underlie pathophysiological dysfunction in seizures remain unclear.

Methods: Biochemical methods were used to assess Nwd1 expression and localization in a mouse model of kainic acid (KA)-induced acute seizures and temporal lobe epilepsy (TLE) patients. Electrophysiological recordings were used to measure the role of Nwd1 in regulating synaptic transmission and neuronal hyperexcitability in a model of magnesium-free-induced seizure in vitro. Behavioral experiments were performed, and seizure-induced pathological changes were evaluated in a KA-induced seizure model in vivo. GluN2B expression was measured and its correlation with Tyr1472-GluN2B phosphorylation was analyzed in primary hippocampal neurons.

Findings: We demonstrated high protein levels of Nwd1 in brain tissues obtained from mice with acute seizures and TLE patients. Silencing Nwd1 in mice using an adeno-associated virus (AAV) profoundly suppressed neuronal hyperexcitability and the occurrence of acute seizures, which may have been caused by reducing GluN2B-containing NMDA receptor-dependent glutamatergic synaptic transmission. Moreover, the decreased activation of Nwd1 reduced GluN2B expression and the phosphorylation of the GluN2B subunit at Tyr1472.

Interpretation: Here, we report a previously unrecognized but important role of Nwd1 in seizure models in vitro and in vivo, i.e., modulating the phosphorylation of the GluN2B subunit at Tyr1472 and regulating neuronal hyperexcitability. Meanwhile, our findings may provide a therapeutic strategy for the treatment of epilepsy or other hyperexcitability-related neurological disorders. FUND: The funders have not participated in the study design, data collection, data analysis, interpretation, or writing of the report.
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http://dx.doi.org/10.1016/j.ebiom.2019.08.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796588PMC
September 2019

Plasma Lipoprotein-associated Phospholipase A2 and Superoxide Dismutase are Independent Predicators of Cognitive Impairment in Cerebral Small Vessel Disease Patients: Diagnosis and Assessment.

Aging Dis 2019 Aug 1;10(4):834-846. Epub 2019 Aug 1.

1Department of Neurology and.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) and superoxide dismutase (SOD) are linked to regulating vascular/neuro-inflammation and stroke. Using a retrospective design, we investigated whether circulating Lp-PLA2 and SOD in cerebral small vessel disease (CSVD) patients were associated with cognitive impairment. Eighty-seven CSVD patients were recruited. Plasma Lp-PLA2 and SOD were determined, and cognitive status was measured by the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The severity of white matter hypoerintensities (WMHs) in CSVD patients was rated according to Fazekas scales, and Lp-PLA2/SOD levels and MMSE/MoCA were compared. Multiple linear regressions were used to evaluate the relationship between Lp-PLA2 and SOD and the cognitive impairment. Ordinal logistic regression and generalized linear models (OLRGLMs) were applied to confirm whether Lp-PLA2 and SOD are independent risk factors for cognitive impairment in CVSD. Lp-PLA2 and SOD with mild or severe cognitive impairment were lower than those with normal congnition. Lp-PLA2 and SOD in CSVD patients with severe WMHs were significantly lower than those with mild or moderate WMH lesions. We noted positive linear associations of Lp-PLA and SOD with cognitive impairment in CSVD, independent of LDL-C. OLRGLMs confirmed that Lp-PLA2 and SOD were independent risk factors of cognitive impairment in CSVD. Lp-PLA2 and SOD are independently associated with cognitive impairment and WMH lesion, and may be useful for the rapid evaluation of cognitive impairment in CSVD. Lp-PLA2/SOD are modifiable factors that may be considered as therapeutic targets for preventing cognitive impairment in CSVD.
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http://dx.doi.org/10.14336/AD.2019.0304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675532PMC
August 2019

Advances in the Research of Risk Factors and Prodromal Biomarkers of Parkinson's Disease.

ACS Chem Neurosci 2019 02 11;10(2):973-990. Epub 2019 Jan 11.

Department of Neurology , Zhujiang Hospital of Southern Medical University , Gongye Road 253 , Guangzhou , Guangdong 510280 , P. R. China.

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. With the advent of an aging population and improving life expectancy worldwide, the number of PD patients is expected to increase, which may lead to an urgent need for effective preventive and diagnostic strategies for PD. Although there is increasing research regarding the pathogenesis of PD, there is limited knowledge regarding the prevention of PD. Moreover, the diagnosis of PD depends on clinical criteria, which require the occurrence of bradykinesia and at least one symptom of rest tremor or rigidity. However, converging evidence from clinical, genetic, neuropathological, and imaging studies suggests the initiation of PD-specific pathology prior to the initial presentation of these classical motor clinical features by years or decades. This latent stage of neurodegeneration in PD is a particularly important stage for effective neuroprotective therapies, which might retard the progression or prevent the onset of PD. Therefore, the exploration of risk factors and premotor biomarkers is not only crucial to the early diagnosis of PD but is also helpful in the development of effective neuroprotection and health care strategies for appropriate populations at risk for PD. In this review, we searched and summarized ∼249 researches and 31 reviews focusing on the risk factors and prodromal biomarkers of PD and published in MEDLINE.
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http://dx.doi.org/10.1021/acschemneuro.8b00520DOI Listing
February 2019

Compound and heterozygous mutations of DSG2 identified by Whole Exome Sequencing in arrhythmogenic right ventricular cardiomyopathy/dysplasia with ventricular tachycardia.

J Electrocardiol 2018 Sep - Oct;51(5):837-843. Epub 2018 Jun 20.

Department of Cardiology and Cardiovascular Intervention, Interventional Medical Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, PR China. Electronic address:

Backgrounds: This study was designed to identify the pathogenic mutations in two Chinese families of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) using the Whole Exome Sequencing (WES).

Methods And Results: The proband 1 (Family 1, II:1) and proband 2 (Family 2, II:1) underwent the WES of DNA from peripheral blood. The genes susceptible to arrhythmias and cardiomyopathies were analyzed and both the probands carried the same exonic mutation of DSG2 p.F531C (NM_001943, exon 11: c.T1592G). The proband 1 also carried the splicing mutation of DSG2 (NM_001943: exon 4:c.217-1G>T), and proband 2 carried the intronic mutation of DSG2 (NM_001943: exon 6: c.524-3C>G) that potentially influenced the splicing function predicted by Human Splicing Finder. The compound heterozygous mutations of the two probands inherited from their paternal and maternal side, respectively. The carriers with DSG2 p.F531C showed early abnormal electrocardiograms, characterized as the subclinical phenotype of ARVC/D.

Conclusions: The DSG2 p.F531C was the main reason for ARVC/D. More severe phenotypes of ARVC/D occurred when coexisting with 217-1G>T or 524-3C>G mutation that potentially affecting the splicing function, as a compound heterozygous recessive inheritance.
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http://dx.doi.org/10.1016/j.jelectrocard.2018.06.012DOI Listing
October 2019

Whole exome sequencing identified a pathogenic mutation in RYR2 in a Chinese family with unexplained sudden death.

J Electrocardiol 2018 Mar - Apr;51(2):309-315. Epub 2017 Oct 10.

Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Medical School of South China University of Technology, Guangzhou, PR China. Electronic address:

Objective: This study aimed to identify the pathogenic mutation in a Chinese family with unexplained sudden death (USD) or occasional syncope.

Materials And Methods: Whole exome sequencing and target capture sequencing were respectively conducted for two related patients. The genetic data was screened using the 1000 genomes project and SNP database (PubMed), and the identified mutations were assessed for predicted pathogenicity using the SIFT and Polyphen-2 algorithms.

Results: We identified a heterozygous mutation in the RYR2 gene at c.490C>T (p.P164S), highly conserved across all species, in three family members of USD, syncope and malignant ventricular tachycardias induced by treadmill exercise test, while another heterozygous de novo mutation in SCN5A at c.5576G>A p.R1859H was detected in one family member. Both variants were verified by Sanger sequencing. Importantly, RYR2 p.P164S is associated with the risk of sudden cardiac death, such as in catecholaminergic polymorphic ventricular tachycardia.

Conclusions: A pathogenic mutation in RYR2 (p.P164S) is the likely cause of USD in a Chinese family associated with malignant ventricular arrhythmias. Whole exome and target capture sequencing can be useful for discovering the genetic causes of USD.
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http://dx.doi.org/10.1016/j.jelectrocard.2017.10.002DOI Listing
February 2019

Digoxin-induced anemia among patients with atrial fibrillation and heart failure: clinical data analysis and drug-gene interaction network.

Oncotarget 2017 Aug 16;8(34):57003-57011. Epub 2017 Jun 16.

Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences and Medical School of South China University of Technology, Guangzhou 510080, P.R. China.

Digoxin is widely used to treat various heart conditions. In order to clarify the association between digoxin and anemia adverse reaction, we inspected case reports submitted to the FDA Adverse Event Reporting System (FAERS) between January 2004 and December 2015. These reports involved 75618 atrial fibrillation patients and 15699 heart failure patients. Compared to other therapies, digoxin treatment was significantly more likely to be concurrent with anemia adverse reaction among both atrial fibrillation patients (pooled OR = 1.38, 95% CI 1.14-1.68, P-value = 0.001) and heart failure patients (pooled OR =1.50, 95% CI 1.33-1.59-, P =4.27×10). We further explored previously published evidences and found 821 human genes directly or indirectly interacting with digoxin. Functional analysis indicated that these genes were significantly enriched in the biological processes of iron transport, which are closely related to iron deficiency anemia. Taken together, our retrospective analysis demonstrated the significant association between digoxin treatment and anemia adverse reaction, which should be seriously considered in clinical practice. Functional enrichment analysis on digoxin-related genes warranted subsequent research on the underlying toxicological mechanisms.
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http://dx.doi.org/10.18632/oncotarget.18504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593620PMC
August 2017

Experimental study on allogenic decalcified bone matrix as carrier for bone tissue engineering.

J Huazhong Univ Sci Technolog Med Sci 2004 ;24(2):147-50

Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

The biocompatibility and osteogenic activity of allogenic decalcified bone matrix (DBM) used as a carrier for bone tissue engineering were studied. Following the method described by Urist, allogenic DBM was made. In vitro, DBM and bone marrow stromal cell (BMSC) from rabbits were co-cultured for 3-7 days and subjected to HE staining, and a series of histomorphological observations were performed under phase-contrast microscopy and scanning electron microscopy (SEM). In vivo the mixture of DBM/BMSC co-cultured for 3 days was planted into one side of muscules sacrospinalis of rabbits, and the DBM without BMSC was planted into other side as control. Specimens were collected at postoperative week 1, 2 and 4, and subjected to HE staining, and observed under SEM. The results showed during culture in vitro, the BMSCs adherent to the wall of DBM grew, proliferated and had secretive activity. The in vivo experiment revealed that BMSCs and undifferentiated mesenchymal cells in the perivascular region invaded gradually and proliferated together in DBM/BMSC group, and colony-forming units of chondrocytes were found. Osteoblasts, trabecular bone and medullary cavity appeared. The inflammatory reaction around muscles almost disappeared at the second weeks. In pure DBM group, the similar changes appeared from the surface of the DBM to center, and the volume of total regenerate bones was less than the DBM/BMSC group at the same time. The results indicated that the mixture of DBM and BMSC had good biocompatibility and ectopic induced osteogenic activity.
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http://dx.doi.org/10.1007/BF02885415DOI Listing
May 2006