Publications by authors named "Junmei Zhang"

111 Publications

Preformulation Characterization of Griffithsin, a Biopharmaceutical Candidate for HIV Prevention.

AAPS PharmSciTech 2021 Feb 24;22(3):83. Epub 2021 Feb 24.

Magee-Womens Research Institute, 204 Craft Avenue, Room B509, Pittsburgh, Pennsylvania, 15213, USA.

Griffithsin (GRFT) has shown potent anti-HIV activity, and it is being developed as a drug candidate for HIV prevention. Successful implementation requires thorough understanding of its preformulation characterization. In this work, preformulation assessments were conducted to characterize GRFT and identify its degradation pathways under selected conditions of temperature, light, pH, shear, ionic strength, and oxidation. Compatibility with vaginal fluid simulant, vaginal enzymes, Lactobacillus spp., and human cervicovaginal secretions was assessed. The purity, melting temperature, and HIV gp120-binding affinity of GRFT stored at 4°C and 25°C in phosphate-buffered saline (PBS) were assessed for 2 years. Chemical modifications were evaluated by intact mass analysis and peptide sequencing. Excised human ectocervical tissue permeability and localization of GRFT were evaluated. Our results demonstrated GRFT to be safe and stable under all the preformulation assessment conditions studied except oxidative stress. When GRFT was exposed to hydrogen peroxide or human cervicovaginal secretion, methionine 78 in the protein sequence underwent oxidation. GRFT did not permeate through human cervical tissue but adhered to the superficial epithelial tissue. The 2-year stability study revealed no significant change in GRFT's aggregation, degradation, melting temperature, or gp120-binding affinity despite a slow increase in oxidation over time. These studies elucidated desirable safety and bioactivity profile for GRFT, showing promise as a potential drug candidate for HIV prevention. However, susceptibility to oxidative degradation was identified. Effective protection of GRFT from oxidation is required for further development.
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http://dx.doi.org/10.1208/s12249-021-01931-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903873PMC
February 2021

Factors associated with prognosis of dysembryoplastic neuroepithelial tumors patients after surgical resection: a retrospective observational study.

Br J Neurosurg 2021 Feb 2:1-6. Epub 2021 Feb 2.

Department of Neurosurgery, Xiangya Hospital Affiliated to Central South University, Changsha, People's Republic of China.

Objective: To explore factors that might be associated with prognosis of dysembryoplastic neuroepithelial tumors (DNTs).

Methods: DNTs patients who were admitted to the Department of Neurosurgery of Xiangya Hospital between 1 January 2010 and 31 December 2018 and underwent surgical resection were retrospectively analyzed. Clinical, neuroimaging, and pathological features of DNTs were compared among patients with different outcomes and analyzed using the Kaplan-Meier curves and univariable Cox regression analysis.

Results: Thirty-three DNTs patients were included finally, of which the average age at seizure onset was 11.59 ± 7.46 years old and the average duration of seizures prior to surgical resection was 3.00 ± 4.68 years. After surgical resection, the patients were followed up for 2.39 ± 1.97 years, and 28 patients (84.85%) were seizure-free (class I of the Engel Outcome Scale) while five patients (15.15%) were seizure-continuous (class II or III of the Engel Outcome Scale). When compared with seizure-free patients, seizure-continuous patients had greater age at seizure onset and longer duration of seizures before surgical resection ( < .05). No variables were found to be statistically significantly associated with prognosis in univariable Cox regression analysis, but patients with extra-temporal DNTs were found to have better prognosis than those with temporal DNTs (log-rank test  = .048).

Conclusions: Elder seizure onset age, longer duration of seizures prior to surgical resection, and a temporal location may be risk factors of poor prognosis for DNTs patients after surgical resection.
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http://dx.doi.org/10.1080/02688697.2021.1878107DOI Listing
February 2021

IL-32 exacerbates adenoid hypertrophy via activating NLRP3-mediated cell pyroptosis, which promotes inflammation.

Mol Med Rep 2021 03 26;23(3). Epub 2021 Jan 26.

Department of Otolaryngology, Tianjin Children's Hospital, Tianjin 300134, P.R. China.

Adenoid hypertrophy (AH) is a common pediatric disease caused by inflammatory stimulation. The pro-inflammatory cytokine IL-32 has been reported to promote airway inflammation and also be involved in the pyroptosis pathway. However, whether IL-32 can contribute to AH by mediating pyroptosis remains to be elucidated. The present study aimed to investigate the role of IL-32 in AH and determine the potential underlying mechanisms. Adenoid tissues were collected from healthy children and children with AH, and the expression of IL-32, NACHT LRR and PYD domains-containing protein 3 (NLRP3) and IL-1β in normal and hypertrophic tissues were measured. Human nasal epithelial cells (HNEpCs) were exposed to a series of IL-32 concentrations. HNEpCs with or without IL-32 silencing were stimulated with lipopolysaccharide (LPS), and cell proliferation, cell apoptosis, gasdermin D (GSDMD) activation, production of inflammatory cytokines and the expression levels of proteins related to the potential mechanisms were evaluated by Cell Counting Kit-8, flow cytometry, immunofluorescence staining, ELISA and western blot assays, respectively. The results showed that IL-32, NLRP3 and IL-1β exhibited higher expression in adenoid tissues with AH compared with normal tissues. In HNEpC cells, treatment with IL-32 (2 and 10 ng/ml) promoted cell proliferation, while 50 ng/ml IL-32 inhibited cell proliferation at 12, 24 and 48 h post-treatment. IL-32 (2, 10 and 50 ng/ml) also resulted in differing degrees of apoptosis, GSDMD activation, release of IL-1β, IL-6 and TNF-α, and increased protein expression levels of NLRP3, cleaved-caspase-1, activated GSDMD, nucleotide-binding oligomerization domain-containing protein (NOD) 1/2 and Toll-like receptor (TLR)4 in a concentration-dependent manner. In addition, compared with the LPS group, IL-32 knockdown significantly inhibited LPS-induced enhancement of cell proliferation, cell apoptosis, GSDMD activation and production of inflammatory cytokines, and reversed the increased protein expression of NLRP3, cleaved-caspase-1, activated GSDMD, NOD1/2 and TLR4. In conclusion, IL-32 may play a role in the progression of AH via promoting inflammation, and the potential mechanism may involve the activation of NLRP3-mediated pyroptosis.
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http://dx.doi.org/10.3892/mmr.2021.11865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851829PMC
March 2021

Side of Lesions Predicts Surgical Outcomes in Patients With Drug-Resistant Temporal Lobe Epilepsy Secondary to Focal Cortical Dysplasia Type IIIa.

Front Neurol 2020 10;11:580221. Epub 2020 Dec 10.

Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.

This study aims to evaluate the surgical outcomes and analyze the predictors of surgical outcomes in patients undergoing anterior temporal lobectomy (ATL) for drug-resistant temporal lobe epilepsy (TLE) secondary to focal cortical dysplasia (FCD) type IIIa. Data on patients with drug-resistant TLE secondary to FCD type IIIa who had undergone ATL at Xiangya Hospital, Central South University from January 2014 to April 2018, were collected retrospectively. International League Against Epilepsy (ILAE) classification was used to evaluate postoperative seizure outcomes. Predictors of surgical outcomes were identified by using univariate and multivariate analyses. A total of 43 patients with drug-resistant TLE secondary to FCD type IIIa who had undergone ATL were included in this study. Twenty patients had right ATL, and 23 patients had left ATL. With a follow-up of 2-6 years, 76.7% (33 of 43) of patients were seizure-free. Univariate and multivariate analysis results indicated that lesions on the right side independently predict postoperative seizure freedom (OR, 0.08; 95% CI, 0.01-0.72; = 0.024). ATL is an effective therapy for patients with drug-resistant TLE secondary to FCD type IIIa. Patients with lesions on the right side are more likely to achieve postoperative seizure freedom.
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http://dx.doi.org/10.3389/fneur.2020.580221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758315PMC
December 2020

The Role of Hippocampal Neurogenesis in ANT-DBS for LiCl-Pilocarpine-Induced Epileptic Rats.

Stereotact Funct Neurosurg 2021 10;99(1):55-64. Epub 2020 Dec 10.

Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.

Purpose: Abnormal neurogenesis in the hippocampus after status epilepticus (SE) has been suggested as a key pathogeny of temporal lobe epilepsy. This study aimed to investigate the effect of deep brain stimulation of the anterior thalamic nucleus (ANT-DBS) on hippocampal neurogenesis in LiCl-pilocarpine-induced epileptic rats and to analyze its relationship with postoperative spontaneous recurrent seizures (SRS) and anxiety.

Method: SE was induced by a systemic LiCl-pilocarpine injection in adult male rats. Rats in the DBS group underwent ANT-DBS immediately after successful SE induction. SRS was only recorded during the chronic stage. An elevated plus maze was used to evaluate the level of anxiety in rats 7, 28, and 60 days after SE onset. After the elevated plus-maze experiment, rats were sacrificed under anesthesia in order to evaluate hippocampal neurogenesis. Doublecortin (DCX) was used as a marker for neurogenesis.

Results: During the chronic stage, SRS in rats in the DBS group were significantly decreased. The level of anxiety was increased significantly in rats in the DBS group 28 days after SE, while no significant differences in anxiety levels were found 7 and 60 days after SE. The number of DCX-positive cells in the hippocampus was significantly increased 7 days after SE and was significantly decreased 60 days after SE in all rats in which SE was induced. However, the number of DCX-positive cells in the DBS group was significantly lower than that in the other groups 28 days after SE.

Conclusions: ANT-DBS may suppress SRS and increase the postoperative anxiety of epileptic rats by influencing hippocampal neurogenesis.
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http://dx.doi.org/10.1159/000509314DOI Listing
December 2020

Chrysophanol Alleviates Metabolic Syndrome by Activating the SIRT6/AMPK Signaling Pathway in Brown Adipocytes.

Oxid Med Cell Longev 2020 12;2020:7374086. Epub 2020 Nov 12.

The First Clinical Medical College of Guangzhou University of Chinese Medicine, 16 Airport Road, Guangzhou 510405, China.

Chrysophanol, a primary active ingredient of or , has various pharmacological properties, including anticancer, antidiabetic, and anti-inflammatory, as well as blood lipid regulation. However, whether chrysophanol can mitigate obesity, and its underlying mechanisms remains unclear. This study investigated whether chrysophanol effects energy metabolism in high-fat diet- (HFD-) induced obese mice and fat-specific Sirtuin 6- (SIRT6-) knockout (FKO) mice, targeting the SIRT6/AMPK signaling pathway in brown and white fat tissue. Our results showed that chrysophanol can effectively inhibit lipid accumulation in vitro and reduce mice's body weight, improve insulin sensitivity and reduced fat content of mice, and induce energy consumption in HFD-induced obese mice by activating the SIRT6/AMPK pathway. However, a treatment with OSS-128167, an SIRT6 inhibitor, or si-SIRT6, SIRT6 target specific small interfering RNA, in vitro blocked chrysophanol inhibition of lipid accumulation. Similar results were obtained when blocking the AMPK pathway. Moreover, in the HFD-induced obese model with SIRT6 FKO mice, histological analysis and genetic test results showed that chrysophanol treatment did not reduce lipid droplets and upregulated the uncoupling protein 1 (UCP1) expression. Rather, it upregulated the expression of thermogenic genes and activated white fat breakdown by inducing phosphorylation of adenosine 5'-monophosphate- (AMP-) activated protein kinase (AMPK), both in vitro and in vivo. OSS-128167 or si-SIRT6 blocked chrysophanol's upregulation of peroxisome proliferator-activated receptor- coactivator-1 (Pgc-1) and Ucp1 expression. In conclusion, this study demonstrated that chrysophanol can activate brown fat through the SIRT6/AMPK pathway and increase energy consumption, insulin sensitivity, and heat production, thereby alleviating obesity and metabolic disorders.
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http://dx.doi.org/10.1155/2020/7374086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683138PMC
November 2020

Gut Microbiome Signatures Are Biomarkers for Cognitive Impairment in Patients With Ischemic Stroke.

Front Aging Neurosci 2020 23;12:511562. Epub 2020 Oct 23.

Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Post-stroke cognitive impairment (PSCI) is a common neuropsychiatric complication of stroke. Mounting evidence has demonstrated a connection between gut microbiota (GM) and neuropsychiatric disease. Our previous study revealed the changes in the GM in a mouse model of vascular dementia. However, the characteristic GM of PSCI remains unclear. This study aimed to characterize the GM of PSCI and explored the potential of GM as PSCI biomarkers. A total of 93 patients with ischemic stroke were enrolled in this study. The patients were divided into two groups according to their MoCA scores 3 months after stroke onset. Clinical data and biological variables were recorded. GM composition was analyzed using 16S ribosomal RNA sequencing, and the characteristic GM was identified by linear discriminant analysis Effect Size (Lefse). Our results showed that was highly increased in the PSCI group compared with the post-stroke non-cognitive impairment (PSNCI) group, the similar alterations were also observed at the class, order, family, and genus levels of . After age adjustments, the abundance of , and its members, including , , , and , were significantly decreased in the age-matched PSCI group compared with the PSNCI group. Besides, the GM was closely associated with MoCA scores and the risk factors for PSCI, including higher baseline National Institute of Health Stroke Scale score, higher homocysteine (Hcy) level, higher prevalence of stroke recurrence, leukoaraiosis, and brain atrophy. The KEGG results showed the enriched module for folding, sorting and degradation (chaperones and folding catalysts) and the decreased modules related to metabolisms of cofactors and vitamins, amino acid, and lipid in PSCI patients. A significant correlation was observed between PSCI and the abundance of after adjustments ( = 0.035). Moreover, the receiver operating characteristic (ROC) models based on the characteristic GM and could distinguish PSCI patients from PSNCI patients [area under the curve (AUC) = 0.840, 0.629, respectively]. Our findings demonstrated that the characteristic GM, especially , might have the ability to predict PSCI in post-stroke patients, which are expected to be used as clinical biomarkers of PSCI.
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http://dx.doi.org/10.3389/fnagi.2020.511562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645221PMC
October 2020

Chronic active Epstein-Barr virus infection manifesting as coronary artery aneurysm and uveitis.

Virol J 2020 10 29;17(1):166. Epub 2020 Oct 29.

Department of Infectious Diseases, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.

Background: Chronic active Epstein-Barr virus (CAEBV) infection is a type of lymphoproliferative disorder characterized by chronic or recurrent infectious mononucleosis (IM)-like symptoms, which can have less-frequent clinical presentations. The prognosis of CAEBV is poor, and hematopoietic stem cell transplantation (HSCT) has been shown to be the only potentially effective treatment. In this article, we present a special CAEBV case of a patient who had no typical IM-like symptoms at the early stage, but manifested with severe and progressive coronary artery aneurysm (CAA), abdominal aortic lesions, and severe uveitis. These manifestations were uncommon features and could only be blocked by HSCT.

Case Presentation: A 4-year-old girl with no special medical history complained of decreased vision for 10 months and cough after physical activities for three months. The blurred vision grew rapidly worse within one month, until only light perception remained. She was diagnosed with uveitis and cataract, and received prednisone and ciclosporin A treatment. However, her vision did not improve. Physical examination showed slight hepatosplenomegaly. Ultrasonic cardiogram showed bilateral CAA (5.0 mm and 5.7 mm for inner diameters), and abdominal CT scan revealed a thickened aortic wall, as well as stenosis and dilation of the segmental abdominal aorta. Other significant findings were increased EBV-DNA (3.29 × 10 copies/mL) from peripheral blood, positive EBV antibodies (EBV-CA-IgG, EBV-EA-IgA, and EBV-NA-IgG), and positive EBV-encoded small RNAs found by bone marrow biopsy. Based on her clinical manifestations and evidence for EBV infection, we diagnosed CAEBV. She received allogeneic HSCT, and the cataract operation was performed after HSCT. EBV-DNA could not be detected in peripheral blood after HSCT. Her CAAs did not progress, and uveitis was well controlled. Her vision recovered gradually over the 3 years after HSCT.

Conclusions: We present a rare CAEBV case of a patient who suffered from uncommon and severe cardiovascular and ocular involvement that was relieved by HSCT. Therefore, early recognition and diagnosis of CAEBV are of vital importance to improve its prognosis. In summary, this atypical CAEBV case could help us recognize similar cases more easily, make the right diagnosis as early as possible, and deliver proper and timely treatment.
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http://dx.doi.org/10.1186/s12985-020-01409-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597064PMC
October 2020

Structural Change of Gut Microbiota in Patients with Post-Stroke Comorbid Cognitive Impairment and Depression and Its Correlation with Clinical Features.

J Alzheimers Dis 2020 ;77(4):1595-1608

Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Background: Post-stroke comorbid cognitive impairment and depression (PSCCID) is a severe neuropsychiatric complication after acute stroke. Gut microbiota dysbiosis is associated with many psychiatric disorders. Alterations in the composition of gut microbiota may serve as a critical role in patients with PSCCID.

Objective: We aimed to characterize the microbial profiles of patients with PSCCID.

Method: A total of 175 stroke patients were recruited in the study. The composition of gut bacterial communities of patients was determined by 16S ribosomal RNA Miseq sequencing, and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was used to demonstrate the functional alterations of gut microbiota. We further identified the characteristic gut microbiota of PSCCID using linear discriminant analysis effect size.

Results: Patients with PSCCID exhibited an increased abundance of Proteobacteria, including Gammaproteobacteria, Enterobacteriales, and Enterobacteriaceae, and a decreased abundance of several short-chain fatty acids-producing bacteria compared with non-PSCCID patients. The abundance of Gammaproteobacteria and Enterobacteriaceae showed negative correlations with the MoCA score. Moreover, the Kyoto Encyclopedia of Genes and Genomes results demonstrated the enriched orthologs of glycan biosynthesis and metabolism and decreased orthologs of amino acid metabolism in PSCCID patients. Importantly, the characteristic gut microbiota was identified and achieved an area under the curve of 0.847 between the two groups.

Conclusion: In this study, we characterized the gut microbiota of PSCCID patients, and revealed the correlations of the altered gut microbiota with clinical parameters, which took a further step towards non-invasive diagnostic biomarkers for PSCCID from fecal samples.
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http://dx.doi.org/10.3233/JAD-200315DOI Listing
January 2020

[The role of rigid bronchoscope combined with high frequency ventilation in the diagnosis and treatment of infantile acute fibrinous laryngotracheobronchitis].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2020 Jun;34(6):492-495

Department of Otolaryngology Head and Neck Surgery,Tianjin Children's Hospital,Tianjin,300400,China.

To explore the role of rigid bronchoscope combined with high frequency ventilation in the diagnosis and treatment of infantile acute fibrinous laryngotracheobronchitis. The clinical data of 7 children with acute fibrinous laryngotracheobronchitis were analyzed retrospectively. Laryngology and bronchoscopy were conducted by hard tube bronchoscopy combined with high frequency ventilation in all cases. During the operation, a large quantity of membranous scabs was removed from subglottic area, trachea and bronchus. Six cases were treated by emergency operation and cured. One patient was treated with mechanical ventilation for 48 hours because of respiratory failure. Then the operation was performed to remove the endogenous foreign body since no improvement was observed after prolonged ventilation. This patient died of multiple organ failure. The histopathological examination of these 7 cases of endogenous foreign bodies showed fibrinous exudation and necrosis, accompanied by a large quantity of inflammatory cells infiltration. Removal of the plastic endogenous foreign bodies which block the respiratory tract by rigid bronchoscope and high frequency ventilation under general anesthesia facilitates the diagnosis and treatment of acute fibrinous laryngotracheobronchitis in pediatric patients. Prompt surgical intervention could relieve the obstruction of respiratory tract, which is crucial to reduce mortality.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2020.06.003DOI Listing
June 2020

Recent Advances of Polycationic siRNA Vectors for Cancer Therapy.

Biomacromolecules 2020 08 7;21(8):2966-2982. Epub 2020 Jul 7.

Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.

Small interfering RNAs (siRNAs) have recently emerged as a new class of biopharmaceuticals for the treatment of various diseases, including genetic diseases, viral infections, heritable disorders, and most prominently, cancer. However, clinical applications of siRNA-based therapeutics through intravenous administration have been limited due to their rapid degradation and renal clearance, poor cellular uptake, low cytoplasmic release by escaping endocytic uptake, and off-target effects. The success of siRNA-based therapeutics depends upon the design and creation of efficient delivery vectors that should be able to protect siRNA from degradation and specifically deliver siRNA to cytosol of target cells. Over the past decade, myriad types of carrier systems composed of cationic polymers have been designed for delivery of siRNA to tumor cells. In this review, we overview recent advances in siRNA delivery by using these promising nonviral carrier systems in diverse approaches to overcome the delivery hindrances and provide valuable understanding to direct the future design of siRNA delivery carriers.
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http://dx.doi.org/10.1021/acs.biomac.0c00438DOI Listing
August 2020

The association between serum uric acid level and the risk of cognitive impairment after ischemic stroke.

Neurosci Lett 2020 08 30;734:135098. Epub 2020 May 30.

Department of Neurology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, 150 Ximen Street, Linhai, Zhejiang, 317000, China. Electronic address:

Post-stroke cognitive impairment (PSCI) is a severe complication of stroke. Predicting PSCI is difficult because some risk factors for stroke, such as blood glucose level and blood pressure, are affected by many other elements. Although recent studies have shown that high serum uric acid (UA) levels are associated with cognitive dysfunction and may be a risk factor for PSCI, its impact remains unclear. Accordingly, the present study aimed to explore the association between serum UA level and PSCI. In total, 274 patients who experienced acute cerebral infarction, confirmed between January 2016 and December 2018, were enrolled. Baseline data and biological indicators were recorded. According to the Montreal Cognitive Assessment (MoCA) scores, patients were divided into two groups: PSCI and non-PSCI. Logistic regression analysis was used to determine possible risk factors for PSCI. Results demonstrated that serum UA levels were significantly higher in the PSCI group than in the non-PSCI group. Multivariable logistic analysis revealed that age, years of education, and UA level were independent risk factors for PSCI. PSCI patients were subdivided according to serum UA level: high and low. Hypertension history and homocysteine (Hcy) levels differed significantly between the high and low UA level groups. Further analysis revealed that a history of hypertension and Hcy demonstrated a certain correlation (r = 0.163, 0.162; P < 0.05), suggesting that serum UA level was an independent risk factor for PSCI. These findings indicate that serum UA level was correlated with PSCI in post-stroke patients and is anticipated to be used in clinical practice to reduce the incidence of PSCI.
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http://dx.doi.org/10.1016/j.neulet.2020.135098DOI Listing
August 2020

Neuropsychiatric symptoms as prognostic makers for the elderly with mild cognitive impairment: a meta-analysis.

J Affect Disord 2020 06 18;271:185-192. Epub 2020 Apr 18.

Department of Nursing, XiangYa School of Medicine, Central South University, Changsha, China; Oceanwide Health management institute, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders Xiangya Hospital, Central South University, Changsha, China. Electronic address:

Background: Although several neuropsychiatric symptoms (NPSs) have been demonstrated to have value in the prediction of the progression of mild cognitive impairment (MCI) to dementia, these symptoms are less studied for the prediction of the transition from normal cognition (NC) to MCI.

Methods: Prospective cohort studies were included if they reported on at least one NPS at baseline and had MCI as the outcome.

Results: We obtained 13 cohort studies with a total population of 33,066. Depression was the most common neuropsychiatric symptom and could significantly predict transition to MCI (RR = 1.49, 95% CI: 1.13-1.86). However, depression was more capable of predicting amnestic MCI (RR=1.43, 95% CI: 1.04-1.83) than non-aMCI (RR= 0.96, 95% CI 95% CI: 0.60-1.33). Subgroup analysis suggested that the association between depression and MCI changed with depression severity, depression criteria, apolipoprotein-E-adjusted status, age, the percentage of females, and follow-up times, but some data were too sparse for a reliable estimate. Regarding other NPSs, there were insufficient data to assess their effect on the development of MCI. However, apathy, anxiety, sleep disturbances, irritability, and agitation might be risk factors for the prediction of NC-MCI transition with strong predictive value.

Conclusions: Depression was associated with an approximately 1.5-fold sincreased risk of the progression to MCI in the population with normal cognition. Other NPSs with underlying predictive value deserve more attention.
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http://dx.doi.org/10.1016/j.jad.2020.03.061DOI Listing
June 2020

Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex.

Elife 2020 04 1;9. Epub 2020 Apr 1.

Department of Cell Biology, University of Virginia Health System, Charlottesville, United States.

Coordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. Many studies have shown that FA disassembly requires Ca influx, however our understanding of this process remains incomplete. Here, we show that Ca influx via STIM1/Orai1 calcium channels, which cluster near FAs, leads to activation of the GTPase Arf5 via the Ca-activated GEF IQSec1, and that both IQSec1 and Arf5 activation are essential for adhesion disassembly. We further show that IQSec1 forms a complex with the lipid transfer protein ORP3, and that Ca influx triggers PKC-dependent translocation of this complex to ER/plasma membrane (PM) contact sites adjacent to FAs. In addition to allosterically activating IQSec1, ORP3 also extracts PI4P from the PM, in exchange for phosphatidylcholine. ORP3-mediated lipid exchange is also important for FA turnover. Together, these findings identify a new pathway that links calcium influx to FA turnover during cell migration.
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http://dx.doi.org/10.7554/eLife.54113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159923PMC
April 2020

Tumor localization of oncolytic adenovirus assisted by pH-degradable microgels with JQ1-mediated boosting replication and PD-L1 suppression for enhanced cancer therapy.

Biomater Sci 2020 May;8(9):2472-2480

Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.

Oncolytic therapy is a fast-developing cancer treatment field based on the promising clinical performance from the selective tumor cell killing and induction of systemic antitumor immunity. The virotherapy efficacy, however, is strongly hindered by the limited virus propagation and negative immune regulation in the tumor microenvironments. To enhance the antitumor activity, we developed injectable pH-degradable PVA microgels encapsulated with oncolytic adenovirus (OA) by microfluidics for localized OA delivery and cancer treatments. PVA microgels were tailored with an OA encapsulation efficiency of 68% and exhibited a pH-dependent OA release as the microgel degradation at mildly acidic conditions. PVA microgels mediated fast viral release and increased replication in HEK293T and A549 cells at a lower pH, and the replication efficiency could be further reinforced by co-loading with one BET bromodomain inhibitor JQ1, inducing significant cytotoxicity against A549 cells. An in vivo study revealed that OA release was highly located at the tumor tissue assisted by PVA microgels, and the OA infection was also enhanced with the addition of JQ1 treatment, meanwhile greatly inhibiting the PD-L1 expression to overcome the immune suppression. OA/JQ1 co-encapsulated injectable microgels exhibited a superior in vivo antitumor activity on the A549 lung tumor-bearing mice by the combination of inhibited proliferation, amplified oncolysis, and potential immune regulation.
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http://dx.doi.org/10.1039/d0bm00172dDOI Listing
May 2020

Tracing the evolution of fatty acid-binding proteins (FABPs) in organisms with a heterogeneous fat distribution.

FEBS Open Bio 2020 05 31;10(5):861-872. Epub 2020 Mar 31.

College of Fisheries, Henan Normal University, Xinxiang, China.

The distribution of fat among both invertebrate and vertebrate groups is heterogeneous. Studies have shown that fatty acid-binding proteins (FABPs), which mainly bind and transport fatty acids, play important roles in the regulation of fat storage and distribution. However, the systematic and genome-wide investigation of FABP genes in organisms with a heterogeneous fat distribution remains in its infancy. The availability of the complete genomes of Caenorhabditis elegans, Callorhinchus milii, and other organisms with a heterogeneous fat distribution allowed us to systematically investigate the gene structure and phylogeny of FABP genes across a wide range of phyla. In this study, we analyzed the number, structure, chromosomal location, and phylogeny of FABP genes in 18 organisms from C. elegans to Homo sapiens. A total of 12 types of FABP genes were identified in the 18 species, and no single organism exhibited all 12 fatty acid-binding genes (FABPs). The absence of a specific FABP gene in tissue may be related to the absence of fat storage in the corresponding tissue. The genomic loci of the FABP genes were diverse, and their gene structures varied. The results of the phylogenetic analysis and the observation of conserved gene synthesis of FABP family genes/proteins suggest that all FABP genes may have evolved from a common ancestor through tandem duplication. This study not only lays a strong theoretical foundation for the study of fat deposition in different organisms, but also provides a new perspective regarding metabolic disease prevention and control and the improvement of agricultural product quality.
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http://dx.doi.org/10.1002/2211-5463.12840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193176PMC
May 2020

Quantitative Serum Proteomic Study Reveals that Fibrinogen-Related Proteins May Participate in the Pathophysiological Process of Simple Febrile Convulsion.

J Am Soc Mass Spectrom 2020 Mar 19;31(3):666-674. Epub 2020 Feb 19.

Department of Pediatric, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Simple febrile convulsion (SFC) is a common disease that is mainly caused by fever from extracranial infections. In this study, we used proteomic approaches involving discovery and validation cohorts to examine the proteomes of serum from children who were diagnosed with SFC, children with fever but without convulsion, and healthy children (normal controls). We identified 86 proteins involved in different biological pathways that were significantly different between the SFC and normal control groups. Of these 86 proteins, 35 had higher expression in the SFC group compared with the normal control group, whereas 51 had lower expression. Notably, fibrinogen-related proteins involved in the coagulation system pathway were markedly decreased in the SFC group. Targeted and absolute quantification of fibrinogen-related proteins was performed and validated the potential of these proteins as biomarkers. Thus, fibrinogen-related proteins may participate in the pathophysiological process of SFC and may be potential biomarkers for the diagnosis of SFC.
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http://dx.doi.org/10.1021/jasms.9b00100DOI Listing
March 2020

Determine what to measure and how to measure in clinical trials for the treatment of pressure injury: A protocol for the development of a core outcome set.

Medicine (Baltimore) 2020 Feb;99(9):e19311

Nursing Department, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, China.

Background: A core outcome set (COS) is an agreed minimum set of outcomes that should be reported in all clinical trials in specific areas of health care. A considerable amount of trials did not report essential outcomes or outcomes measurement methods, which makes it challenging to evaluate the efficacy and safety of treatment strategies for pressure injury (PI) and produced significant heterogeneity of reported outcomes. It is necessary to develop a COS, which can be used for clinical trials in PI treatment.

Methods/design: The development of this COS will be guided by an advisory group composed of clinicians, senior nurses, patients, and methodologists. We will search six databases and 2 registry platforms to identify currently reported PI treatment outcomes and outcome measurement instruments in randomized controlled trials, meta-analysis, and systematic reviews. We will also conduct a semi-structured interview with clinicians, nurses, and adult PI patients to collect their opinions on important outcomes. Each outcome of the initial list generated from systematic review and interviews will be scored and reach a consensus through two rounds of international Delphi survey with all key stakeholders. A face-to-face consensus meeting with key stakeholders will be conducted to finish a final COS and recommend measurement instruments for each outcome.

Results: We will develop a COS that should be reported in future clinical trials to evaluate the effectiveness of PI treatment.

Discussion: The COS will follow current guidance to develop a high-quality COS in the field of PI treatment to reduce heterogeneity in trial reporting, facilitate valid comparisons of new therapies, and improve the quality of clinical trials.
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http://dx.doi.org/10.1097/MD.0000000000019311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478718PMC
February 2020

CB2R orchestrates neuronal autophagy through regulation of the mTOR signaling pathway in the hippocampus of developing rats with status epilepticus.

Int J Mol Med 2020 Feb 23;45(2):475-484. Epub 2019 Dec 23.

Department of Pediatric Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.

Neuronal loss and gliosis are the major pathological changes after status epilepticus (SE). The authors' previous study revealed the time‑dependent changes of cannabinoid receptor type 2 (CB2R) in hippocampal neurons of developing rats after SE, which were accompanied by a decrease in the number of neurons. Meanwhile, growing evidence indicates that CB2R stimulation exerts anti‑convulsant properties in seizure models. However, the activation of CB2R in neuronal repair in response to the damage after SE is still unclear. In this experiment, a highly‑selective CB2R agonist JWH133 and antagonist AM630 were administered to determine the activity of CB2R in neuronal autophagy and apoptosis of the post‑SE repair in developing rats. The present results revealed that activation of CB2R by JWH133, not only obviously lowered the success rate, 24‑h death rate and the Racine stage in the model, but also extended the latency period to SE. In addition, compared with the vehicle control group, CB2R activation increased neuronal autophagy and the expression of phosphorylated‑mammalian target of rapamycin (p‑mTOR)/mTOR, Beclin‑1, and LC3II/LC3I while decreasing the expression of p‑Unc‑51‑like autophagy‑activating kinase 1 (ULK‑1)/ULK1, p62, and cleaved caspase‑3. These results were dose‑dependent and were especially evident in the high‑dose group, and interestingly the opposite results were obtained in the AM630 group. Thus, CB2R orchestrates neuronal autophagy through regulation of the mTOR signaling pathway in the hippocampus of developing rats with SE. These findings might provide an important basis for further investigation of the therapeutic role of CB2R in ameliorating epilepsy‑related neuronal damage.
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http://dx.doi.org/10.3892/ijmm.2019.4439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984801PMC
February 2020

Microarray analysis reveals the inhibition of intestinal expression of nutrient transporters in piglets infected with porcine epidemic diarrhea virus.

Sci Rep 2019 12 24;9(1):19798. Epub 2019 Dec 24.

Department of Animal Science, Texas A&M University, College Station, Texas, 77843, USA.

Porcine epidemic diarrhea virus (PEDV) infection can induce intestinal dysfunction, resulting in severe diarrhea and even death, but the mode of action underlying these viral effects remains unclear. This study determined the effects of PEDV infection on intestinal absorption and the expression of genes for nutrient transporters via biochemical tests and microarray analysis. Sixteen 7-day-old healthy piglets fed a milk replacer were randomly allocated to one of two groups. After 5-day adaption, piglets (n = 8/group) were orally administrated with either sterile saline or PEDV (the strain from Yunnan province) at 10 TCID (50% tissue culture infectious dose) per pig. All pigs were orally infused D-xylose (0.1 g/kg BW) on day 5 post PEDV or saline administration. One hour later, jugular vein blood samples as well as intestinal samples were collected for further analysis. In comparison with the control group, PEDV infection increased diarrhea incidence, blood diamine oxidase activity, and iFABP level, while reducing growth and plasma D-xylose concentration in piglets. Moreover, PEDV infection altered plasma and jejunal amino acid profiles, and decreased the expression of aquaporins and amino acid transporters (L-type amino acid transporter 1, sodium-independent amino acid transporter, B(°)-type amino acid transport protein, sodium-dependent neutral amino acid transporter 1, sodium-dependent glutamate/aspartate transporter 3, and peptide transporter (1), lipid transport and metabolism-related genes (lipoprotein lipase, apolipoprotein A1, apolipoprotein A4, apolipoprotein C2, solute carrier family 27 member 2, solute carrier family 27 member 4, fatty acid synthase, and long-chain acyl-CoA synthetase (3), and glucose transport genes (glucose transporter-2 and insulin receptor) in the jejunum. However, PEDV administration increased mRNA levels for phosphoenolpyruvate carboxykinase 1, argininosuccinate synthase 1, sodium/glucose co-transporter-1, and cystic fibrosis transmembrane conductance regulator in the jejunum. Collectively, these comprehensive results indicate that PEDV infection induces intestinal injury and inhibits the expression of genes encoding for nutrient transporters.
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http://dx.doi.org/10.1038/s41598-019-56391-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930262PMC
December 2019

Insomnia and risk of mortality from all-cause, cardiovascular disease, and cancer: Systematic review and meta-analysis of prospective cohort studies.

Sleep Med Rev 2019 12 24;48:101215. Epub 2019 Sep 24.

Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, 730000, China; Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China; Key Laboratory of Evidence-Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, 730000, China. Electronic address:

Growing evidence indicates that insomnia may be associated with mortality. However, these findings have been inconsistent. We systematically searched MEDLINE and EMBASE to identify prospective cohort studies that assessed the association between insomnia disorder/individual insomnia symptoms and the risk of mortality among adults aged ≥18 yrs. We addressed this association using summary hazard ratios (HRs) and 95% confidence intervals (CIs) calculated using random-effects meta-analysis, and the GRADE approach to rate the certainty of evidence. Twenty-nine cohorts including 1,598,628 individuals (55.3% men; mean age 63.7 yrs old) with a median follow-up duration of 10.5 yrs proved eligible. Difficulty falling asleep (DFA) and non-restorative sleep (NRS) were associated with an increased risk of all-cause mortality (DFA: HR = 1.13, 95%CI 1.03 to 1.23, p = 0.009, moderate certainty; NRS: HR = 1.23, 95%CI 1.07 to 1.42, p = 0.003, high certainty) and cardiovascular disease mortality (DFA: 1.20, 95%CI: 1.01, 1.43; p = 0.04, moderate certainty; NRS: HR = 1.48, 95%CI 1.06 to 2.06, p = 0.02, moderate certainty). Convincing associations between DFA and all-cause mortality were restricted to the mid to older-aged population (moderate credibility). Insomnia disorder, difficulty maintaining sleep, and early morning awakening proved to be unassociated with all-cause and cardiovascular disease mortality. No insomnia symptoms proved to be associated with cancer-related mortality.
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http://dx.doi.org/10.1016/j.smrv.2019.101215DOI Listing
December 2019

Crosstalk between the Ketogenic Diet and Epilepsy: From the Perspective of Gut Microbiota.

Mediators Inflamm 2019 3;2019:8373060. Epub 2019 Jun 3.

Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, CAS Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan 410125, China.

Given the association between a range of neurological disorders and changes in the gut microbiota, interest in the gut microbiota has recently increased. In particular, the significant involvement of the autoimmune processes in the development of epilepsy, one of the most serious and widespread neurological diseases, has led to a suggested link with the gut microbiome. Because the constitution of the gut microbiome can be influenced by diet, dietary therapy has been shown to have a positive impact on a wide range of conditions via alteration of the gut microbiota. An example of one such diet is the ketogenic diet (KD), which promotes a diet that contains high levels of fat, adequate levels of protein, and low levels of carbohydrate. Due to the near-total elimination of carbohydrates from the individual's food in this ultra-high-fat diet, ketone bodies become an important source of energy. Although the ketogenic diet has proven successful in the treatment of refractory epilepsy and other illnesses, the underlying mechanisms of its neuroprotective effects have yet to be fully elucidated. Nevertheless, recent studies strongly indicate a role for the gut microbiota in the effective treatment of epilepsy with the ketogenic diet. The latest advances regarding the links between the ketogenic diet, gut microbiota, and epilepsy are reviewed in this article, with a particular focus on the role of the gut microbiota in the treatment outcome.
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http://dx.doi.org/10.1155/2019/8373060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589192PMC
January 2020

Dietary Modulation of Intestinal Microbiota: Future Opportunities in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis.

Front Microbiol 2019 16;10:740. Epub 2019 Apr 16.

Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.

Multiple sclerosis (MS) is an autoimmune disease that affects the functioning of the central nervous system (CNS). Recent studies on MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have shown that the composition and abundance of microbes in the intestinal microbiota are an environmental risk factor for the development of MS and EAE. Changes in certain microbial populations in the gastrointestinal tract can cause MS in humans, but MS inflammation can be reduced or even prevented by introducing other commensal microbes that produce beneficial metabolites. Other risk factors for MS include the presence of an altered gut physiology and the interaction between the intestinal microbiota and the immune system. Metabolites including short-chain fatty acids (SCFAs), such as butyrate, are the primary signaling molecules produced by the intestinal microbiota that interact with the host immune system, suggesting an association between MS pathophysiology and gut microbiota. In addition, several host microRNAs present in the gut have been found to interact with the intestinal microbial community, these interactions may indirectly affect the neurological system. Increasing evidence has shown that regulation of the intestinal microbiota is an important approach for reducing MS inflammation. Thus, here we review the use of diet to alter the gut microbiota and its application in the treatment and prevention of MS.
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http://dx.doi.org/10.3389/fmicb.2019.00740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476896PMC
April 2019

PM-bound polycyclic aromatic hydrocarbons (PAHs) and nitrated PAHs (NPAHs) in rural and suburban areas in Shandong and Henan Provinces during the 2016 Chinese New Year's holiday.

Environ Pollut 2019 Jul 10;250:782-791. Epub 2019 Apr 10.

Environment Research Institute, Shandong University, Jinan, 250100, China.

Eighteen polycyclic aromatic hydrocarbons (PAHs) and fourteen nitrated PAHs (NPAHs) in PM samples were collected during the 2016 Chinese New Year's holiday (CNY) at one suburban and three rural sites in Shandong and Henan Provinces. The PAH and NPAH concentrations were highest at the suburban site. The rural PAH concentrations in Qingzhou (QZ), Heze (HZ), and Liaocheng (LC) were higher than those measured at many other urban sites, indicating that PAHs pollution was notably higher in the suburban and rural sites during this festive period. Elevated PAH concentrations were observed during fireworks periods, but fireworks burning was not a significant or direct PAHs or NPAHs source based on molecular profiles and diagnostic ratios. The measured PAHs and NPAHs at the sampling sites mainly originated from coal and biomass burning. The increased concentrations during CNY's Eve may be related to behavioural changes during the period. Secondary formation of NPAHs mainly occurred via OH radical chemistry at all four sites. Fireworks burning did not increase secondary formation of NPAHs. ∑BaP concentrations exhibited strong correlations with PAHs concentrations, and the highest and lowest concentrations were observed in QZ and Xiping (XP), respectively. The incremental lifetime cancer risk (ILCR) was calculated to be between 10 and 10 for 1-70 years old persons, with the highest risks observed in the adult (30-70 years) and the toddler (1-6 years) groups.
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http://dx.doi.org/10.1016/j.envpol.2019.04.040DOI Listing
July 2019

Impact of subthalamic nucleus stimulation did not differ on young-onset and older-onset Parkinson's disease: A three-year follow up.

Neurosci Lett 2019 07 25;705:99-105. Epub 2019 Apr 25.

Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan, People's Republic of China. Electronic address:

Objective: To assess the role of onset age in the results of bilateral subthalamic nucleus deep brain stimulation (STN-DBS), we carried out a retrospective study of two groups of patients regarding age at disease onset.

Methods: We compared, up to 3 years after surgery, the clinical effects, quality of life and the levodopa equivalent daily dose (LEDD) in patients with young-onset Parkinson's disease (onset age <50 years, YOPD) vs patients with older-onset Parkinson's disease (onset age ≥50 years, OOPD).

Results: A dramatic improvement in motor symptoms was equally observed in both groups of patients after DBS. The improvements of the Unified Parkinson's Disease Rating Scale part III motor scale (UPDRS-III) score, axial sub-score and non-axial sub-score from baseline gradually decreased over time. The benefit of STN-DBS for the axial symptoms decreased most rapidly, which directly resulted in a progressive decline in stimulation efficacy in both groups. Nevertheless, the improvement in non-axial symptoms after DBS was remarkable and long-lasting. The quality of life in both groups were also improved after DBS but were slightly decreased in the following years. The reduced LEDD were equivalent in both groups.

Conclusions: STN-DBS alleviates motor symptoms and improves quality of life equally in both YOPD and OOPD patients with similar LEDD. The initial therapeutic benefit of STN-DBS for PD gradually decreases over time, mainly due to the progression of PD and the rapid withdrawal of the benefit for axial symptoms.
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http://dx.doi.org/10.1016/j.neulet.2019.04.041DOI Listing
July 2019

Seasonal variations of NPAHs and OPAHs in PM at heavily polluted urban and suburban sites in North China: Concentrations, molecular compositions, cancer risk assessments and sources.

Ecotoxicol Environ Saf 2019 Aug 15;178:58-65. Epub 2019 Apr 15.

Environment Research Institute, Shandong University, Qingdao, Shandong 266237, China.

16 nitrated polycyclic aromatic hydrocarbons (NPAHs) and 5 oxygenated polycyclic aromatic hydrocarbons (OPAHs) in PM at two locations in Northern China were analyzed by Gas Chromatography-Mass Spectrometry (GC-MS). Sampling was conducted at an urban site in Shandong University in Jinan (SDU) and a suburban site in Qixingtai in Jinan (QXT) in March, June, September and December in 2016. Overall, the concentrations of NPAHs and OPAHs were higher at SDU (1.88 and 9.49 ng/m, respectively) than QXT (1.57 and 6.90 ng/m, respectively), and the NPAHs and OPAHs concentrations were significantly higher during the winter than the other seasons at both sites. The incremental lifetime cancer risk (ILCR) values were lower than 10 for all sites, seasons and age groups (ranging between 1.85E-08 and 2.56E-07), so there was no risk of carcinogenesis due to exposure to these pollutants. Total cancer risk at SDU was higher than QXT and NPAHs have the highest carcinogenic risk for adults aged from 30 to 70 years. The positive matrix factorization (PMF) results revealed that coal/biomass combustion, diesel vehicle emissions, gasoline vehicle emissions and secondary formation were the main sources of NPAHs and OPAHs at SDU and QXT. Coal/biomass combustion contributed more in spring, autumn and winter; diesel vehicle emission contributed the most in summer; secondary formation made greatest contributions in winter; the contributions of gasoline vehicle emission were similar in summer, autumn and winter. Diagnostic ratios clearly demonstrated that secondary formation is more active in winter than in other seasons, and the reactions of PAHs and OH radical were the dominant secondary formation pathway at both SDU and QXT. In addition, the potential source contribution function (PSCF) identified that the Beijing-Tianjin-Hebei region, Shandong province, Bohai Sea, Yellow Sea, Anhui province and Henan province were the main source regions of NPAHs and OPAHs in Jinan.
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http://dx.doi.org/10.1016/j.ecoenv.2019.04.009DOI Listing
August 2019

Folated pH-degradable nanogels for the simultaneous delivery of docetaxel and an IDO1-inhibitor in enhancing cancer chemo-immunotherapy.

Biomater Sci 2019 Jun;7(7):2749-2758

Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China.

Combining chemotherapy and immunotherapy has been considered as an attractive approach to improve cancer therapy. Here we prepared folated PVA-based nanogels for the simultaneous delivery of docetaxel (DTX) and the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919 (N9) for enhancing cancer chemo-immunotherapy. FDA-approved poly(vinyl alcohol) (PVA) with good biocompatibility was modified with vinyl ether acrylate (VEA) groups for UV-crosslinking and acidic degradation. Carboxyl groups were introduced via modification with succinic anhydride for improved drug loading and folic acid (FA) ligands were incorporated for tumor targeting. UV-crosslinked folated PVA nanogels were efficiently taken up by tumor cells followed by endo/lysosomal pH-triggered intracellular drug release, which induced significant cytotoxicity towards 4T1 breast cancer cells in vitro. DTX and N9 co-loaded PVA nanogels exhibited a much higher antitumor efficiency in 4T1 mouse breast cancer models in vivo as compared to the free drug controls. The drug-laden nanogels not only directly killed the tumor cells by DTX, but also induced immunogenic cell death (ICD) promoting intratumoral accumulation of cytotoxic T lymphocytes, and further combining with N9 elevated the intratumoral infiltration of CD8+ T cells and NK cells and inhibited the infiltration of MDSCs, downregulating IDO1-mediated immunosuppression.
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http://dx.doi.org/10.1039/c9bm00324jDOI Listing
June 2019

Features of Childhood Arterial Ischemic Stroke in China.

Fetal Pediatr Pathol 2019 Aug 19;38(4):317-325. Epub 2019 Mar 19.

a Shengjing Hospital of China Medical University , Shenyang , China.

: The aim of this study was to identify the features and risk factors for arterial ischemic stroke (AIS) in children. : We retrospectively analyzed the initial symptoms, clinical manifestations, risk factors, neuroradiological findings, and treatment data of 75 Chinese children aged between 1 month and 14 years (median 5.7 years) who were diagnosed with AIS in our hospital between 2013 and 2018. : Among these 75 cases of childhood AIS, 53 patients (70.67%) were male, and the male-to-female ratio was 2.41:1. A total of 55 cases (73.33%) had respiratory tract infection with fever. Seventy cases had lesions in the basal ganglia (46 left, 24 right). All patients were treated conservatively without thrombolytic therapy. Intravenous immunoglobulin treatment was given to children with fever and drowsiness. : Infection was an important risk factor for children with AIS in China. Infection and thrombophilia risk factors were more likely to occur in isolation. The stroke lesions commonly occurred in the basal ganglia region.
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http://dx.doi.org/10.1080/15513815.2019.1588438DOI Listing
August 2019

Regulation of protein synthesis in porcine mammary epithelial cells by L-valine.

Amino Acids 2019 Apr 23;51(4):717-726. Epub 2019 Feb 23.

Department of Animal Science, Texas A&M University, College Station, TX, 77843, USA.

This study was conducted to determine the catabolism of L-valine in porcine mammary epithelial cells (PMECs) and its role in stimulating protein synthesis in these cells. PMECs were incubated with 0.05-, 0.10-, 0.25-, 0.5-, and 1.0-mM L-valine at 37 C for 2 h. Cell viability and expressions of α-lactalbumin and β-casein were measured after culture with L-valine for 3 days. L-[1-C]valine was used to study valine catabolism, whereas [H]phenylalanine was employed as a tracer to determine protein synthesis and degradation in PMECs. The abundances of proteins involved in the mTOR signaling pathway and the mRNA levels for the related key genes were determined using the western blot and RT-PCR techniques, respectively. Cell numbers and the synthesis of proteins (including α-lactalbumin and β-casein) were greater (P < 0.05) in the presence of 0.5-mM L-valine, compared with 0.05- or 0.1-mM L-valine. L-Valine at 0.5 mM also enhanced (P < 0.05) the production of α-lactalbumin by PMECs, in comparison with 0.25 mM L-valine. Increasing the extracellular concentration of L-valine from 0.05 to 0.5 mM stimulated protein synthesis in a concentration-dependent manner without affecting proteolysis. Although L-valine was actively transaminated in PMECs, its α-ketoacid product (α-ketoisovalerate) at 0.05-0.2 mM did not affect protein synthesis or degradation in the cells. Thus, the effect of L-valine on protein synthesis was independent of its metabolism to yield α-ketoisovalerate. At the molecular level, 0.5-mM L-valine increased (P < 0.05) the mRNA levels for Ras, ERK1/2, and p70S6K, and the abundances of mTOR, p-4EBP1, total 4EBP1, p-ERK1/2, and total ERK1/2 proteins. These findings establish the critical role of L-valine in enhancing PMEC growth and milk protein synthesis possibly by regulating the mTOR and Ras/ERK signaling pathways. Further studies are warranted to understand how L-valine regulates gene expression and mTOR activation in PMECs.
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http://dx.doi.org/10.1007/s00726-019-02709-2DOI Listing
April 2019

A sensitive and robust UPLC-MS/MS method for quantitation of estrogens and progestogens in human serum.

Contraception 2019 04 24;99(4):244-250. Epub 2019 Jan 24.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA. Electronic address:

Objective: With the widespread use of sex-steroid hormones in contraceptives and hormone replacement therapy, there is an increasing need for reliable analytical methods. We report the development of a sensitive and robust UPLC-MS/MS method for quantitation of both endogenous and synthetic sex-steroid hormones in human serum.

Study Design: We developed and validated a UPLC-MS/MS method to quantify progestogens (etonogestrel, levonorgestrel, medroxyprogesterone acetate, norethindrone, progesterone) and estrogens (estradiol and ethinyl estradiol) with good accuracy, high sensitivity, and excellent robustness. We then applied the method to the analysis of sex-steroid hormones in serum from 451 clinical research participants.

Results: Each UPLC-MS/MS analysis was 6.5 min. The lower limits of quantitation (LLOQs) were 25 pg/ml for the progestogens, and 2.5 and 5.0 pg/ml for estradiol and ethinyl estradiol, respectively. When estradiol was analyzed without assessment of progestogens, the LLOQ was reduced to 1 pg/ml. The calibration curves were linear from 25-50,000, 2.5-2000 (1-2000 for estrogens-only analysis) and 5-2000 pg/ml, respectively. Both the accuracy and precision were below±15% not only for routine validation (intraday and interday), but for long-term (>2 years) assay robustness with external controls, thereby, demonstrating the utility of this method for multi-year clinical trial assessments of progestogens and estrogens. We applied the method to quantify sex-steroid levels in 1804 clinical samples.

Conclusions: We successfully developed a UPLC-MS/MS method, and overcame the matrix suppression to allow sensitive quantitation of both synthetic and endogenous sex-steroid hormones in human serum.

Implications: We developed a sensitive and robust UPLC-MS/MS method to accurately measure the levels of sex-steroid hormones in serum. The method overcame matrix interference barriers and achieved excellent long-term stability and reproducibility (≥96.9% accuracy; ≤13.0% relative variability measured with external controls over 2 years), demonstrating its utility in clinical sample analysis.
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http://dx.doi.org/10.1016/j.contraception.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441366PMC
April 2019