Publications by authors named "Lingling Xu"

300 Publications

C-terminal truncation modulates α-Synuclein's cytotoxicity and aggregation by promoting the interactions with membrane and chaperone.

Commun Biol 2022 Aug 9;5(1):798. Epub 2022 Aug 9.

Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, 430071, Wuhan, China.

α-Synuclein (α-syn) is the main protein component of Lewy bodies, the major pathological hallmarks of Parkinson's disease (PD). C-terminally truncated α-syn is found in the brain of PD patients, reduces cell viability and tends to form fibrils. Nevertheless, little is known about the mechanisms underlying the role of C-terminal truncation on the cytotoxicity and aggregation of α-syn. Here, we use nuclear magnetic resonance spectroscopy to show that the truncation alters α-syn conformation, resulting in an attractive interaction of the N-terminus with membranes and molecular chaperone, protein disulfide isomerase (PDI). The truncated protein is more toxic to mitochondria than full-length protein and diminishes the effect of PDI on α-syn fibrillation. Our findings reveal a modulatory role for the C-terminus in the cytotoxicity and aggregation of α-syn by interfering with the N-terminus binding to membranes and chaperone, and provide a molecular basis for the pathological role of C-terminal truncation in PD pathogenesis.
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http://dx.doi.org/10.1038/s42003-022-03768-0DOI Listing
August 2022

Effects of prenatal and infant daily exposure to pyrethroid pesticides on the language development of 2-year-old toddlers: a prospective cohort study in rural Yunnan, China.

Neurotoxicology 2022 Aug 6. Epub 2022 Aug 6.

School of Public Health, Kunming Medical University, Kunming, China. Electronic address:

Background: Prenatal and infant daily exposures to pyrethroid pesticides (PYRs), used in the elimination of harmful organisms in the family environment and agricultural activities, may have an impact on children's language development.

Objectives: To determine the impacts of prenatal and infant PYRs exposure on 2-year-old toddlers' language development.

Methods: From January 2016 to December 2018, women in the third trimester of pregnancy, in Yunnan rural area, China, were recruited, and the development of their newborns was observed from birth till the age of two. We examined three PYRs metabolites: 3-phenoxybenzoic acid (3PBA), 4-fluoro-3-phenoxybenzoic acid (4F3PBA), and cis-2,2dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA) in urine samples collected from women in the third trimester of pregnancy and their infants of 6-8 months after birth, and assessed language development of 2-year-old toddlers by the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Generalized linear models were used to analyze the impacts of exposure to PYRs on 2-year-old toddlers' language development.

Results: The median concentrations of 3PBA, 4F3PBA and DBCA creatinine-adjusted were 0.21, 0.19, and 0.15μg/g in pregnancy, and 0.25, 0.72, and
Conclusion: Women in the third trimester of pregnancy and their infants were widely exposed to low-dose PYRs. Infant daily exposure to PYRs may negatively impact toddlers' language development, with the 6-8 months age bracket being a sensitive window. The probability of toddlers' language development delay may be predicted by PYRs metabolites of infants aged 6-8 months.
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http://dx.doi.org/10.1016/j.neuro.2022.08.002DOI Listing
August 2022

New insights on hyperglycemia in 17-hydroxylase/17,20-lyase deficiency.

Front Endocrinol (Lausanne) 2022 22;13:917420. Epub 2022 Jul 22.

Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China.

Objective: The adrenal glands of patients with 17-hydroxylase/17,20-lyase deficiency (17OHD) synthesize excessive 11-deoxycorticosterone(DOC) and progesterone, and produce less amount of sex steroid production. Mineralocorticoids and sex hormones play an important role in regulating glucose homeostasis. This study aimed to describe the glucose metabolism in 17OHD patients diagnosed at Peking Union Medical College Hospital (PUMCH).

Design/methods: A total of 69 patients diagnosed with 17OHD after adolescence in PUMCH from 1995 to June in 2021. Among them 23 patients underwent a 3-hours oral glucose tolerance test (3hOGTT) after being diagnosed with 17OHD. Insulin response in patients with normal glucose tolerance (NGT) were further compared between the study two groups with different kalemia status. Another 19 patients were followed up to 30 years and older. All clinical data were obtained from the hospital information system of PUMCH.

Results: : (1) The average body mass index(BMI) of all patients at baseline was 20.3 ± 3.7kg/m. Twenty-three patients underwent 3hOGTT, of whom three were diagnosed with diabetes mellitus, and one with impaired glucose tolerance (IGT). Positive correlation between the ratio of progesterone to upper limit of normal range (P times) and hyperglycaemia was exist(r=0.707, P=0.005). (2) In 19 NGT patients, the insulin concentrations at 0 minute, results of the homeostasis model assessment for β-cell function and insulin resistance were lower in the hypokalaemia group than in the normal kalemia group(7.0(5.8-13.2) 12.4(8.9-14.9) μIU/ml, P=0.017; 115.5(88.2-240.9) 253.1(177.2-305.8), P=0.048; 1.54(1.17-2.61) 2.47(1.91-2.98), P=0.022, respectively). : Four patients had IGT, while seven patients had diabetes mellitus. Of the 19 patients,11 had hyperglycaemia. P times was significantly higher(7.6(5.0-11.0) 3.75(2.2-5.3), P=0.008) in hyperglycemia group than in the normal glucose group.

Conclusions: Abnormal glucose metabolism was common in 17OHD patients, which was possibly associated with hypokalaemia and high progesterone levels. Routine monitoring on glucose metabolism in 17OHD patient should be conducted.
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http://dx.doi.org/10.3389/fendo.2022.917420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354396PMC
August 2022

A Self-Powered Optogenetic System for Implantable Blood Glucose Control.

Research (Wash D C) 2022 16;2022:9864734. Epub 2022 Jun 16.

Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.

Diabetes treatment and rehabilitation are usually a lifetime process. Optogenetic engineered designer cell-therapy holds great promise in regulating blood glucose homeostasis. However, portable, sustainable, and long-term energy supplementation has previously presented a challenge for the use of optogenetic stimulation . Herein, we purpose a self-powered optogenetic system (SOS) for implantable blood glucose control. The SOS consists of a biocompatible far-red light (FRL) source, FRL-triggered transgene-expressing cells, a power management unit, and a flexible implantable piezoelectric nanogenerator (i-PENG) to supply long-term energy by converting biomechanical energy into electricity. Our results show that this system can harvest energy from body movement and power the FRL source, which then significantly enhanced production of a short variant of human glucagon-like peptide 1 (shGLP-1) and . Indeed, diabetic mice equipped with the SOS showed rapid restoration of blood glucose homeostasis, improved glucose, and insulin tolerance. Our results suggest that the SOS is sufficiently effective in self-powering the modulation of therapeutic outputs to control glucose homeostasis and, furthermore, present a new strategy for providing energy in optogenetic-based cell therapy.
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http://dx.doi.org/10.34133/2022/9864734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9275083PMC
June 2022

Electronegativity Enhanced Strong Metal-Support Interaction in [email protected] for Enhanced Alkaline Hydrogen Evolution.

ACS Appl Mater Interfaces 2022 Aug 5. Epub 2022 Aug 5.

School of Physics, Harbin Institute of Technology, Harbin 150001, China.

Precious metals (Pt, Ir, Ru, and so on) and related compounds usually demonstrate superb catalytic activity for electrochemical hydrogen production. However, scarcity and stability are still challenges for hydrogen evolution reaction, even for single-atomic-site electrocatalysts. Herein, a fluorine (F) doping strategy is proposed to enhance the strong metal-support interaction between the F-doped NiN support and the loaded ruthenium (Ru) species. Via synergistically modulating both the Ru loading amount and F doping concentration, outstanding HER activity was achieved in [email protected] with an overpotential (η) of 115 mV at 100 mA cm, superior to the benchmark Pt/C (η = 201 mV). Density functional theory simulation in combination with X-ray photoelectron spectra and X-ray absorption spectroscopy characterizations convincingly demonstrate that, with the strongest electronegativity, F doping could effectively stabilize Ru atoms doped in the F-NiN substrate and simultaneously reduce the H bonding strength, which accelerated the desorption of H. These findings provide a facile strategy to modulate both catalytic activities and stabilities of heteroatom-loaded catalytic materials.
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http://dx.doi.org/10.1021/acsami.2c09507DOI Listing
August 2022

Correction: Functional drug carriers formed by RGD-modified β-CD-HPG for the delivery of docetaxel for targeted inhibition of nasopharyngeal carcinoma cells.

RSC Adv 2022 Jun 1;12(30):19317. Epub 2022 Jul 1.

Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences Guangzhou Guangdong 510080 China

[This corrects the article DOI: 10.1039/D2RA02301F.].
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http://dx.doi.org/10.1039/d2ra90065cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9248366PMC
June 2022

Computed Tomography Three-Dimensional Reconstruction Algorithm in the Diagnosis of Periodontitis and Its Correlation with Hypertension.

Comput Math Methods Med 2022 1;2022:1880178. Epub 2022 Jul 1.

Department of Stomatology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China.

This study was aimed at exploring the value of iterative reconstruction (IR) algorithm to treat the periodontitis using computed tomography (CT) image and analyze the relationship between periodontitis and hypertension. 95 patients with periodontitis were selected, including 43 patients with periodontitis, 41 patients with advanced periodontitis and hypertension, and 11 patients with periodontitis and nonhigh blood pressure (NBP). The IR algorithm was introduced to the CT image scanning of them to reduce the noise. In addition, the CT value was statistically analyzed. High-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) were dramatically increased compared with periodontitis patients with NBP and with hypertension ( < 0.05). After the IR algorithm of the image, the quality, information, and mean square error (MSE) of the image were all effectively improved. Image with a 50% dose showed the lowest noise, but the reconstruction algorithm improved the low-contrast resolution. Moderate and severe periodontitis was independently related to hypertension. Inflammatory cytokines were independently related to hypertension of periodontitis patients ( < 0.05). Therefore, it was concluded that the IR algorithm could effectively improve the spatial resolution of the CT image when it was adopted to treat periodontitis and showed a high accuracy rate; the incidence of hypertension in patients with periodontitis was relatively high, and it had a certain relationship with periodontitis; and inflammatory cytokines were related to periodontitis and hypertension of patients.
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http://dx.doi.org/10.1155/2022/1880178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270138PMC
July 2022

Functional drug carriers formed by RGD-modified β-CD-HPG for the delivery of docetaxel for targeted inhibition of nasopharyngeal carcinoma cells.

RSC Adv 2022 Jun 17;12(28):18004-18011. Epub 2022 Jun 17.

Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences Guangzhou Guangdong 510080 China

In this study, a drug delivery system was prepared by grafting the targeting molecule arginine-glycine-aspartic acid (RGD) onto hyperbranched polyglycerol (HPG)-modified β-cyclodextrin (β-CD-HPG) for the targeted inhibition of nasopharyngeal carcinoma (NPC) cells. The obtained β-CD-HPG-RGD with a relatively small size and low surface charge delivered docetaxel (Doc) effectively and displayed a targeting effect to human NPC HNE-1 cells, as confirmed by confocal laser scanning microscopy and flow cytometry. The drug release analysis exhibited the controlled drug release kinetics of the β-CD-HPG-RGD/Doc nanomedicine. β-CD-HPG-RGD/Doc effectively inhibited the proliferation of HNE-1 cells and promoted apoptosis. Moreover, its biocompatibility and was assessed. The results indicate that the β-CD-HPG-RGD/Doc nanomedicine has potential application in NPC targeting therapy.
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http://dx.doi.org/10.1039/d2ra02301fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204710PMC
June 2022

Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials.

BMJ 2022 06 28;377:e068882. Epub 2022 Jun 28.

Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Objective: To examine the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases.

Design: Systematic review and pairwise and network meta-analysis.

Data Sources: PubMed, EMBASE, Web of Science, and CENTRAL from inception until 31 July 2021.

Eligibility Criteria: Randomised controlled trials of adult patients with type 2 diabetes who received dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors compared with placebo or other antidiabetes drugs.

Main Outcome Measures: Composite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases.

Data Extraction And Data Synthesis: Two reviewers independently extracted the data and assessed the quality of the studies. The quality of the evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluations framework (GRADE) approach. The meta-analysis used pooled odds ratios and 95% confidence intervals.

Results: A total of 82 randomised controlled trials with 104 833 participants were included in the pairwise meta-analysis. Compared with placebo or non-incretin drugs, dipeptidyl peptidase-4 inhibitors were significantly associated with an increased risk of the composite of gallbladder or biliary diseases (odds ratio 1.22 (95%confidence interval 1.04 to 1.43); risk difference 11 (2 to 21) more events per 10 000 person years) and cholecystitis (odds ratio 1.43 (1.14 to 1.79); risk difference 15 (5 to 27) more events per 10 000 person years) but not with the risk of cholelithiasis and biliary diseases. The associations tended to be observed in patients with a longer duration of dipeptidyl peptidase-4 inhibitor treatment. In the network meta-analysis of 184 trials, dipeptidyl peptidase-4 inhibitors increased the risk of the composite of gallbladder or biliary diseases and cholecystitis compared with sodium-glucose cotransporter-2 inhibitors but not compared with glucagon-like peptide-1 receptor agonists.

Conclusions: Dipeptidyl peptidase-4 inhibitors increased the risk of cholecystitis in randomised controlled trials, especially with a longer treatment duration, which requires more attention from physicians in clinical practice.

Systematic Review Registration: PROSPERO CRD42021271647.
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http://dx.doi.org/10.1136/bmj-2021-068882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237836PMC
June 2022

Sensorimotor Responses in Post-Stroke Hemiplegic Patients Modulated by Acupuncture at Yanglingquan (GB34): A fMRI Study Using Intersubject Functional Correlation (ISFC) Analysis.

Front Neurol 2022 6;13:900520. Epub 2022 Jun 6.

Department of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.

Motor dysfunction is common in patients with stroke. Acupuncture has become an acceptable alternative method for stroke rehabilitation. Previous studies have shown various functional connectivity changes activated by acupuncture. We introduced intersubject correlation (ISC) and intersubject functional correlation (ISFC) analyses into the functional magnetic resonance imaging (fMRI) for ischemic stroke to seek a common activation and suppression pattern triggered by acupuncture. In this study, 63 ischemic stroke patients with motor dysfunction and 42 normal controls were analyzed. Three functional scans were conducted during the resting state, motor task, and acupuncture at Yanglingquan (GB34) task. Twenty-two sensory, motor, and movement-imagination cortices in the bilateral hemispheres were selected as the region of interest (ROI). We performed ISC and ISFC analyses among these ROIs in three fMRI runs on patients and controls. Subgroup analyses by course or severity were also conducted. The results showed that acupuncture at GB34 triggered ISFC among upper limb motor, upper limb/hand/face, lower limb, tongue/larynx sensory, and movement imagination regions in the patient group. Subgroup ISC and ISFC analyses showed that patients tended to have increasing responses in the early stage of stroke (within 1 month) and decreasing responses afterward (1-3 months). Patients with mild clinical functional damage (NIHSS 2-4) tended to generate more responses acupuncture than those with moderate damage (NIHSS 5-15). Our findings may help understand the clinical effects and modulatory features of acupuncture based on the group-level post-stroke neuroplasticity.
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http://dx.doi.org/10.3389/fneur.2022.900520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208550PMC
June 2022

Trident Molecule with Nanobrush-Nanoparticle-Nanofiber Transition Property Spatially Suppresses Tumor Metastasis.

J Am Chem Soc 2022 07 22;144(26):11897-11910. Epub 2022 Jun 22.

State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China.

Metastasis-induced high mortality of cancers urgently demands new approaches to simultaneously inhibit primary tumor metastasis and distant tumor growth. Herein, by rational design of a trident molecule Nap-Phe-Phe-Lys(SA-CPT)-Lys(SA-HCQ)-Tyr(HPO)-OH (---) with three functional "spears" (i.e., a phosphotyrosine motif for enzymatic self-assembly, camptothecin (CPT) motif for chemotherapy, and hydroxychloroquine (HCQ) motif for autophagy inhibition) and nanobrush-nanoparticle-nanofiber transition property, we propose a novel strategy of intracellular enzymatic nanofiber formation and synergistic autophagy inhibition-enhanced chemotherapy and immunotherapy for spatial suppression of tumor metastasis. Under sequential alkaline phosphatase catalysis and carboxylesterase hydrolysis, --- undergoes nanobrush-nanoparticle-nanofiber transition, accompanied by the releases of CPT and HCQ. The formed intracellular nanofibers effectively inhibit the metastasis and invasion behaviors of cancer cells. Meanwhile, the released CPT and HCQ synergistically induce a prominent therapeutic effect through autophagy inhibition-enhanced chemotherapy. Furthermore, chemotherapy of --- enhances immunogenic cell death, resulting in the activation of toxic T-cells. Finally, a combination of checkpoint blockade therapy and ----mediated chemotherapy elicits systemic antitumor immunity, thereby achieving efficient inhibitions of primary tumors as well as distant tumors in a breast tumor model. Our work offers a simple and feasible strategy for the design of "smart" multifunctional prodrugs to spatially suppress tumor metastasis.
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http://dx.doi.org/10.1021/jacs.2c05743DOI Listing
July 2022

Insulin and liraglutide attenuate brain pathology in diabetic mice by enhancing the Wnt/β-catenin signaling pathway.

Exp Ther Med 2022 Jul 11;24(1):439. Epub 2022 May 11.

Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China.

Insulin and liraglutide have been demonstrated to control blood glucose and exert neuroprotective effects. However, the impact of liraglutide or insulin alone or in combination on brain pathology in type 1 diabetes mellitus (T1DM) and their underlying mechanisms are unclear. In the present study, diabetes mellitus (DM) was induced via intraperitoneal injection of streptozotocin in mice and subsequently mice were treated with insulin, liraglutide, a combination of the two drugs or saline. Changes in body weight and blood glucose were assessed weekly. The pathological changes in the brain tissue and the apoptosis of neurons were assessed using H&E staining and TUNEL staining. The mRNA and protein expression levels of apoptosis-related proteins were detected using reverse transcription-quantitative PCR (RT-qPCR) and western blotting, respectively. Moreover, Ki67 protein expression was analyzed using immunohistochemistry and the mRNA and protein expression levels of Wnt/β-catenin signaling pathway-related proteins were examined using RT-qPCR and western blotting, respectively. The results of the present study suggested that DM mice developed hyperglycemia and weight loss and also exhibited significantly increased neural cell apoptosis and significantly reduced numbers of Ki67-positive cells. Liraglutide significantly decreased blood glucose levels in DM mice, whereas both insulin and the combination of the two drugs failed to control blood glucose well. Insulin, liraglutide and their combination also failed to control body weight well, but significantly attenuated brain pathological changes and activation of the pro-apoptotic proteins Caspase-3 and Bax, which may have resulted in the significant increase in the expression levels of Wnt/β-catenin signaling pathway-associated molecules such as Wnt3a and S9-pGSK-3β. Liraglutide also promoted the protein expression of the neurogenesis marker of Ki67 and the antiapoptotic factor Bcl-2. These results suggested that insulin and liraglutide may improve brain damage via upregulation of the Wnt/β-catenin signaling pathway and could be of therapeutic relevance for improvement of cognitive impairment in patients with DM.
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http://dx.doi.org/10.3892/etm.2022.11366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9185805PMC
July 2022

Influence of Framing Effect on Consumers' Purchase Intention of Artificial Meat-Based on Empirical Analysis of Consumers in Seven Cities.

Front Psychol 2022 2;13:911462. Epub 2022 Jun 2.

Institute for Food Safety Risk Management, Wuxi, China.

Artificial meat is a type of food that has emerged in recent years. It is similar in shape, color, and taste to meat. Its market scale is developing rapidly, and its future development prospect is bright. To explore Chinese consumers' purchasing intention regarding artificial meat products, this study used the framing effect theory to analyze the differences in consumers' purchasing intentions under different information frames based on the survey data of 6,906 consumers from seven cities in China. Hierarchical regression and variance analysis explored the moderating effects of consumers' product knowledge level and health motivation on the frame effect. The results show that consumers' purchase intention under the positive information frame is significantly higher than that under the negative information frame. Consumers with higher product knowledge levels have higher purchase intention under the positive information frame, whereas consumers with lower health motivation have lower purchase intention under the two information frames. The government and relevant enterprises should focus on promoting positive information about artificial meat products, improving consumers' cognition level of artificial meat products, guiding consumers to form a scientific diet concept to enhance their purchase intention of artificial meat products, and promoting the healthy development of the artificial meat industry.
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http://dx.doi.org/10.3389/fpsyg.2022.911462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201214PMC
June 2022

Clinical Characteristics of Hospitalized Pediatric Patients With Hypertensive Crisis-A Retrospective, Single-Center Study in China.

Front Cardiovasc Med 2022 31;9:891804. Epub 2022 May 31.

Department of Paediatric Cardiology, Heart Centre, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Background: A hypertensive crisis is a medical emergency that causes acute damage to multiple organs. However, the etiology, clinical features, and prognosis of hypertensive crisis in Chinese children remain relatively unknown. The purpose of this study was to analyze the clinical characteristics of pediatric hypertensive crisis patients from a single center in China.

Methods: We analyzed data from 70 children with hypertensive crisis between January, 2000, and January, 2022. The patients were divided into two groups: those diagnosed with a hypertensive emergency ( = 46) and those diagnosed with hypertensive urgency ( = 24). Baseline etiologies and risk factors were compared between the two groups. The following data were collected and analyzed: age, sex, weight, height, family history of hypertension, blood pressure, clinical manifestations of hypertensive crisis, underlying causes, biochemical indicators, and antihypertensive drugs.

Results: The major symptoms of hypertensive crisis were headache ( = 31, 44.29%), followed by visual symptoms ( = 15, 21.43%), and dizziness ( = 13, 18.57%). Further analysis showed that the incidence of convulsions was significantly higher in patients with hypertensive emergency than those with hypertensive urgency (χ = 5.38, = 0.02). The leading underlying causes were renal disease ( = 34, 48.57%), followed by vascular disease ( = 11, 15.71%), essential hypertension ( = 9, 12.86%), oncological disease ( = 9, 12.86%), central nervous system disease ( = 3, 4.29%), endocrine and metabolic diseases ( = 2, 2.86%), and other (one case with lead poisoning, one case with histiocytosis). End-organ damage occurred in 46 patients with hypertensive crisis, including retinal damage ( = 20, 43.48%), brain damage ( = 19, 41.30%), heart damage ( = 15, 32.61%), and renal damage ( = 3, 6.52%). Hypertensive crisis was most common among children aged 7-12 years. Among children aged 13-18 years, hypertensive urgency was more common than hypertensive emergency. The incidence of dyslipidemia, elevated serum creatinine, and elevated uric acid did not differ significantly between the two groups. Most patients with hypertensive crisis need combined antihypertensive therapy ( = 60, 85.71%). There were no cases of mortality.

Conclusions: Hypertensive crisis is caused by secondary diseases, especially renal disease and vascular disease, in the majority of pediatric patients. Combination therapy with antihypertensive agents and treatment of secondary etiology results in a good prognosis.
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http://dx.doi.org/10.3389/fcvm.2022.891804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9193964PMC
May 2022

Localized Myocardial Anti-Inflammatory Effects of Temperature-Sensitive Budesonide Nanoparticles during Radiofrequency Catheter Ablation.

Research (Wash D C) 2022 31;2022:9816234. Epub 2022 May 31.

Beijing Key Laboratory of Micro-Nano Energy and Sensor, Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences, Beijing 101400, China.

Radiofrequency (RF) catheter ablation has emerged as an effective alternative for the treatment of atrial fibrillation (AF), but ablation lesions will result in swelling and hematoma of local surrounding tissue, triggering inflammatory cell infiltration and increased release of inflammatory cytokines. Some studies have shown that the inflammatory response may be related to the early occurrence of AF. The most direct way to inhibit perioperative inflammation is to use anti-inflammatory drugs such as glucocorticoids. Here, we prepared polylactic-co-glycolic acid (PLGA) nanoparticles loaded with budesonide (BUD) and delivered them through irrigation of saline during the onset of ablation. Local high temperature promoted local rupture of PLGA nanoparticles, releasing BUD, and produced a timely and effective local myocardial anti-inflammatory effect, resulting in the reduction of acute hematoma and inflammatory cell infiltration and the enhancement of ablation effect. Nanoparticles would also infiltrate into the local myocardium and gradually release BUD ingredients to produce a continuous anti-inflammatory effect in the next few days. This resulted in a decrease in the level of inflammatory cytokine IL-6 and an increase of anti-inflammatory cytokine IL-10. This study explored an extraordinary drug delivery strategy to reduce ablation-related inflammation, which may prevent early recurrence of AF.
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http://dx.doi.org/10.34133/2022/9816234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9178488PMC
May 2022

Analysis of 55 patients with multiple endocrine neoplasia type 1-associated insulinoma from a single center in China.

Orphanet J Rare Dis 2022 06 13;17(1):219. Epub 2022 Jun 13.

Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China.

Objective: To investigate the clinical characteristics of patients with multiple endocrine neoplasia type 1 (MEN1)-related insulinoma and their relationship with specific biochemical changes and to summarize the features of treatment options for the Chinese population with this disease and the impact on long-term prognosis.

Methods: "MEN1" and "insulinoma" were used when searching the Peking Union Medical College Hospital (PUMCH) medical record retrieval system to obtain clinical information about patients. We identified patients diagnosed with MEN1-associated insulinoma based on endocrinological, radiological, and pathological examinations, and subsequently analyzed their clinical data.

Results: A total of 55 patients with MEN1-associated insulinoma were included, including 29 (52.7%) men and 26 (47.3%) women. The parathyroid gland was the most commonly affected (78.2%), followed by the pituitary gland (69.1%) and adrenal gland (16.4%). Insulinoma was the first manifestation of MEN1 in at least 23.6% (13/55) of patients. Nineteen (34.5%) patients presented with initial symptoms of hypoglycemia before the age of 22 years. Among the 24 Patients with high serum calcium (Ca) had significantly lower serum insulin levels than those with normal serum Ca levels (p < 0.001) during hypoglycemic episodes. However, serum C-peptide level at 0.5 h and serum insulin level at 1 h was higher in patients with hypercalcemia than in patients with normal serum Ca levels in the oral glucose tolerance test (OGTT), although the differences were not statistically significant. Multifocal pancreatic neuroendocrine tumors (pNETs) were present in 38 (69.1%) patients; most of them (55.6%, 20/36) underwent multiple enucleations, and 45% (9/20) had a postoperative recurrence. Five patients (10%) who underwent distal pancreatectomy developed pancreatic insufficiency after an average of seven years. patients who underwent genetic testing, 23 (95.8%) were positive for MEN1 mutation, with mutations most commonly found in exons 2 (21.7%) and 3 (13%).

Conclusions: In our study, the rates of postoperative recurrence and long-term complications in patients with MEN1 with multifocal pNETs were significantly different from those in other international centers and might be related to the choice of surgical method. In addition, elevated serum Ca levels in patients with primary hyperparathyroidism may affect insulin secretion.
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http://dx.doi.org/10.1186/s13023-022-02370-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9195405PMC
June 2022

miR-451a targeting IL-6R activates JAK2/STAT3 pathway, thus regulates proliferation and apoptosis of multiple myeloma cells.

J Musculoskelet Neuronal Interact 2022 06;22(2):251-260

Department of Hematology, The Second Affiliated Hospital of Qiqihar Medical College, China.

Objectives: To investigate the effects of miR-451a targeting interleukin-6 (IL-6) on the proliferation and apoptosis of multiple myeloma (MM) cells and its potential mechanism via JAK2/STAT3 pathway.

Methods: mRNA expression of miR-451a and IL-6R in the plasma of patients with MM and normal controls were determined by RT-qPCR. U266 cells were cultured, transfected with miR-451a mimics, the proliferative ability of U266 cells was determined by CCK-8. Potential targets of miR-451a were predicted with the biological software TargetScan, and the direct relationship between miR-451a and the target IL-6R was analyzed by a dual-luciferase reporter assay. U266 cells were stimulated with IL-6R (100 ng/ml), and the proliferative ability and apoptosis rate were determined by CCK-8 and flow cytometry after 48h.

Results: In the plasma of patients with MM, miR-451a expression was low and IL-6R expression was high. miR-451a targeted and negatively regulated IL-6R. Overexpressing miR-451a inhibited the proliferation and promoted the apoptosis of U266 cells. IL-6R acting on U266 cells promoted the proliferation and inhibited the apoptosis of U266 cells. Overexpressing miR-451a inhibited the activation of JAK2/STAT3 pathway and down-regulating miR-451a promoted the activation of JAK2/STAT3 pathway.

Conclusions: miR-451a targeting IL-6R activates JAK2/STAT3 pathway, thus regulates the proliferation and apoptosis in MM cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9186451PMC
June 2022

PEIGel: A biocompatible and injectable scaffold with innate immune adjuvanticity for synergized local immunotherapy.

Mater Today Bio 2022 Jun 18;15:100297. Epub 2022 May 18.

The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, The First Affiliated Hospital, Jinan University, Guangzhou, 510632, PR China.

Intratumoral immunotherapeutic hydrogel administration is emerging as an effective method for inducing a durable and robust antitumor immune response. However, scaffold hydrogels that can synergize with the loaded drugs, thus potentiating therapeutic efficacy, are limited. Here, we report a ternary hydrogel composed of polyvinyl alcohol (PVA), polyethylenimine (PEI)‒a cationic polymer with potential immunoactivation effects, and magnesium ions‒a stimulator of the adaptive immune response, which exhibits an intrinsic immunomodulation function of reversing the immunologically "cold" phenotype of a murine breast tumor to a "hot" phenotype by upregulating PD-L1 expression and promoting M1-like macrophage polarization. PEI hydrogel (PEIGel) encapsulating an immune checkpoint blockade (ICB) inhibitor‒anti-PD-L1 antibody (α-PDL1) exhibits synergistic effects resulting in elimination of primary tumors and remote metastases and prevention of tumor relapse after surgical resection. A preliminary mechanistic study revealed a probably hidden role of PEI in modulating the polyamine metabolism/catabolism of tumors to potentiate the immune adjuvant effect. These results deepen our understanding of the innate immune activation function of PEI and pave the way for harnessing PEI as an immune adjuvant for ICB therapy.
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http://dx.doi.org/10.1016/j.mtbio.2022.100297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9142629PMC
June 2022

The Association Between Oxygenation Status at 24 h After Diagnosis of Pulmonary Acute Respiratory Distress Syndrome and the 30-Day Mortality among Pediatric Oncological Patients.

Front Pediatr 2022 11;10:805264. Epub 2022 May 11.

Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Background: Pediatric oncology patients with acute respiratory distress syndrome (ARDS) secondary to pneumonia are at high risk of mortality. Our aim was to describe the epidemiology of ARDS in this clinical population and to identify the association between the oxygenation status at 24 h after diagnosis and the 30-day mortality rates, stratified by the severity of ARDS.

Methods: This was a retrospective cohort study of 82 pediatric oncology patients, with a median age of 4 years, admitted to our pediatric intensive care unit with a diagnosis of ARDS between 2013 and 2021. Demographic and clinical factors were compared between the survivor ( = 52) and non-survivor ( = 30) groups. Univariate and multivariate Cox proportional hazards regression models were used to determine the association between the oxygenation status at 24 h after diagnosis and the 30-day mortality rates.

Results: The mean airway pressure at ARDS diagnosis, PaO/FiO (P/F) ratio, oxygenation index (OI) value, peak inspiratory pressure, and lactate level at 24 h after ARDS diagnosis, as well as complications (i.e., septicemia and more than two extrapulmonary organ failures) and adjunctive continuous renal replacement therapy, were significant mortality risk factors. After adjusting for other covariates, the oxygenation status P/F ratio (Hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.96-1.00, = 0.043) and OI value (HR = 1.12, 95% CI = 1.02-1.23, = 0.016) at 24 h remained independent mortality risk factors. According to the Kaplan-Meier survival curve, a low P/F ratio (≤ 150) and high OI (>10) were associated with a higher risk of 30-day mortality (50.9 and 52.9%, respectively; both < 0.05).

Conclusion: The P/F ratio and OI value measured at 24 h after ARDS diagnosis can provide a better stratification of patients according to ARDS disease severity to predict the 30-day mortality risk.
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http://dx.doi.org/10.3389/fped.2022.805264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9130705PMC
May 2022

Long-read sequencing unveils high-resolution HPV integration and its oncogenic progression in cervical cancer.

Nat Commun 2022 05 10;13(1):2563. Epub 2022 May 10.

Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Integration of human papillomavirus (HPV) DNA into the human genome is considered as a key event in cervical carcinogenesis. Here, we perform comprehensive characterization of large-range virus-human integration events in 16 HPV16-positive cervical tumors using the Nanopore long-read sequencing technology. Four distinct integration types characterized by the integrated HPV DNA segments are identified with Type B being particularly notable as lacking E6/E7 genes. We further demonstrate that multiple clonal integration events are involved in the use of shared breakpoints, the induction of inter-chromosomal translocations and the formation of extrachromosomal circular virus-human hybrid structures. Combined with the corresponding RNA-seq data, we highlight LINC00290, LINC02500 and LENG9 as potential driver genes in cervical cancer. Finally, we reveal the spatial relationship of HPV integration and its various structural variations as well as their functional consequences in cervical cancer. These findings provide insight into HPV integration and its oncogenic progression in cervical cancer.
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http://dx.doi.org/10.1038/s41467-022-30190-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9091225PMC
May 2022

Maresin 1 improves cognitive decline and ameliorates inflammation and blood-brain barrier damage in rats with chronic cerebral hypoperfusion.

Brain Res 2022 08 6;1788:147936. Epub 2022 May 6.

Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, Hubei 430071, China. Electronic address:

Background: Chronic inflammation and blood-brain barrier destruction are interrelated pathological changes in chronic cerebral hypoperfusion (CCH) that promote vascular cognitive impairment (VCI). Therefore, we discussed the impact of the macrophage mediator in resolving inflammation 1 (Maresin 1) on the CCH-induced cognitive impairment and its underlying mechanisms.

Methods: 66 rats were randomly divided into three groups: Sham (n = 22), 2VO (n = 22), and 2VO + MaR1 (n = 22). Rats in three groups received 2-Vessel Occlusion (2VO) or sham operation and received intrathecal delivery of PBS or MaR1. Hippocampal blood flow and Modified neurological severity scores (mNSS) were used to confirm models' effect. Blood-brain barrier (BBB) damage was assessed by Evans blue (EB) leakage experiments and spectrophotometry, the BBB ultrastructure was observed with a transmission electron microscope (TEM), and the expression of zonula occluden-1 (ZO-1), claudin-5, and matrix metalloproteinases-9 (MMP-9) were detected with Enzyme-Linked Immunosorbent Assay (ELISA). Morris water maze (MWM) was used to assess cognitive function. Tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and nuclear factor-κB (NF-κB) expression were examined by Western blotting (WB) and ELISA. Immunofluorescence was used to detect microglia, astrocytes and oligodendrocytes.

Results: Rats developed obvious cognitive impairment by CCH. BBB showed EB leakage, ultrastructural destruction, degradation of ZO-1, Claudin-5, and up-regulation of MMP-9. Inactivation of oligodendrocytes, activation of microglia and astrocyte and increased expression of NF-κB, TNF-α, and IL-1β has been detected. MaR1 administration significantly reverted these changes.

Conclusion: MaR1 can improve the CCH-induced cognitive impairment. Inflammatory resolution and BBB protection may be the mechanism of MaR1 to prevent CCH-induced cognitive impairment.
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http://dx.doi.org/10.1016/j.brainres.2022.147936DOI Listing
August 2022

ROS Turn Nanoparticle Fluorescence on for Imaging Staphylococcus aureus Infection In Vivo.

Adv Healthc Mater 2022 07 12;11(14):e2200453. Epub 2022 May 12.

State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2 Sipailou Road, Nanjing, 210096, P. R. China.

Direct, noninvasive, and real-time imaging of Staphylococcus aureus (S. aureus) infection is of great value for quick diagnosis of related disease in clinic, but remains challenging. Herein, employing a rationally designed near-infrared fluorescence probe Cys(StB u)-EDA-Thioketal-Lys(Cy5.5)-CBT (TK-CBT) and a CBT-Cys click reaction, the fluorescence-quenched nanoparticles TK-CBT-NPs are facilely prepared. Upon oxidation by the abundant reactive oxygen species in S. aureus-infected macrophages, TK-CBT-NPs are fractured, turning the fluorescence "on" for imaging infections in vitro and in vivo. Specifically, TK-CBT-NPs show a 6.1-fold fluorescence imaging signal enhancement of the macrophages that are infected by S. aureus for 20 h in vitro. At 4 h postinjection, TK-CBT-NPs show a 2.8-fold fluorescence imaging signal enhancement of the sites in mice that are infected by S. aureus for 24 h. It is anticipated that TK-CBT-NPs could be applied for diagnosis of S. aureus infections in clinic in the near future.
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http://dx.doi.org/10.1002/adhm.202200453DOI Listing
July 2022

In vivo imaging of astrocytes in the whole brain with engineered AAVs and diffusion-weighted magnetic resonance imaging.

Mol Psychiatry 2022 Apr 28. Epub 2022 Apr 28.

Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, 430071, Wuhan, PR of China.

Astrocytes constitute a major part of the central nervous system and the delineation of their activity patterns is conducive to a better understanding of brain network dynamics. This study aimed to develop a magnetic resonance imaging (MRI)-based method in order to monitor the brain-wide or region-specific astrocytes in live animals. Adeno-associated virus (AAVs) vectors carrying the human glial fibrillary acidic protein (GFAP) promoter driving the EGFP-AQP1 (Aquaporin-1, an MRI reporter) fusion gene were employed. The following steps were included: constructing recombinant AAV vectors for astrocyte-specific expression, detecting MRI reporters in cell culture, brain regions, or whole brain following cell transduction, stereotactic injection, or tail vein injection. The astrocytes were detected by both fluorescent imaging and Diffusion-weighted MRI. The novel AAV mutation (Site-directed mutagenesis of surface-exposed tyrosine (Y) residues on the AAV5 capsid) significantly increased fluorescence intensity (p < 0.01) compared with the AAV5 wild type. Transduction of the rAAV2/5 carrying AQP1 induced the titer-dependent changes in MRI contrast in cell cultures (p < 0.05) and caudate-putamen (CPu) in the brain (p < 0.05). Furthermore, the MRI revealed a good brain-wide alignment between AQP1 levels and ADC signals, which increased over time in most of the transduced brain regions. In addition, the rAAV2/PHP.eB serotype efficiently introduced AOP1 expression in the whole brain via tail vein injection. This study provides an MRI-based approach to detect dynamic changes in astrocytes in live animals. The novel in vivo tool could help us to understand the complexity of neuronal and glial networks in different pathophysiological conditions.
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http://dx.doi.org/10.1038/s41380-022-01580-0DOI Listing
April 2022

LINC00022 acts as an oncogene in colorectal cancer progression via sponging miR-375-3p to regulate FOXF1 expression.

BMC Cancer 2022 Apr 26;22(1):453. Epub 2022 Apr 26.

Department of Gastrointestinal Oncology, The Second Hospital of Dalian Medical University, No. 467 Zhongshan Road, Dalian, 116027, Liaoning, China.

Background: Abnormal expression of long non-coding RNAs (lncRNAs) has been shown to be associated with the pathogenesis of cancers, including colorectal cancer (CRC). It has been reported that LINC00022 is highly expressed in some typs of cancer and its overexpression indicates poor prognosis. The function of LINC00022 in CRC progression remains unclear and is mainly investigated in the present study.

Methods: LINC00022 expression in CRC tissues was analyzed by using the TNMplot software. LINC00022 expression in CRC cells was measured by quantitative real-time PCR. The effects of LINC00022 on the malignant behaviors of CRC cells were detected by a series of in vitro and in vivo experiments. Dual-luciferase assays were used to verify the targeting relationship between LINC00022 and miR-375-3p and between miR-375-3p and Forkhead box F1 (FOXF1), followed by the rescue experiment.

Results: LINC00022 was highly expressed in CRC tissues compared with paired para-carcinoma tissues (n = 41). CRC cells with LINC00022 knockdown exhibited decreased cell proliferation, migration, and invasion abilities but increased apoptosis accompanied by decreased protein levels of c-Myc, cyclin D1, cleaved caspase 3, cleaved poly(ADP-ribose) polymerase, matrix metalloproteinase (MMP) 2, and MMP9. Additionally, LINC00022 downregulation in CRC cells suppressed the tube formation of human umbilical vein endothelial cells (HUVECs) as evidenced by decreased vascular endothelial growth factor A levels in LINC00022-silenced cells. The inhibitory effect of LINC00022 knockdown on tumor growth was also observed in an in vivo model. Conversely, LINC00022 overexpression showed that opposite effect. We further demonsrtaed that LINC00022 could upregulate FOXF1 expression through sponging miR-375-3p. Moreover, miR-375-3p knockdown reversed the effects of LINC00022 down-regulation.

Conclusions: LINC00022 may up-regulate FOXF1 expression via competitively binding miR-375-3p, thereby promoting the development of CRC.
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http://dx.doi.org/10.1186/s12885-022-09566-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9040237PMC
April 2022

Lossless Data Hiding in Encrypted Images Compatible With Homomorphic Processing.

IEEE Trans Cybern 2022 Apr 15;PP. Epub 2022 Apr 15.

Reversible data hiding in ciphertext has potential applications for privacy protection and transmitting extra data in a cloud environment. For instance, an original plain-text image can be recovered from the encrypted image generated after data embedding, while the embedded data can be extracted before or after decryption. However, homomorphic processing can hardly be applied to an encrypted image with hidden data to generate the desired image. This is partly due to that the image content may be changed by preprocessing or/and data embedding. Even if the corresponding plain-text pixel values are kept unchanged by lossless data hiding, the hidden data will be destroyed by outer processing. To address this issue, a lossless data hiding method called random element substitution (RES) is proposed for the Paillier cryptosystem by substituting the to-be-hidden bits for the random element of a cipher value. Moreover, the RES method is combined with another preprocessing-free algorithm to generate two schemes for lossless data hiding in encrypted images. With either scheme, a processed image will be obtained after the encrypted image undergoes processing in the homomorphic encrypted domain. Besides retrieving a part of the hidden data without image decryption, the data hidden with the RES method can be extracted after decryption, even after some processing has been conducted on encrypted images. The experimental results show the efficacy and superior performance of the proposed schemes.
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http://dx.doi.org/10.1109/TCYB.2022.3163245DOI Listing
April 2022

Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

JAMA Intern Med 2022 05;182(5):513-519

Department of Endocrinology, Key Laboratory of Endocrinology of the National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Importance: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial.

Objective: To evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations.

Data Sources: MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions.

Study Selection: Randomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non-GLP-1 RA drugs in adults.

Data Extraction And Synthesis: Two reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework.

Main Outcomes And Measures: The primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021.

Results: A total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P  = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P  = .03 for interaction).

Conclusions And Relevance: This systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.

Trial Registration: PROSPERO Identifier: CRD42021271599.
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http://dx.doi.org/10.1001/jamainternmed.2022.0338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961394PMC
May 2022

Comparative study of DHEA and letrozole induced polycystic ovary syndrome in post-pubertal rats.

Gynecol Endocrinol 2022 May 21;38(5):425-431. Epub 2022 Mar 21.

Department of Pharmacy, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Aim: In order to select a suitable rat model for studying polycystic ovary syndrome (PCOS).

Methods: Post-pubertal Sprague Dawley (SD) rats were allocated to four groups, abbreviated as the control 1 group, DHEA subcutaneous injection (DHEA) group, control 2 group, letrozole intragastric injection (letrozole) group. Body weight and the estrous cycle were monitored during the modeling. Serum stress hormones and reproductive hormones were evaluated by ELISA. The uterus and ovaries were weighed, ovarian follicle counts were calculated, and AR, LHR, FSHR, and AMH expression were assessed by immunohistochemistry.

Results: In both model group subjected to the 30-day protocol of DHEA or letrozole, the mean body weights were significantly increased. Rats from both model group exhibited a significant increase of the mean length of the diestrous phase of the estrous cycle, the DHEA group had a longer diestrous phase. There was also a significant increase of serum T, E2, LH, insulin, and a significant decrease of AMH in both model group. There was a significant decrease of ovarian weight, P, and serum FSH, and a significant increase of uterus weight, serum LH/FSH in DHEA model group. There was no significant difference in serum P, FSH, and LH/FSH in letrozole model group. Both two model groups showed significantly higher AR, LHR, and AMH protein expression in rats' ovaries. FSHR protein expression in DHEA group was lower, and in letrozole model group was not different.

Conclusion: Compared with letrozole intragastric injection group, the pathological characteristics of DHEA subcutaneous injection group rats were closer to the characteristics of PCOS.
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http://dx.doi.org/10.1080/09513590.2022.2052843DOI Listing
May 2022

Effects of prenatal exposure to pyrethroid pesticides on neurodevelopment of 1-year- old children: A birth cohort study in China.

Ecotoxicol Environ Saf 2022 Mar 12;234:113384. Epub 2022 Mar 12.

School of Public Health, Kunming Medical University, Kunming, Yunnan, China. Electronic address:

Pregnant women have been ubiquitously exposed to pyrethroid pesticides. Previous studies, mainly based on third trimester measurements of maternal urinary pyrethroid metabolites, have reported inconsistent findings in the effects of prenatal pyrethroid exposure on children's neurodevelopmental outcomes. The purpose of this study was to clarify if pyrethroid exposure during the entire three trimesters of pregnancy may be associated with deleterious effects on infant neurodevelopmental status, particularly at a high dosage of exposure. We measured maternal urinary concentrations of pyrethroid metabolites in all trimesters of pregnancy and assessed children's neurodevelopment at one year of age using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Multiple linear regression models were used to estimate the effects of metabolites (3-PBA, 4 F-3-PBA, cis-DBCA) in each trimester on BSID-III composite scores. Logistic regression analyses were applied to predict developmental delay vs non-delayed status (cut-off composite score of below 80 for developmental delay) based on the maternal levels of pyrethroid metabolites. In the first, second and third trimesters of pregnancy, the detection rates of pyrethroid metabolites were 94.7%, 90.7%, and 89.0%; the 50th percentiles of exposure level were 0.24 μg/g, 0.24 μg/g and 0.21 μg/g for 3-PBA, 0.14 μg/g, 0.17 μg/g and 0.15 μg/g for 4 F-3PBA, 0.21 μg/g, 0.25 μg/g and 0.19 μg/g for cis-DBCA respectively. In the second trimester, 3-PBA was inversely associated with Cognition and Language scores [β = -3.34 (95% CI = -6.11, -0.57) and β = -2.90 (95% CI = -5.20, -0.61), respectively], and significantly increased the risk of Cognition and Language developmental delay [OR= 1.64 (95% CI = 1.03, 2.62) and OR = 1.52 (95% CI = 1.06, 2.19), respectively]; cis-DBCA was inversely associated with Adaptive Behavior scores [β = -0.73 (95% CI = -1.27, -0.19)], and significantly increased the risk of Adaptive Behavior developmental delay [OR= 1.11 (95% CI = 1.02, 1.21)]. When the maternal levels of pyrethroid metabolites were stratified into the regression models according to the 90th percentile of exposure, in the first trimester, Cognition and Motor scores were inversely associated with higher cis-DBCA [β = -7.19 (95% CI = -12.97, -1.41) and β = -8.20 (95% CI = -13.35, -3.05), respectively], Language scores were inversely associated with higher 3-PBA [β = -6.01 (95% CI = -10.96, -1.06)]; in the second trimester, Cognition scores were inversely associated with higher cis-DBCA [β = -6.64 (95% CI = -12.51, -0.76)], Language scores were inversely associated with higher 3-PBA [β = -5.17 (95% CI = -10.07, -0.27)] and cis-DBCA [β = -5.40 (95% CI = -10.28, -0.52)]. We concluded that pyrethroid exposure in the first and second trimesters was associated with poorer infants neurodevelopmental outcomes at one year of age, and these effects were particularly pronounced at high levels of pyrethroid exposure.
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http://dx.doi.org/10.1016/j.ecoenv.2022.113384DOI Listing
March 2022

The Role of Lactate Exercise Test and Fasting Plasma C-Peptide Levels in the Diagnosis of Mitochondrial Diabetes: Analysis of Clinical Characteristics of 12 Patients With Mitochondrial Diabetes in a Single Center With Long-Term Follow-Up.

Front Endocrinol (Lausanne) 2022 21;13:835570. Epub 2022 Feb 21.

Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Objective: The aim of this study was to analyze the clinical characteristics and the pattern of long-term changes of fasting plasma C-peptide in patients with mitochondrial diabetes (MD), and to provide guidance for the diagnosis and treatment of MD.

Methods: We retrieved MD patients with long-term follow-up at Peking Union Medical College Hospital from January 2005 to July 2021 through the medical record retrieval system and retrospectively analyzed their clinical data, biochemical parameters, fasting plasma C-peptide, glycosylated hemoglobin and treatment regimens. Non-parametric receiver operating characteristic (ROC) curves were used to assess the relationship between exercise test-related plasma lactate levels and suffering from MD.

Results: A total of 12 MD patients were included, with clinical characteristics of early-onset, normal or low body weight, hearing loss, maternal inheritance, and negative islet-related autoantibodies. In addition, patients with MD exhibited significantly higher mean plasma lactate levels immediately after exercise compared to patients with type 1 diabetes mellitus (T1DM) (8.39 ± 2.75 vs. 3.53 ± 1.47 mmol/L, p=0.003) and delayed recovery time after exercise (6.02 ± 2.65 vs. 2.17 ± 1.27 mmol/L, p=0.011). The optimal cut-off points identified were 5.5 and 3.4 mmol/L for plasma lactate levels immediately after and 30 minutes after exercise, respectively. The fasting plasma C-peptide levels decreased as a negative exponential function with disease progression (Y= 1.343*e, R = 0.4154). Treatment regimens in MD patients were varied, with no metformin users and a weak correlation between insulin dosage and body weight.

Conclusions: The increased level of plasma lactate during exercise or its delayed recovery after exercise would contribute to the diagnosis of MD. Changes of fasting plasma C-peptide in MD patients over the course of the disease indicated a rapid decline in the early stages, followed by a gradual slowing rate of decline.
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http://dx.doi.org/10.3389/fendo.2022.835570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899008PMC
April 2022

Successful treatment of hemophagocytic syndrome in a patient with T cell lymphoma, EBV infection, and bone marrow necrosis: A case report.

Medicine (Baltimore) 2022 Mar;101(9):e28943

Department of Hematology, Yantai Yuhuangding Hospital Affilliated to Qingdao University, Yantai, China.

Rationale: Hemophagocytic syndrome (HPS) is associated with a high mortality rate, and Epstein-Barr virus infection and hematological malignancies, especially T/natural killer cell lymphomas, are the most common causes; however, due to the complexity of clinical manifestations, the diagnosis is usually delayed. There are few reports of lymphoma-associated HPS (LAPS) in combination with bone marrow necrosis, and there is still no standard treatment for LAPS.

Patient Concerns: A 64-year-old man developed a fever, mild jaundice, fatigue, and bone pain. Positron emission tomography and bone marrow biopsy with immunohistochemistry were performed.

Diagnosis: Imaging analysis and bone marrow examinations were compatible with HPS, T-cell lymphoma, and bone marrow necrosis.

Interventions: The patient received combination therapy of rituximab and Cyclophosphamide, epirubicin, vincristine, glucocorticoid, etoposide.

Outcomes: The patient achieved complete remission and a disease-free survival of 52 months.

Lessons: HPS and its potential diseases should be diagnosed and treated as soon as possible. Clinicians should be aware of the presence of lymphoma in patients with HPS. Rituximab plays an important role in the prognosis of HPS, particularly Epstein-Barr virus positivity. Cyclophosphamide, epirubicin, vincristine, glucocorticoid remains an effective regimen for the treatment of T-cell LAPS. This study provides a better understanding of the diagnosis and treatment of LAPS.
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http://dx.doi.org/10.1097/MD.0000000000028943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8896522PMC
March 2022
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