Publications by authors named "Yanling Zhang"

416 Publications

Distinct Polarization Dynamics of Microglia and Infiltrating Macrophages: A Novel Mechanism of Spinal Cord Ischemia/Reperfusion Injury.

J Inflamm Res 2021 13;14:5227-5239. Epub 2021 Oct 13.

Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.

Purpose: Recent studies indicate that microglia and monocyte-derived macrophages (MDMs) have different roles in diseases such as stroke and spinal cord injury, yet their respective polarized phenotypes and roles remain unclear in spinal cord ischemia/reperfusion injury (SCIRI).

Methods: We established a mouse model of SCIRI by transient aortic occlusion followed by reperfusion. Basso mouse scale (BMS) scores were used to test the locomotor functions. The histopathological changes in spinal cord were assessed by hematoxylin-eosin staining and NF-200 immunohistochemistry. Real-time PCR, immunofluorescence and flow cytometry were employed to analyze the polarized phenotypes of the microglia and infiltrating MDMs, and the resulting inflammatory responses. Furthermore, the role of infiltrating MDMs were investigated by MDMs depletion using systemic administration of clodronate-liposomes.

Results: SCIRI significantly impaired locomotor function of mice, accompanied with progressed necrosis, infiltration of inflammatory cells and neuron loss in the spinal cord. M1-related pro-inflammatory markers (iNOS, CD16, CD86 and TNF-α) increased dramatically in the early phase following SCIRI. In contrast, M2-related anti-inflammatory markers (CD204 and CD206) elevated at later stage. Besides, the invading MDMs were principally pro-inflammatory M1 type, transiently restricted to the first week after SCIRI. In contrast, microglia were the main source of anti-inflammatory M2 type. Furthermore, depletion of MDMs by clodronate-liposomes significantly preserved neurological functions and relieved neuronal damage caused by SCIRI.

Conclusion: These findings suggested distinct polarized status of resident microglia and MDMs following SCIRI. Inhibition of the invading MDMs may represent a novel approach for SCIRI treatment.
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http://dx.doi.org/10.2147/JIR.S335382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521441PMC
October 2021

Circ_0075804 promotes the malignant behaviors of retinoblastoma cells by binding to miR-138-5p to induce PEG10 expression.

Int Ophthalmol 2021 Oct 11. Epub 2021 Oct 11.

Department of Ophthalmology, Shenzhen Longhua District Maternity & Child Healthcare Hospital, Shenzhen, Guangdong Province, China.

Background: It has been gradually recognized that circular RNAs (circRNAs) are important modulators in multiple malignancies. Here, we analyzed the function of circ_0075804 and explored its associated mechanism in regulating retinoblastoma (RB) progression.

Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were utilized to measure RNA and protein expression, respectively. Cell proliferation was analyzed by Cell counting kit-8 (CCK8) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay. Cell apoptosis was assessed by flow cytometry. Cell migration and invasion abilities were analyzed by wound healing assay and transwell invasion assay. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were applied to verify intermolecular target relations. Xenograft tumor model was used to analyze the role of circ_0075804 in tumor growth in vivo.

Results: Circ_0075804 expression was markedly up-regulated in RB tissues and cell lines. Circ_0075804 knockdown restrained the proliferation, migration and invasion whereas promoted the apoptosis of RB cells. Circ_0075804 acted as a molecular sponge for microRNA-138-5p (miR-138-5p), and circ_0075804 silencing-induced effects were partly reversed by miR-138-5p knockdown in RB cells. MiR-138-5p interacted with the 3' untranslated region (3'UTR) of paternally expressed 10 (PEG10). Circ_0075804 positively regulated PEG10 level by sponging miR-138-5p in RB cells. PEG10 overexpression largely overturned miR-138-5p overexpression-mediated effects in RB cells. Circ_0075804 knockdown blocked xenograft tumor growth in vivo.

Conclusion: Circ_0075804 promoted RB progression via miR-138-5p-dependent regulation of PEG10, which provided new insight in RB therapy.
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http://dx.doi.org/10.1007/s10792-021-02067-7DOI Listing
October 2021

TREM-1 amplifies trophoblastic inflammation via activating NF-κB pathway during preeclampsia.

Placenta 2021 Sep 24;115:97-105. Epub 2021 Sep 24.

Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. Electronic address:

Introduction: Excessive activation of maternal systemic inflammation is one of the underlying causes of pathology during the disease course of preeclampsia (PE). The triggering receptor expressed on myeloid cells-1 (TREM-1) participates in the development and persistence of inflammation. We hypothesized that dysregulated TREM-1 may be involved in the pathogenesis of PE by promoting the secretion of trophoblastic pro-inflammatory cytokines that augment inflammation.

Methods: The localization of TREM-1 in placenta and the extravillous trophoblast cell line (TEV-1) was determined by immunohistochemical staining. The expression level of TREM-1 and pro-inflammatory cytokines in placentas were compared between normal pregnancies and PE. We used lipopolysaccharide (LPS) to simulate trophoblastic inflammation. TEV-1 cells were transfected with TREM-1 plasmid and si-TREM-1 respectively, and then were incubated with LPS. The expression levels of pro-inflammatory cytokines and key molecules featured in nuclear transcription factor-kappaB (NF-κB) pathway were detected. Transwell assays were used to detect the effects of TREM-1 on cell migration and invasion.

Results: TREM-1 was localized on both villous trophoblasts (VTs) and extravillous trophoblasts (EVTs). TREM-1 and pro-inflammatory cytokines were up-regulated in preeclamptic placenta. Overexpression of TREM-1 promoted the activation of NF-κB pathway and the release of pro-inflammatory factors induced by LPS, and enhanced migration and invasion of TEV-1 cells. Inhibition of TREM-1 significantly attenuated LPS-induced effects and suppressed migration and invasion.

Discussion: This study suggested that TREM-1 was up-regulated in PE, and may promote the production of downstream inflammatory factors by activating NF-κB pathway in trophoblastic cells, thus exerting pro-inflammatory effects in the pathogenesis of PE.
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http://dx.doi.org/10.1016/j.placenta.2021.09.016DOI Listing
September 2021

Dual-Light-Triggered In Situ Structure and Function Regulation of Injectable Hydrogels for High-Efficient Anti-Infective Wound Therapy.

Adv Healthc Mater 2021 Sep 26:e2101722. Epub 2021 Sep 26.

College of Chemistry and Chemical Engineering Engineering Research Center of Dairy Quality and Safety Control Technology, Ministry of Education, Inner Mongolia University, 235 University West Street, Hohhot, 010021, China.

Most injectable hydrogels used in biomedical engineering have unsatisfactory and untunable mechanical properties, making it difficult to match them with the mechanical strengths of different tissues and organs, which can cause a series of adverse consequences such as immune rejection and soft tissue contusion. In this contribution, dopamine-modified hyaluronic acid (HA-DA) is developed as the backbone for an injectable hydrogel using a catechol-Fe coordination crosslinking strategy. Due to dynamic physical crosslinking, the hydrogel can be easily injected through a single syringe. Into the hydrogel, black phosphorous nanosheets loaded with a Zr-based porphyrinic metal-organic framework ([email protected]) are introduced that could generate reactive oxygen species (ROS) under 660 nm laser irradiation, this promotes the oxidative coupling of dopamine in the presence of the ROS, introducing in situ chemical crosslinking into the hydrogel. A physical/chemical double-crosslinked hydrogel is obtained, effectively improving the hydrogel's mechanical properties, which are tuned in situ by adjusting the irradiation time to match the mechanical modulus of different biological tissues. Combining the excellent photothermal properties and photodynamic performance of the [email protected] nanosheets yields effective sterilization under mild conditions (below 50 °C, low ROS production). The results show that this hydrogel is an excellent multifunctional wound dressing.
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http://dx.doi.org/10.1002/adhm.202101722DOI Listing
September 2021

Oxidative stress and EROD activity in Caco-2 cells upon exposure to chlorinated hydrophobic organic compounds from drinking water reservoirs.

Sci Total Environ 2021 Aug 30;804:150015. Epub 2021 Aug 30.

School of Resources and Environment, University of Electronic Science and Technology of China, Chengdu 611731, China.

Our previous studies showed hydrophobic organic compounds (HOCs) in the sediments of drinking water reservoirs caused DNA damage in human cells (Caco-2) after chlorination. However, the main mechanisms remained unclear. This study compared oxidative damage and EROD activity in Caco-2 cells upon exposure to chlorinated HOCs, and the role of antioxidants (catalase, vitamin C and epigallocatechin gallate (EGCG)) in reducing the toxicities was examined. The result showed that chlorinated HOCs induced a 4-fold increase in production of reactive oxygen species (ROS) compared with HOCs. Antioxidants supplement significantly reduced ROS yields and DNA peroxidation. HOCs with relatively higher TEQ were greatly reduced (about 98%) after chlorination, indicating dioxin-like toxicity is not the main factor inducing oxidative damage by chlorinated HOCs. Yet, ROS and the associated oxidative damage seem to be more responsible for causing DNA damage in the cells. Antioxidants including catalase, Vitamin C and EGCG showed protective effect against chlorination.
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http://dx.doi.org/10.1016/j.scitotenv.2021.150015DOI Listing
August 2021

Polystyrene nanoplastics exacerbated the ecotoxicological and potential carcinogenic effects of tetracycline in juvenile grass carp (Ctenopharyngodon idella).

Sci Total Environ 2021 Aug 30;803:150027. Epub 2021 Aug 30.

College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), 528478, China; Institute of Eco-Environmental Research, Guangxi Key Laboratory of Marine Natural Products and Combinatorial Biosynthesis Chemistry, Biophysical and Environmental Science Research Center, Guangxi Academy of Sciences, Nanning 530007, China. Electronic address:

This study aims to evaluate the ecotoxicity effects of single tetracycline (TC) exposure and mixture exposure in presence of polystyrene nanoplastics (PS-NPs, 80 nm) on juvenile Ctenopharyngodon idella. We carried out single and combined exposure of TC (5000 μg/L) and PS-NPs (20, 200, 2000 μg/L) for 7 days. Compared to TC single exposure, co-exposure to PS-NPs and TC significantly changed the levels of antioxidant entities, including T-AOC, SOD, and CAT in the liver and intestine of C. idella, indicating that PS-NPs might enhance the oxidative damage caused by TC. Further, the co-exposure significantly upregulated the mRNA expression levels of MMP2, MMP9, and IL-8 in a concentration-dependent manner in the liver and intestine tissues of C. idella, compared to the control and TC single exposure groups. Moreover, the phylogenetic tree showed that MMP2 and MMP9 in C. idella are relatively conservative, and the mRNA expressions of MMP2 are significantly positively correlated with TGFβ1, IL8, and MMP9 in Liver hepatocellular carcinoma (LIHC) and Colon adenocarcinoma (COAD). The above genes in LIHC and COAD were significantly correlated with various immune cells. Further, histopathological analysis revealed tissue lesions in the intestine and gill of fish in all the exposed groups, compared to the control group. In short, the present study illustrated that the toxicological effects of organic pollutants such as TC could be influenced by the presence of NPs in the C. idella.
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http://dx.doi.org/10.1016/j.scitotenv.2021.150027DOI Listing
August 2021

Current Understanding of Hearing Loss in Sporadic Vestibular Schwannomas: A Systematic Review.

Front Oncol 2021 12;11:687201. Epub 2021 Aug 12.

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

Objective: Hearing loss is the most common initial symptom in patients with sporadic vestibular schwannomas (SVS). Hearing preservation is an important goal of both conservative and surgical therapy. However, the mechanism of SVS-associated hearing loss remains unclear. Thus, we performed this systematic review to summarize the current understanding of hearing loss in the SVS and distill a testable hypothesis to further illuminate its underlying mechanism.

Methods: A systematic review querying four databases (PubMed, Medline, Embase, and Web of Science) was performed to identify studies evaluating hearing loss in patients with SVS and exploring the potential mechanisms of hearing impairment.

Results: A total of 50 articles were eligible and included in this review. After analysis, the retrieved studies could be categorized into four types: (1) 29 studies explore the relationship between hearing loss and the growth pattern of the tumor (e.g., tumor size/volume, growth rate, tumor location, .); (2) ten studies investigate the potential role of cochlear dysfunction in hearing deterioration, including structural abnormality, protein elevation in perilymph, and cochlear malfunctioning; (3) two studies looked into SVS-induced impairment of auditory pathway and cortex; (4) in the rest nine studies, researchers explored the molecular mechanism underlying hearing loss in SVS, which involves molecular and genetic alterations, inflammatory response, growth factors, and other tumor-associated secretions.

Conclusions: Multiple factors may contribute to the hearing impairment in SVS, including the growth pattern of tumor, cochlear dysfunction, impairment of auditory pathway and cortex, genetic and molecular changes. However, our current understanding is still limited, and future studies are needed to explore this multifactorial hypothesis and dig deeper into its underlying mechanism.
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http://dx.doi.org/10.3389/fonc.2021.687201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406761PMC
August 2021

Using a material database and data fusion method to accelerate the process model development of high shear wet granulation.

Sci Rep 2021 08 13;11(1):16514. Epub 2021 Aug 13.

Department of Chinese Medicine Informatics, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No.11, North Third Ring East Road, Beijing, 100029, People's Republic of China.

High shear wet granulation (HSWG) has been wildly used in manufacturing of oral solid dosage (OSD) forms, and process modeling is vital to understanding and controlling this complex process. In this paper, data fusion and multivariate modeling technique were applied to develop a formulation-process-quality model for HSWG process. The HSWG experimental data from both literature and the authors' laboratory were fused into a single and formatted representation. A material database and material matching method were used to compensate the incomplete physical characterization of literature formulation materials, and dimensionless parameters were utilized to reconstruct process variables at different granulator scales. The exploratory study on input materials properties by principal component analysis (PCA) revealed that the formulation data collected from different articles generated a formulation library which was full of diversity. In prediction of the median granule size, the partial least squares (PLS) regression models derived from literature data only and a combination of literature data and laboratory data were compared. The results demonstrated that incorporating a small number of laboratory data into the multivariate calibration model could help significantly reduce the prediction error, especially at low level of liquid to solid ratio. The proposed data fusion methodology was beneficial to scientific development of HSWG formulation and process, with potential advantages of saving both experimental time and cost.
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http://dx.doi.org/10.1038/s41598-021-96097-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363627PMC
August 2021

Current Progress in Natural Deep Eutectic Solvents for the Extraction of Active Components from Plants.

Crit Rev Anal Chem 2021 Jul 29:1-22. Epub 2021 Jul 29.

College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, China.

In the last decade, natural deep eutectic solvents (NADESs) have gained more and more attention due to their green, convenient preparation, low toxicity and biodegradability. It is widely used in various fields, especially in the extraction of active components from plants, formed by the combination of hydrogen bond donors (HBDs) and hydrogen bond acceptors (HBAs) at a certain condition. In this article, six preparation methods of NADESs were summarized and the interactions that occur in the eutectic behavior of NADES including hydrogen bonding, electrostatic interaction and van der Waals force were also reviewed. What is more, its significant extraction capacity on flavonoids, phenols, alkaloids and plant pigments endows its extensive applications in the extraction of active components from medicinal plants. Extraction factors including solvents properties (viscosity, carbon chain length, number of hydroxyl groups), extraction condition (water content, extraction temperature, extraction time, solid-liquid ratio), extraction method and recycling method were discussed. In addition, NADESs can also be combined with other technologies, like molecular imprinting, monolithic column, to achieve efficient and specific extraction of active ingredients. Further systematic studies on the biodegradability and biotoxicity are put forward to be urgent.
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July 2021

Altered Cerebral Blood Flow in Alzheimer's Disease With Depression.

Front Psychiatry 2021 8;12:687739. Epub 2021 Jul 8.

Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Depression is common in Alzheimer's disease (AD) with an unclear neural mechanism. This study aimed to investigate the underlying cerebral perfusion associated with depression in AD and evaluate its clinical significance. Twenty-one AD patients and 21 healthy controls (HCs) were enrolled in this study. The depressive symptom was defined according to the Hamilton Depression Rating Scale (HAMD). Nine patients were diagnosed as AD with depression symptoms (HAMD >7). Three-dimensional pseudocontinuous arterial spin labeling MR imaging was conducted to measure regional cerebral blood flow (CBF). Neuropsychological tests covered cognition and depressive scores. Between-group comparisons on clinical variables and regional CBFs, relationship between regional CBF and depressive score, and identification of AD patients with depression were performed using covariance analysis, linear regression, and receiver operating characteristic (ROC) analysis, respectively. Compared with HCs, AD patients without depression exhibited lower gray matter CBF ( = 0.016); compared with AD patients without depression, AD patients with depression had higher CBF in the right supplementary motor area (39.23 vs. 47.91 ml/100 g/min, = 0.017) and right supramarginal gyrus (35.54 vs. 43.85 ml/100 g/min, = 0.034). CBF in the right supplementary motor area was correlated with depressive score (β = 0.46, = 0.025). The combination of CBF in the right supplementary motor area and supramarginal gyrus and age could identify AD patients with depression from those without depression with a specificity of 100%, sensitivity of 66.67%, accuracy of 85.71%, and area under the curve of 0.87. Our findings suggested that hyperperfusion of the right supplementary motor area and right supramarginal gyrus were associated with depression syndrome in AD, which could provide a potential neuroimaging marker to evaluate the depression state in AD.
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http://dx.doi.org/10.3389/fpsyt.2021.687739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295555PMC
July 2021

Unresponsive thin endometrium caused by Asherman syndrome treated with umbilical cord mesenchymal stem cells on collagen scaffolds: a pilot study.

Stem Cell Res Ther 2021 07 22;12(1):420. Epub 2021 Jul 22.

Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, NO.3 Qingchun East Road, Shangcheng District, Hangzhou, 310016, People's Republic of China.

Background: Unresponsive thin endometrium caused by Asherman syndrome (AS) is the major cause of uterine infertility. However, current therapies are ineffective. This study is to evaluate the effect of transplantation with collagen scaffold/umbilical cord mesenchymal stem cells (CS/UC-MSCs) on this refractory disease.

Methods: Eighteen infertile women with unresponsive thin endometrium, whose frozen-thawed embryo transfers (FETs) were cancelled due to reduced endometrial thickness (ET ≤ 5.5 mm), were enrolled in this before and after self-control prospective study. Hysteroscopic examination was performed to confirm no intrauterine adhesions, then twenty million UC-MSCs loaded onto a CS were transplanted into the uterine cavity in two consecutive menstrual cycles. Then uterine cavity was assessed through hysteroscopy after two transplants. FETs were performed in the following cycle. Pregnancy outcomes were followed up. Endometrial thickness, uterine receptivity and endometrial angiogenesis, proliferation and hormone response were compared before and after treatment.

Results: Sixteen patients completed the study. No treatment-related serious adverse events occurred. Three months after transplantation, the average ET increased from 4.08 ± 0.26 mm to 5.87 ± 0.77 mm (P < 0.001). Three of 15 patients after FET got pregnant, of whom 2 gave birth successfully and 1 had a miscarriage at 25 weeks' gestation. One of 2 patients without FET had a natural pregnancy and gave birth normally after transplantation. Immunohistochemical analysis showed increased micro-vessel density, upregulated expression of Ki67, estrogen receptor alpha, and progesterone receptor, indicating an improvement in endometrial angiogenesis, proliferation, and response to hormones.

Conclusion: CS/UC-MSCs is a promising and potential approach for treating women with unresponsive thin endometrium caused by AS.

Trial Registration: ClinicalTrials.gov NCT03724617 . Registered on 26 October 2018-prospectively registered, https://register.clinicaltrials.gov/.
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http://dx.doi.org/10.1186/s13287-021-02499-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296628PMC
July 2021

TCM-Blast for traditional Chinese medicine genome alignment with integrated resources.

BMC Plant Biol 2021 Jul 17;21(1):339. Epub 2021 Jul 17.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Yangguang South Avenue, Fangshan District, Beijing, 102488, China.

The traditional Chinese medicine (TCM) genome project aims to reveal the genetic information and regulatory network of herbal medicines, and to clarify their molecular mechanisms in the prevention and treatment of human diseases. Moreover, the TCM genome could provide the basis for the discovery of the functional genes of active ingredients in TCM, and for the breeding and improvement of TCM. The traditional Chinese Medicine Basic Local Alignment Search Tool (TCM-Blast) is a web interface for TCM protein and DNA sequence similarity searches. It contains approximately 40G of genome data on TCMs, including protein and DNA sequence for 36 TCMs with high medical value.The development of a publicly accessible TCM genome alignment database hosted on the TCM-Blast website ( http://viroblast.pungentdb.org.cn/TCM-Blast/viroblast.php ) has expanded to query multiple sequence databases to obtain TCM genome data, and provide user-friendly output for easy analysis and browsing of BLAST results. The genome sequencing of TCMs helps to elucidate the biosynthetic pathways of important secondary metabolites and provides an essential resource for gene discovery studies and molecular breeding. The TCMs genome provides a valuable resource for the investigation of novel bioactive compounds and drugs from these TCMs under the guidance of TCM clinical practice. Our database could be expanded to other TCMs after the determination of their genome data.
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http://dx.doi.org/10.1186/s12870-021-03096-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285853PMC
July 2021

Losartan prevents tumor-induced hearing loss and augments radiation efficacy in NF2 schwannoma rodent models.

Sci Transl Med 2021 07;13(602)

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Hearing loss is one of the most common symptoms of neurofibromatosis type 2 (NF2) caused by vestibular schwannomas (VSs). Fibrosis in the VS tumor microenvironment (TME) is associated with hearing loss in patients with NF2. We hypothesized that reducing the fibrosis using losartan, an FDA-approved antihypertensive drug that blocks fibrotic and inflammatory signaling, could improve hearing. Using NF2 mouse models, we found that losartan treatment normalized the TME by (i) reducing neuroinflammatory IL-6/STAT3 signaling and preventing hearing loss, (ii) normalizing tumor vasculature and alleviating neuro-edema, and (iii) increasing oxygen delivery and enhancing efficacy of radiation therapy. In preparation to translate these exciting findings into the clinic, we used patient samples and data and demonstrated that IL-6/STAT3 signaling inversely associated with hearing function, that elevated production of tumor-derived IL-6 was associated with reduced viability of cochlear sensory cells and neurons in ex vivo organotypic cochlear cultures, and that patients receiving angiotensin receptor blockers have no progression in VS-induced hearing loss compared with patients on other or no antihypertensives based on a retrospective analysis of patients with VS and hypertension. Our study provides the rationale and critical data for a prospective clinical trial of losartan in patients with VS.
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http://dx.doi.org/10.1126/scitranslmed.abd4816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409338PMC
July 2021

Impact of sodium glucose linked cotransporter-2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus.

Physiol Rep 2021 06;9(12):e14890

Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.

Background: The mechanisms whereby inhibitors of sodium-glucose linked cotransporter-2 (SGLT2) exert their nephroprotective effects in patients with diabetes are incompletely understood but have been hypothesized to include improved tissue oxygen tension within the renal cortex. The impact of SGLT2 inhibition is likely complex and region specific within the kidney. We hypothesize that SGLT2 inhibitors have differential effects on renal tissue oxygen delivery and consumption in specific regions of the diabetic kidney, including the superficial cortex, containing SGLT2-rich components of proximal tubules, versus the deeper cortex and outer medulla, containing predominantly SGLT1 receptors.

Methods: We measured glomerular filtration rate (GFR), microvascular kidney oxygen tension (P O ), erythropoietin (EPO) mRNA, and reticulocyte count in diabetic rats (streptozotocin) treated with the SGLT2 inhibitor, dapagliflozin. Utilizing phosphorescence quenching by oxygen and an intravascular oxygen sensitive probe (Oxyphor PdG4); we explored the effects of SGLT2 inhibition on P O in a region-specific manner, in vivo, in diabetic and non-diabetic rats. Superficial renal cortical or deeper cortical and outer medullary P O were measured utilizing excitations with blue and red light wavelengths, respectively.

Results: In diabetic rats treated with dapagliflozin, measurement within the superficial cortex (blue light) demonstrated no change in P O . By contrast, measurements in the deeper cortex and outer medulla (red light) demonstrated a significant reduction in P O in dapagliflozin treated diabetic rats (p = 0.014). Consistent with these findings, GFR was decreased, hypoxia-responsive EPO mRNA levels were elevated and reticulocyte counts were increased with SGLT2 inhibition in diabetic rats (p < 0.05 for all).

Conclusions: These findings indicate that microvascular kidney oxygen tension is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of SGLT-2 inhibition on tissue metabolism. This reduction in deeper P O had biological impact as demonstrated by increased renal EPO mRNA levels and circulating reticulocyte count.
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http://dx.doi.org/10.14814/phy2.14890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239445PMC
June 2021

The Goto Kakizaki rat: Impact of age upon changes in cardiac and renal structure, function.

PLoS One 2021 24;16(6):e0252711. Epub 2021 Jun 24.

St. Michael's Hospital, Keenan Research Centre, Li Ka Shing Knowledge Institute, Toronto, Canada.

Background: Patients with diabetes are at a high risk for developing cardiac dysfunction in the absence of coronary artery disease or hypertension, a condition known as diabetic cardiomyopathy. Contributing to heart failure is the presence of diabetic kidney disease. The Goto-Kakizaki (GK) rat is a non-obese, non-hypertensive model of type 2 diabetes that, like humans, shares a susceptibility locus on chromosome 10. Herein, we perform a detailed analysis of cardio-renal remodeling and response to renin angiotensin system blockade in GK rats to ascertain the validity of this model for further insights into disease pathogenesis.

Methods: Study 1: Male GK rats along with age matched Wistar control animals underwent longitudinal assessment of cardiac and renal function for 32 weeks (total age 48 weeks). Animals underwent regular echocardiography every 4 weeks and at sacrifice, early (~24 weeks) and late (~48 weeks) timepoints, along with pressure volume loop analysis. Histological and molecular characteristics were determined using standard techniques. Study 2: the effect of renin angiotensin system (RAS) blockade upon cardiac and renal function was assessed in GK rats. Finally, proteomic studies were conducted in vivo and in vitro to identify novel pathways involved in remodeling responses.

Results: GK rats developed hyperglycaemia by 12 weeks of age (p<0.01 c/w Wistar controls). Echocardiographic assessment of cardiac function demonstrated preserved systolic function by 48 weeks of age. Invasive studies demonstrated left ventricular hypertrophy, pulmonary congestion and impaired diastolic function. Renal function was preserved with evidence of hyperfiltration. Cardiac histological analysis demonstrated myocyte hypertrophy (p<0.05) with evidence of significant interstitial fibrosis (p<0.05). RT qPCR demonstrated activation of the fetal gene program, consistent with cellular hypertrophy. RAS blockade resulted in a reduction blood pressure(P<0.05) cardiac interstitial fibrosis (p<0.05) and activation of fetal gene program. No significant change on either systolic or diastolic function was observed, along with minimal impact upon renal structure or function. Proteomic studies demonstrated significant changes in proteins involved in oxidative phosp4horylation, mitochondrial dysfunction, beta-oxidation, and PI3K/Akt signalling (all p<0.05). Further, similar changes were observed in both LV samples from GK rats and H9C2 cells incubated in high glucose media.

Conclusion: By 48 weeks of age, the diabetic GK rat demonstrates evidence of preserved systolic function and impaired relaxation, along with cardiac hypertrophy, in the presence of hyperfiltration and elevated protein excretion. These findings suggest the GK rat demonstrates some, but not all features of diabetes induced "cardiorenal" syndrome. This has implications for the use of this model to assess preclinical strategies to treat cardiorenal disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252711PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224913PMC
June 2021

Dermal Delivery of Niacinamide-In Vivo Studies.

Pharmaceutics 2021 May 14;13(5). Epub 2021 May 14.

Department of Pharmaceutics, University College London School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.

In vivo human studies are considered to be the "gold standard" when investigating (trans)dermal delivery of actives. Previously, we reported the effects of a range of vehicles on the delivery of niacinamide (NIA) using conventional Franz cell studies. In the present work, dermal delivery of NIA was investigated in vivo in human subjects using confocal Raman spectroscopy (CRS) and tape stripping (TS). The vehicles investigated included propylene glycol (PG), Transcutol P (TC), binary combinations of PG with oleic acid (OA) or linolenic acid (LA) and a ternary system comprising of TC, caprylic/capric triglyceride (CCT) and dimethyl isosorbide (DMI). For the CRS studies, higher area under curve (AUC) values for NIA were observed for the PG:LA binary system compared with PG, TC and TC:CCT:DMI ( < 0.05). A very good correlation was found between the in vitro cumulative permeation of NIA and the AUC values from Raman intensity depth profiles, with a Pearson correlation coefficient (R) of 0.84. In addition, an excellent correlation (R = 0.97) was evident for the signal of the solvent PG and the active. CRS was also shown to discriminate between NIA in solution versus crystalline NIA. The findings confirm that CRS is emerging as a powerful approach for dermatopharmacokinetic studies of both actives and excipients in human.
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http://dx.doi.org/10.3390/pharmaceutics13050726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156363PMC
May 2021

Chemoproteomic profiling of itaconations in .

Chem Sci 2021 Mar 31;12(17):6059-6063. Epub 2021 Mar 31.

Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education China.

Itaconate is an immunoregulatory and anti-bacterial metabolite, and plays important roles in host-pathogen interactions. Chemoproteomic strategies have been used to explore the anti-inflammatory effects of itaconate on activated macrophages and it has been found that many key proteins in immune pathways were modified; however, how itaconate modulates pathogens was not fully understood. Here, we have designed and synthesized a series of itaconate-based bioorthogonal probes, which enable quantitative and site-specific profiling of itaconated proteins and sites in . Among many proteins related to energy metabolism, we identified a key enzyme involved in the glyoxylate cycle, isocitrate lyase (ICL), as the most prominent target. Covalent modification of the active-site cysteine in ICL by itaconate abolishes the enzyme activity and suppresses bacterial growth. Our chemoproteomic study has uncovered the wide array of itaconation targets in and provided a comprehensive resource for understanding the anti-bacterial function of this intriguing metabolite.
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http://dx.doi.org/10.1039/d1sc00660fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098682PMC
March 2021

Improved delivery system for celastrol-loaded magnetic FeO/α-FeO heterogeneous nanorods: HIF-1α-related apoptotic effects on SMMC-7721 cell.

Mater Sci Eng C Mater Biol Appl 2021 Jun 17;125:112103. Epub 2021 Apr 17.

Affiliated Kunshan Hospital, Jiangsu University, Suzhou 215300, PR China. Electronic address:

FeO/α-FeO heterogeneous nanorods were prepared by a rapid combustion method with α-FeOOH nanorods as precursors. FeO/α-FeO heterogeneous nanorods with a saturation magnetization of 33.2 emu·g were obtained using 30 mL of absolute ethanol at a calcination temperature of 300 °C. Their average length was around 140 nm, and average diameter was about 20 nm. To improve the dispersion characteristics of the FeO/α-FeO heterogeneous nanorods in aqueous solution, citric acid and PEG were applied to modify the nanorod surface via the Mitsunobu reaction. The results showed that the hydrodynamic size range of FeO/α-FeO/CA-PEG-celastrol was 250-500 nm, the surface potential was -15 mV, and the saturation magnetization was approximately 23 emu·g. The drug loading capacity of FeO/α-FeO/CA-PEG was larger than the non-PEG modified version. FeO/α-FeO/CA-PEG-celastrol had slow-release characteristics and was sensitive to changes in pH. Application of a magnetic field significantly promoted the inhibition of SMMC-7721 human liver cancer cell growth after treatment with FeO/α-FeO/CA-PEG-celastrol. Celastrol and FeO/α-FeO/CA-PEG-celastrol increased the production of reactive oxygen species in SMMC-7721 cells and promoted apoptosis and apoptosis-related proteins (p53, Bax, Bcl-2) were also changed. In addition, the expression of hypoxia-inducible factor 1α (HIF-1α) was enhanced. We may conclude that celastrol-loaded magnetic FeO/α-FeO heterogeneous nanorods may be applied in the chemotherapy of human cancer with good biocompatibility and delivery.
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http://dx.doi.org/10.1016/j.msec.2021.112103DOI Listing
June 2021

Dermal delivery of amitriptyline for topical analgesia.

Drug Deliv Transl Res 2021 Apr 22. Epub 2021 Apr 22.

Great Ormond Street Hospital for Children, Great Ormond Street, London, WC1N 3JH, UK.

Amitriptyline, administered orally, is currently one of the treatment options for the management of neuropathic pain and migraine. Because of the physicochemical properties of the molecule, amitriptyline is also a promising candidate for delivery as a topical analgesic. Here we report the dermal delivery of amitriptyline from a range of simple formulations. The first stage of the work required the conversion of amitriptyline hydrochloride to the free base form as confirmed by nuclear magnetic resonance (NMR). Distribution coefficient values were measured at pH 6, 6.5, 7, and 7.4. Solubility and stability of amitriptyline were assessed prior to conducting in vitro permeation and mass balance studies. The compound demonstrated instability in phosphate-buffered saline (PBS) dependent on pH. Volatile formulations comprising of isopropyl alcohol (IPA) and isopropyl myristate (IPM) or propylene glycol (PG) were evaluated in porcine skin under finite dose conditions. Compared with neat IPM, the IPM:IPA vehicles promoted 8-fold and 5-fold increases in the amount of amitriptyline that permeated at 24 h. Formulations containing PG also appear to be promising vehicles for dermal delivery of amitriptyline, typically delivering higher amounts of amitriptyline than the IPM:IPA vehicles. The results reported here suggest that further optimization of topical amitriptyline formulations should be pursued towards development of a product for clinical investigational studies.
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http://dx.doi.org/10.1007/s13346-021-00982-xDOI Listing
April 2021

A Robust Oxygen Microbubble Radiosensitizer for Iodine-125 Brachytherapy.

Adv Sci (Weinh) 2021 04 10;8(7):2002567. Epub 2021 Feb 10.

Department of Imaging and Interventional Radiology Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou 510060 P. R. China.

Iodine-125 (I) brachytherapy, a promising form of radiotherapy, is increasingly applied in the clinical treatment of a wide range of solid tumors. However, the extremely hypoxic microenvironment in solid tumors can cause hypoxia-induced radioresistance to I brachytherapy, resulting in therapeutic inefficacy. In this study, the aim is to sensitize hypoxic areas in solid tumors using ultrasound-activated oxygen microbubbles for I brachytherapy. A modified emulsion freeze-drying method is developed to prepare microbubbles that can be lyophilized for storage and easily reconstituted in situ before administration. The filling gas of the microbubbles is modified by the addition of sulfur hexafluoride to oxygen such that the obtained O/SF microbubbles (OS MBs) achieve a much longer half-life (>3×) than that of oxygen microbubbles. The OS MBs are tested in nasopharyngeal carcinoma (CNE2) tumor-bearing mice and oxygen delivery by the OS MBs induced by ultrasound irradiation relieve hypoxia instantly. The post-treatment results of brachytherapy combined with the ultrasound-triggered OS MBs show a greatly improved therapeutic efficacy compared with brachytherapy alone, illustrating ultrasound-mediated oxygen delivery with the developed OS MBs as a promising strategy to improve the therapeutic outcome of I brachytherapy in hypoxic tumors.
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http://dx.doi.org/10.1002/advs.202002567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025033PMC
April 2021

Long Noncoding RNA GAS5 Accelerates Cholangiocarcinoma Progression by Regulating hsa-miR-1297.

Cancer Manag Res 2021 23;13:2745-2753. Epub 2021 Mar 23.

Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, Henan, People's Republic of China.

Background: Long noncoding RNAs (lncRNAs) have been reported as important molecules in cholangiocarcinoma (CCA) occurrence and development. A previous study showed that lncRNA GAS5 (GAS5) was an oncogene in some tumors. But the role of GAS5 in CCA progression reminds unclear. This research was designed to study the expression and potential effects of GAS5 in the progression of CCA.

Methods: The expression of GAS5 in CCA tissues was evaluated through mining of the TCGA and GEPIA databases. qRT-PCR was applied to validate the results in our clinical samples. test was used to analyze the association between the expression level of tissue GAS5 and different clinicopathological parameters of CCA patients. The target gene of GAS5 was predicted by bioinformatic databases, and further verified by luciferase reporter assays. Finally, the role of GAS5 in CCA cells invasion and proliferation was detected by Transwell assay and CCK-8 assay.

Results: Compared to the adjacent nontumor tissues and the normal human intrahepatic biliary epithelial cell, the expression of GAS5 was markedly increased in CCA tissues (p<0.001) and cell lines (p<0.01), respectively. CCA patients with high GAS5 expression tended to present lymph node metastasis (p<0.001) and had advanced clinical stage (p=0.006). The bioinformatics analysis predicted that hsa-miR-1297 was the potential target gene of GAS5, which was validated by luciferase reporter assays. In addition, the function study showed that GAS5 acted as a "sponge" to downregulate hsa-miR-1297, thus modulating CCA cell proliferation and invasion.

Conclusion: GAS5 acts as an endogenous sponge of hsa-miR-1297 to promote CCA cell proliferation and invasion, which might be a potential biomarker and therapeutic target for CCA.
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http://dx.doi.org/10.2147/CMAR.S297868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001187PMC
March 2021

Thyroid-stimulating hormone decreases the risk of osteoporosis by regulating osteoblast proliferation and differentiation.

BMC Endocr Disord 2021 Mar 16;21(1):49. Epub 2021 Mar 16.

Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.

Background: As the incidence of secretory osteoporosis has increased, bone loss, osteoporosis and their relationships with thyroid-stimulating hormone (TSH) have received increased attention. In this study, the role of TSH in bone metabolism and its possible underlying mechanisms were investigated.

Methods: We analyzed the serum levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSH and the bone mineral density (BMD) levels of 114 men with normal thyroid function. In addition, osteoblasts from rat calvarial samples were treated with different doses of TSH for different lengths of time. The related gene and protein expression levels were investigated.

Results: A comparison of the BMD between the high-level and low-level serum TSH groups showed that the TSH serum concentration was positively correlated with BMD. TSH at concentrations of 10 mU/mL and 100 mU/mL significantly increased the mRNA levels of ALP, COI1 and Runx2 compared with those of the control (P < 0.05, P < 0.01). Bone morphogenetic protein (BMP)2 activity was enhanced with both increased TSH concentration and increased time. The protein levels of Runx2 and osterix were increased in a dose-dependent manner.

Conclusions: The circulating concentrations of TSH and BMD were positively correlated with normal thyroid function in males. TSH promoted osteoblast proliferation and differentiation in rat primary osteoblasts.
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http://dx.doi.org/10.1186/s12902-021-00715-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968288PMC
March 2021

Hyperglycemia aggravates monocyte-endothelial adhesion in human umbilical vein endothelial cells from women with gestational diabetes mellitus by inducing Cx43 overexpression.

Ann Transl Med 2021 Feb;9(3):234

Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Gestational diabetes mellitus (GDM) is among the most common metabolic diseases during pregnancy and inevitably leads to maternal and fetal complications. Hyperglycemia results in injury to vascular endothelial cells, including monocyte-endothelial adhesion, which is considered to be the initiating factor of vascular endothelial cell injury. Connexin 43 (Cx43) plays a key role in this adhesion process. Therefore, this study aimed to explore the effects of Cx43 on monocyte-endothelial adhesion in GDM-induced injury of vascular endothelial cells.

Methods: Human umbilical vein endothelial cells (HUVECs) were isolated from umbilical cords from pregnant women with and without GDM. THP-1 cells (a human leukemia monocytic cell line) adhering to HUVECs, related molecules [intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)], and the activity of the phosphoinositide 3-kinase/protein kinase B/Nuclear factor- kappa B (PI3K/AKT/NF-κB) signaling pathway were compared between the normal and GDM-HUVECs. Oleamide and specific small interfering ribonucleic acids (siRNAs) were used to inhibit Cx43 expression in GDM-HUVECs to observe the effects of Cx43 on the adhesion of THP-1 cells and HUVECs.

Results: A much higher number of THP-1 cells adhered to GDM-HUVECs than to normal HUVECs. This was accompanied by an increased expression of Cx43, ICAM-1, and VCAM-1, as well as activation of the PI3K/AKT/NF-κB signaling pathway. After the inhibition of Cx43 expression in GDM-HUVECs with oleamide and specific siRNA, THP-1-HUVEC adhesion, ICAM-1 and VCAM-1 expression, and activation of PI3K/AKT/NF-κB signaling pathway were all attenuated. Hyperglycemia was able to increase expression of Cx43 in HUVECs.

Conclusions: For the first time, Cx43 expression was found to be substantially higher in GDM-HUVECs than in normal HUVECs. Hyperglycemia caused the overexpression of Cx43 in HUVECs, which resulted in the activation of the PI3K/AKT/NF-κB signaling pathway and the increase of its downstream adhesion molecules, including ICAM-1 and VCAM-1, ultimately leading to increased monocyte-endothelial adhesion.
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http://dx.doi.org/10.21037/atm-19-4738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940931PMC
February 2021

Quantitative chemoproteomics reveals O-GlcNAcylation of cystathionine γ-lyase (CSE) represses trophoblast syncytialization.

Cell Chem Biol 2021 06 23;28(6):788-801.e5. Epub 2021 Feb 23.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Innovation Academy of Stem Cell and Regenerative Medicine, Chinese Academy of Sciences, Beijing 100101, China; Beijing Academy of Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 101408, China. Electronic address:

Emerging evidence indicates the involvement of O-GlcNAc modification in placental development and pregnant health through mechanisms that are not well understood. Herein, by applying the quantitative O-GlcNAc proteomics, we established a database of O-GlcNAcylated proteins in human placental trophoblasts. Hundreds of proteins that were dynamically O-GlcNAcylated during trophoblast differentiation were identified, among which cystathionine γ-lyase (CSE) exhibited the most significant change. Site-specific analysis by mass spectrometry revealed Ser as the core O-GlcNAc site in CSE, and its O-GlcNAcylation promoted the enzymatic activity to produce HS, which in turn repressed trophoblast differentiation via inhibiting androgen receptor dimerization. Consistently, in preeclamptic placentas, remarkably enhanced CSE O-GlcNAcylation and HS production were associated with restricted trophoblast differentiation. The findings establish a resource of O-GlcNAc dynamics in human placenta, and provide a deeper insight into the biological significance of O-GlcNAcylation in placental development as well as potential therapeutic targets for the relevant pregnant complications.
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http://dx.doi.org/10.1016/j.chembiol.2021.01.024DOI Listing
June 2021

Design of a workstation based on a human-interfacing robot for occupational health and safety.

Work 2021 ;68(3):863-870

Wenzhou Kean University, Wenzhou, China.

Background: Robots communicate with the physical world program with the mechanic's simulations. They recommend that people-to-people robotics will prepare for cognitive models. Presently, there is a considerable concern for greater flexibility and efficiency in the scope of human-robot interfacing collaboration across hospitals. Nevertheless, interfacing is still in its infancy in manufacturing; industrial practitioners have many questions and doubts about the efficiency of the device and the health of human operators.

Objectives: Therefore, research on processes and methods of design is required to ensure that the intended human-computer interaction-based workstations effectively meet system performance, human safety, and ergonomics standards for realistic applications. This study provides a design process for a workstation appropriate for occupational health and safety. This article outlines the perspectives learned from incorporation into the preparation and operation of robotics of digital cognitive models.

Results: This ends with an overarching game-theoretical model of contact and analyses how different approaches contribute to effective communicating activities for the robot in its interaction with people.

Conclusion: The new feature of this design process is the approach for testing alternative workstation designs, taking into account efficiency and safety features with computer simulations.
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http://dx.doi.org/10.3233/WOR-203420DOI Listing
June 2021

Cellulose-based electrospun nanofiber membrane with core-sheath structure and robust photocatalytic activity for simultaneous and efficient oil emulsions separation, dye degradation and Cr(VI) reduction.

Carbohydr Polym 2021 Apr 22;258:117676. Epub 2021 Jan 22.

Shaanxi Provincial Key Laboratory of Papermaking Technology and Specialty Paper Development, National Demonstration Center for Experimental Light Chemistry Engineering Education, Shaanxi University of Science and Technology, Xi'an, 710021, China; Limerick Pulp and Paper Centre, University of New Brunswick, Fredericton, New Brunswick, E3B 5A3, Canada.

Electrospun nanofiber membrane (ENM) shows great advantage and potential in wastewater treatment due to its unique properties. However, exploring a green and efficient ENM for remediation of complex wastewater, such as simultaneous containing oils, dyes and heavy metal ion, remains challenging. In this work, a cellulose-based photocatalytic ENM, is constructed for this purpose. The hybrid ENM is prepared via electrospinning deacetylated cellulose acetate/polyvinyl pyrrolidone (CeP) nanofibers as skeleton cores and in-situ synthesis of beta hydroxyl oxidize iron decorated iron-based MOF (β[email protected](Fe)) heterojunctions as photocatalytic sheaths. The core-sheath structured ENM has ultrahigh MIL-100(Fe) loading (78 wt%), large surface areas (1105 m/g) and well-dispersed β-FeOOH nanorods. Thanks to these porous and hydrophilic MIL-100(Fe), along with a robust photocatalysis-Fenton synergy from β[email protected](Fe), the as-prepared ENM shows outstanding performances with simultaneous high removal efficiency for oils (99.5 %), dyes (99.4 %) and chromium ion (Cr(VI)) (99.7 %). Additionally, the photocatalytic ENM can achieve a long-term reuse owing to its inherent self-cleaning function.
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http://dx.doi.org/10.1016/j.carbpol.2021.117676DOI Listing
April 2021

Analysis of risk factors for obstetric outcomes after hysteroscopic adhesiolysis for Asherman syndrome: A retrospective cohort study.

Int J Gynaecol Obstet 2021 Jan 23. Epub 2021 Jan 23.

Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Objective: To investigate the factors influencing placenta accreta in pregnant women who previously underwent hysteroscopic adhesiolysis (HA).

Methods: This retrospective study enrolled 265 women with intrauterine adhesions (IUAs) at the Sir Run Run Shaw Hospital from January 2014 to December 2018. We followed up their pregnancy outcomes and maternal complications.

Results: The menstrual pattern and gestational history before operation were significantly different between the live birth and pregnancy loss groups. The age, extent of cavity involved, type of adhesions, times of adhesiolysis performed, and time interval from surgery to pregnancy were not significantly different between these two groups. In the third trimester, 48 of 140 patients had 53 perinatal complications, including placenta accreta (27), gestational diabetes mellitus (10), pregnancy-induced hypertension (6), postpartum hemorrhage (4), intrahepatic cholestasis of pregnancy (2), placenta previa (1), oligohydramnios (1), and intrauterine growth restriction (1). Logistic regression analysis showed that extent of cavity involved and times of adhesiolysis performed were associated with placenta accreta.

Conclusion: The extent of cavity involved and times of adhesive separation surgeries were risk factors for placenta accreta in patients. The menstrual model and gestational history may provide the main predictive factors for pregnancy loss.
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http://dx.doi.org/10.1002/ijgo.13616DOI Listing
January 2021

A novel oncotherapy strategy: Direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non-small cell lung cancer.

Br J Pharmacol 2021 Jan 22. Epub 2021 Jan 22.

Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Fudan University, Shanghai, China.

Background And Purpose: Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer. Nevertheless, thrombin expression in non-small cell lung cancer (NSCLC) primary tumour tissues and the association between prognosis of NSCLC patients remain largely unknown.

Experimental Approach: Clinical pathological analysis was performed to determine the relationship between thrombin and tumour progression. Effects of r-hirudin and direct thrombin inhibitor peptide (DTIP) on cancer progression were evaluated. Western blotting, immunohistochemistry, and immunofluorescence were used to explore the inhibition mechanism of r-hirudin and DTIP. The therapeutic effect of the combination of DTIP and chemotherapy was determined.

Key Results: Thrombin expression in NSCLC tissues was closely related to clinicopathological features and the prognosis of patients. Thrombin deficiency inhibited tumour progression. The novel thrombin inhibitors, r-hirudin and DTIP, inhibited cell invasion and metastasis in vitro. They inhibited tumour growth and metastasis in orthotopic lung cancer model, inhibited cell invasion, and prolonged survival after injection of tumour cells via the tail vein. They also inhibited angiogenesis and spontaneous metastases from subcutaneously inoculated tumours. The promotion by thrombin of invasion and metastasis was abolished in PAR-1-deficient NSCLC cells. r-hirudin and DTIP inhibited tumour progression through the thrombin-PAR-1-mediated RhoA and NF-κB signalling cascades via inhibiting MMP9 and IL6 expression. DTIP potentiated chemotherapy-induced growth and metastatic inhibition and inhibited chemotherapy-induced resistance in mice.

Conclusions And Implications: Thrombin makes a substantial contribution, together with PAR-1, to NSCLC malignancy. The anti-coagulants, r-hirudin and DTIP, could be used in anti-tumour therapy and a combination of DTIP and chemotherapy might improve therapeutic effects.
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http://dx.doi.org/10.1111/bph.15384DOI Listing
January 2021

Effect of Equal Channel Angular Pressing on the Dynamic Softening Behavior of Ti-6Al-4V Alloy in the Hot Deformation Process.

Materials (Basel) 2021 Jan 5;14(1). Epub 2021 Jan 5.

AVIC Manufacturing Technology Institute, Beijing 100024, China.

To investigate the effect of equal channel angular pressing (ECAP) on the deformation of Ti-6Al-4V alloy at a higher temperature, hot compression tests were conducted on alloys having two different initial microstructures (the original alloy (Pre-ECAP) and ECAP-deformed alloy (Post-ECAP)). Post-ECAP, the alloy showed a higher degree of dynamic softening during the hot deformation process due to its finer grain size and higher distortion energy. The flow stress of Post-ECAP alloy was higher than the Pre-ECAP alloy at 500 °C when ε˙= 0.003 s-1. However, the stress of the Post-ECAP alloy decreased rapidly with increasing temperature and strain rate, until the stress value was much lower than that of Pre-ECAP at 700 °C when ε˙= 0.03 s-1. The value of the dynamic softening coefficient revealed that the dynamic softening behavior of Post-ECAP was more pronounced than that of Pre-ECAP in the hot compression deformation process. The main dynamic softening mechanism of Pre-ECAP is dynamic recovery, while the dynamic recrystallization process plays a more important role in the deformation process of Post-ECAP alloy. The microstructures observation results showed that dynamic recrystallization was more likely to occur to Post-ECAP alloys under the same deformation condition. Almost fully dynamic recrystallization had occurred in the deformation process of Post-ECAP at 700 °C and a strain rate of ε˙= 0.01 s-1. The grains of Post-ECAP alloys were further refined. The Post-ECAP alloy exhibits better plastic deformation at temperatures higher than 600 °C due to its significant dynamic recrystallization.
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http://dx.doi.org/10.3390/ma14010232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796470PMC
January 2021

Tracing Carbon Nanotubes (CNTs) in Rat Peripheral Nerve Regenerated with Conductive Conduits Composed of Poly(lactide--glycolide) and Fluorescent CNTs.

ACS Biomater Sci Eng 2020 11 15;6(11):6344-6355. Epub 2020 Oct 15.

State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China.

Nerve regeneration can be promoted using nerve guide conduits (NGCs). Carbon nanotubes (CNTs) are often used to prepare conductive NGCs, however, the major concern for their applications is the final location of the implanted CNTs in vivo. Herein, photoluminescent multiwalled CNTs (MWCNTs) were prepared and electrospun with poly(lactide--glycolide) (PLGA), followed by shaping into multichannel NGCs for repairing of injured rat sciatic nerve, thereby the distribution of CNTs in vivo could be detected via bioimaging. Photoluminescent MWCNTs (MWCNT-FITC) were prepared by functionalization with poly(glycidyl methacrylate) (PGMA) and fluorescein-isothiocyanate-isomer I (FITC) subsequently. The conductivity of the PLGA/MWCNT-FITC fibers was approx. 10 S/cm at 3 wt % MWCNTs. Compared with PLGA fibers, Schwann cells on PLGA/MWCNT-FITC fibers matured at a faster rate, accordingly, nerve regeneration was promoted by the PLGA/MWCNT-FITC NGC. With a confocal laser scanning microscope and small-animal imaging system, the location of MWCNTs was detected. Alongside the degradation of PLGA, MWCNTs intended to aggregate and were entrapped in the regenerated nerve tissue without migrating into surrounding tissues and other organs (liver, kidneys, and spleen). This study provides a useful characterization method for MWCNTs and the guidance for in vivo applications of MWCNTs in tissue engineering.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01065DOI Listing
November 2020
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