Publications by authors named "Xiaohong Xu"

322 Publications

The characteristics and novel clinical implications of CD4+CXCR5+Foxp3+ follicular regulatory T cells in breast cancer.

Ann Transl Med 2021 Aug;9(16):1332

Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China.

Background: Follicular regulatory T cells (Tfr) are a subset of regulatory T cells (Tregs) that suppress the humoral immune response in the germinal center. They are associated with increased rates of disease stabilization and decreased autoantibody levels in a variety of tumor and autoimmune diseases. The binding of T-cell immunoglobulin mucin 3 (TIM-3) and its ligand on the surface of Tfr cells could result in the depletion of T lymphocytes and the termination of the immune response mediated by helper T cell 1. However, the role of Tfr cells in breast cancer (BC) remains unclear.

Methods: In this study, we detected the expression of CD4+CXCR5+Foxp3+Tfr cells in the peripheral blood of 35 BC patients and 30 healthy control patients by flow cytometry, and analyzed the relationship between Tfr cells and the clinical characteristics of patients. In addition, the expression of TIM-3 on the surface of Tfr cells in 6 triple-negative BC (TNBC) patients was further investigated using mass spectrometry.

Results: We found a significant increase in Tfr cells in BC patients compared to healthy control patients (23.47%±9.70% . 10.99%±4.68%; P=0.001). Notably, the increase was more significant in early stage than advanced stage TNBC patients (28.52%±10.75% . 18.69%±5.19%; P=0.006), and there was a negative correlation between Tfr cells and serum lactate dehydrogenase (LDH) in early stage TNBC patients (r=-0.585; P=0.008). Additionally, we found that the expression of Tfr cells was higher in TNBC patients than luminal BC patients (28.25%±10.11% . 18.5%±8.15%; P=0.028); however, there was no significant difference in expression in hormone receptor positive (HR+) BC and hormone receptor negative (HR-) BC (P=0.141) patients. Notably, the surface of Tfr cells of TNBC patients had higher levels of TIM-3 expression than those of healthy control patients (3.93±0.92 . 2.65±0.15, respectively; t=-3.02; P<0.05), which the mass spectrometry showed were positively correlated with the intracellular Foxp3 expression of Tfr cells (r=0.82; P=0.036).

Conclusions: Our results suggest that circulating Tfr cells and the expression of TIM-3 were significantly increased in BC patients, which were related to stage and histological type, and may be involved in the pathogenesis of BC.
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http://dx.doi.org/10.21037/atm-21-3848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422094PMC
August 2021

One-Pot Synthesis Enables Magnetic Coupled CrTe/MnTe/CrTe Integrated Heterojunction Nanorods.

Nano Lett 2021 Aug 26. Epub 2021 Aug 26.

Key Laboratory of Magnetic Molecules and Magnetic Information Materials of Ministry of Education, School of Chemistry and Materials Science, Shanxi Normal University, Linfen 041004, China.

Magnetic heterostructures offer great promise in spintronic devices due to their unique magnetic properties, such as exchange bias effect, topological superconductivity, and magneto-resistance. Although various magnetic heterostructures including core/shell, multilayer, and van der Waals systems have been fabricated recently, the construction of perfect heterointerfaces usually rely on complicated and high-cost fabrication methods such as molecular-beam epitaxy; surprisingly, few one-dimensional (1D) bimagnetic heterojunctions, which provide multidegrees of freedom to modulate magnetic properties via magnetic anisotropy and interface coupling, have been fabricated to date. Here we report a one-pot solution-based method for the synthesis of ferromagnetic/antiferromagnetic/ferromagnetic heterojunction nanorods with excellent heterointerfaces in the case of CrTe/MnTe/CrTe. The precise control of homogeneous nucleation of MnTe and heterogeneous nucleation of CrTe is a key factor in synthesizing this heterostructure. The resulting 1D bimagnetic heterojunction nanorods exhibit high coercivity of 5.8 kOe and exchange bias of 892.5 Oe achieved by the magnetic MnTe/CrTe interface coupling.
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http://dx.doi.org/10.1021/acs.nanolett.1c02481DOI Listing
August 2021

Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity.

Neurobiol Dis 2021 Oct 12;158:105479. Epub 2021 Aug 12.

Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada. Electronic address:

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to multiple post-translational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains largely unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be pharmacologically modulated. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that mHTT palmitoylation decreases further with aging. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons.
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http://dx.doi.org/10.1016/j.nbd.2021.105479DOI Listing
October 2021

Electric Field Control of the Magnetic Weyl Fermion in an Epitaxial SrRuO (111) Thin Film.

Adv Mater 2021 Sep 24;33(36):e2101316. Epub 2021 Jul 24.

Department of Materials Science and Engineering, National University of Singapore, Singapore, 117575, Singapore.

The magnetic Weyl fermion originates from the time reversal symmetry (TRS)-breaking in magnetic crystalline structures, where the topology and magnetism entangle with each other. Therefore, the magnetic Weyl fermion is expected to be effectively tuned by the magnetic field and electrical field, which holds promise for future topologically protected electronics. However, the electrical field control of the magnetic Weyl fermion has rarely been reported, which is prevented by the limited number of identified magnetic Weyl solids. Here, the electric field control of the magnetic Weyl fermion is demonstrated in an epitaxial SrRuO (111) thin film. The magnetic Weyl fermion in the SrRuO films is indicated by the chiral anomaly induced magnetotransport, and is verified by the observed Weyl nodes in the electronic structures characterized by the angle-resolved photoemission spectroscopy (ARPES) and first-principles calculations. Through the ionic-liquid gating experiment, the effective manipulation of the Weyl fermion by electric field is demonstrated, in terms of the sign-change of the ordinary Hall effect, the nonmonotonic tuning of the anomalous Hall effect, and the observation of the linear magnetoresistance under proper gating voltages. The work may stimulate the searching and tuning of Weyl fermions in other magnetic materials, which are promising in energy-efficient electronics.
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http://dx.doi.org/10.1002/adma.202101316DOI Listing
September 2021

NDV related exosomes enhance NDV replication through exporting NLRX1 mRNA.

Vet Microbiol 2021 Sep 29;260:109167. Epub 2021 Jun 29.

Key Laboratory of Zoonosis Research, Ministry of Education, Jilin University, Changchun, 130062, China. Electronic address:

Virulent Newcastle disease virus (NDV) is a violent infection in avian species. The understanding of its pathogenic mechanism is consistently evolving along with the development of molecular biological advancement. Exosomes derived from NDV infected cells (NDV Ex) were reported to promote virus replication through transportation of viral proteins and miRNAs. However, the function of mRNAs in NDV Ex remains unknown. In this study, a novel mechanism of NDV Ex to facilitate NDV infection was explored. Through transcriptome analysis, seven immune related genes were found to up-regulate in NDV Ex. Among them, NLRX1 mRNA was notably enriched in NDV Ex, and decreased inside the cells after virulent NDV infection. Further investigation suggested that NLRX1 mRNA decrease was in accordance with the NLRX1 protein expression reduction. This process can be reversed by the inhibition of exosome release. Therefore, NDV infection could utilize NDV Ex to export NLRX1 mRNA and reduce cellular NLRX1 protein. As NLRX1 is a crucial anti-viral protein of MAVS signal pathway, and NDV Ex transported NLRX1 cannot counteract its function in recipient cells, it can be concluded that NDV could benefit its replication through exporting NLRX1 mRNA to relieve the anti-viral pressure on its survival.
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http://dx.doi.org/10.1016/j.vetmic.2021.109167DOI Listing
September 2021

Real-World Study of Cisplatin, Etoposide, and Bleomycin Chemotherapy Regimen in Gestational Trophoblastic Neoplasia.

Biomed Res Int 2021 24;2021:6661698. Epub 2021 Jun 24.

Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

Objective: Little observational data exist regarding the use of cisplatin, etoposide, and bleomycin (BEP) chemotherapy regimen in patients with gestational trophoblastic neoplasia (GTN).

Methods: This is a retrospective study of 95 patients with GTN in our center from June/2010 to June/2018. All patients received at least 2 cycles of BEP chemotherapy. The primary outcomes were the rate of complete remission (CR) and overall survival (OS). The secondary outcomes were disease-free survival (DFS), pregnancy rates after BEP exposure, drug resistance rate, and other adverse events.

Results: Of the 95 patients included, 66 (69.5%) patients received BEP as primary treatment and 29 (30.5%) were Salvage chemotherapy. The median age at diagnosis was 37 years (range 29.75-46) and 34 years (range 27-40) in two groups, respectively. The median WHO prognostic scores were 6 (range 3.5-8), and 77.32% of patients were FIGO stage III-IV in the primary treatment group. The median WHO prognostic scores were 5 (range 3-9), and 66.55% of patients were FIGO stage III-IV in the salvage treatment group. Median cycles of BEP treatment were 4 (3, 5) and 3 (2, 4) in two groups, respectively. In the primary chemotherapy group, 18.2% received additional hysterectomy, 4.5% received UAE for vaginal bleeding, and 1.52% received whole-brain radiotherapy. In the salvage chemotherapy group, 20.7% received hysterectomy, 6.9% received lobectomy, 3.4% received hysteroscopic lesion resection, and 3.4% received whole-brain radiotherapy. CR rates to initial chemotherapy were 86.4%, including 87.9% in the primary chemotherapy group and 82.8% in the salvage chemotherapy group. No predictive factor of chemotherapy resistance was identified. The rate of 5 year-DFS was 96.52% (95% CI 86.78-99.12) in the primary chemotherapy group and 92.44% (95% CI 73.02-98.06) in the salvage chemotherapy group. The rate of 5 year-OS was 98.31% (95% CI 88.57-99.76) and 95.65% (95% CI 79.93-99.38) in the two groups, respectively. During the treatment, neutropenia, thrombocytopenia, anemia, and liver dysfunction occurred in 80.3%, 6.1%, 25.8%, and 50% primary chemotherapy patients and 82.8%, 31%, 10.3%, and 86.2% salvage chemotherapy patients. In patients with fertility requirements, live birth rates were 100% (10/10) in primary chemotherapy patients and 80% (4/5) in salvage chemotherapy patients.

Conclusions: BEP regimen was effective in the treatment of GTINs. The treatment was well tolerated, with no safety concerns on patients' fertility.
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http://dx.doi.org/10.1155/2021/6661698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249144PMC
June 2021

Self-assembled micelles enhance the oral delivery of curcumin for the management of alcohol-induced tissue injury.

Pharm Dev Technol 2021 Oct 13;26(8):880-889. Epub 2021 Jul 13.

School of Pharmacy, Institute of Materia Medica, Chengdu Medical College, Chengdu, China.

Curcumin (CUR) shows great potential in the management of alcohol-use disorders. However, the hydrophobicity and poor oral bioavailability result in the limited therapeutic efficacy of CUR against alcohol-induced tissue injury. Here, self-assembled Soluplus® micelles (Ms) were developed for the enhanced oral delivery of CUR. CUR-loaded Soluplus® micelles (CUR-Ms) were prepared using a thin-film hydration method and these micelles displayed nearly spherical shape with an average size of 62.80 ± 1.29 nm. CUR in micelles showed the greater stability, solubility and dissolution than free CUR. With the increased water solubility of CUR-Ms and P glycoprotein inhibition of Soluplus®, the absorption rate constant (Ka) and apparent permeability coefficient (Papp) of CUR-Ms in intestines was respectively 3.50 and 4.10 times higher than that of free CUR. Pharmacokinetic studies showed that CUR-Ms significantly improved the oral bioavailability of CUR. Specifically, the AUC0-∞ and C of CUR-Ms were increased by 9.45 and 47.38 folds compared to free CUR, respectively. In mice with alcohol-induced tissue injury, the oral administration of CUR-Ms greatly reduced oxidative stress, and significantly defended liver and gastric mucosa from alcoholic damages. The results demonstrated CUR-Ms with good oral bioavailability could represent a promising strategy for the management of alcohol-induced tissue injury.
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http://dx.doi.org/10.1080/10837450.2021.1950185DOI Listing
October 2021

Expression and Prognostic Significance of PD-L2 in Diffuse Large B-Cell Lymphoma.

Front Oncol 2021 10;11:664032. Epub 2021 Jun 10.

Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong, China.

Recent studies suggest that programmed death ligand-2 (PD-L2) constitutes an important antitumor immune response. Here, we investigated the relationship between PD-L2 expression and clinicopathological features in diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry showed that positive expression of PD-L2 was observed in 45 of 181 newly diagnosed patients, including 14 cases with expression exclusively on tumor cells (TCs) and 31 cases with the expression on both TCs and immune cells (ICs) in the tumor microenvironment (TME). In 21 recurrent patients, positive expression of PD-L2 was present in six cases, including two cases with expression exclusively on TCs, and four cases with the expression on both TCs and ICs in the TME. Patients with PD-L2 tumor proportion score (TPS) ≥1% exhibited a better ECOG performance status (PS) (ECOG PS score <2, = 0.041), lower international prognostic index (IPI) score ( < 0.001), and early Ann Arbor stage (Ann Arbor stage I or II, = 0.010). Similarly, patients with PD-L2 immune proportion score (IPS) ≥1% also exhibited a better ECOG PS (ECOG PS score < 2, = 0.006) and lower IPI score ( = 0.001). Survival analysis showed that patients with PD-L2 TPS ≥1% exhibited prolonged overall survival (OS) and progression-free survival (PFS). However, survival analysis showed no prognostic significance based on expression of PD-L2 on ICs in the TME. TC PD-L2 expression was significantly associated with OS ( = 0.041) and PFS ( = 0.001). In the multivariate analysis, TC PD-L2 expression was an independent prognostic risk factor for PFS ( = 0.013), but not for OS ( = 0.249). Furthermore, we found that higher TC and IC PD-L2 expression was associated with higher objective response rate (ORR). Moreover, we demonstrated that the expression level of PD-L2 was positively correlated with the expression status of M1 macrophage markers CD86. Our findings highlight PD-L2 as a promising therapeutic target in DLBCL.
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http://dx.doi.org/10.3389/fonc.2021.664032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222690PMC
June 2021

Selective Substrate-Orbital-Filtering Effect to Realize the Large-Gap Quantum Spin Hall Effect.

Nano Lett 2021 Jul 22;21(13):5828-5833. Epub 2021 Jun 22.

Department of Materials Science and Engineering, University of Utah, Salt Lake City, Utah 84112, United States.

Although Pb harbors a strong spin-orbit coupling effect, pristine plumbene (the last group-IV cousin of graphene) hosts topologically trivial states. Based on first-principles calculations, we demonstrate that epitaxial growth of plumbene on the BaTe(111) surface converts the trivial Pb lattice into a quantum spin Hall (QSH) phase with a large gap of ∼0.3 eV via a substrate-orbital-filtering effect. Tight-binding model analyses show the orbital in half of the Pb overlayer is selectively removed by the BaTe substrate, leaving behind a - band inversion. Based on the same working principle, the gap can be further increased to ∼0.5-0.6 eV by surface adsorption of H or halogen atoms that filters out the other half of the Pb orbitals. The mechanism of substrate-orbital-filtering is general, opening an avenue to explore large-gap QSH insulators in heavy-metal-based materials. It is worth noting that plumbene has already been widely grown on various substrates experimentally.
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http://dx.doi.org/10.1021/acs.nanolett.1c01765DOI Listing
July 2021

High Expression of Cancer-IgG Is Associated With Poor Prognosis and Radioresistance PI3K/AKT/DNA-PKcs Pathway Regulation in Lung Adenocarcinoma.

Front Oncol 2021 2;11:675397. Epub 2021 Jun 2.

Department of Radiation Oncology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China.

Background: Lung adenocarcinoma (LUAD) is the dominant type of lung neoplasms, and radiotherapy is its mainstay treatment, yet poor prognosis caused by radioresistance remains problematic. Cancer-derived immunoglobulin G (cancer-IgG) has been detected in multiple cancers and plays important roles in carcinogenesis. This study aimed to demonstrate that cancer-IgG is associated with poor prognosis of LUAD and to identify its role in radioresistance.

Methods: Cancer-IgG expression was detected by immunohistochemistry from 56 patients with stage III LUAD and by western blot and immunofluorescence in LUAD cell lines and in a human bronchial epithelial cell line. The effects of cancer-IgG silencing on the proliferation and apoptosis of PC9 and H292 cells were evaluated by plate cloning and apoptosis assay; the effects of cancer-IgG silencing on DNA damage repair ability and radiosensitivity were evaluated by colony-forming assay, γH2AX immunofluorescence, and neutral comet assay. Finally, we used the protein phosphorylation microarray and western blot to explore mechanisms involving cancer-IgG that increased radioresistance.

Results: Cancer-IgG is widely expressed in stage III LUAD, and the overall survival and disease-free survival of patients with positive expression are notably lower than those of patients with negative expression, indicating the associations between cancer-IgG and poor prognosis as well as radioresistance. The expression of cancer-IgG in the four LUAD cell lines was located mainly on the cell membrane and cytoplasm and not in the normal lung epithelial cell. Knockdown of cancer-IgG in PC9 and H292 cells resulted in increased apoptosis and negatively affected cancer cell proliferation. After irradiation, silencing of cancer-IgG showed a decrease in colonies as well as increases in the Olive tail moment and γH2AX foci in nucleus, indicating that the knockdown of cancer-IgG resulted in a decrease in the damage repair ability of DNA double-strand breaks in LUAD cells and an enhanced radiosensitivity. The expression of p-AKT, p-GSK3β, and p-DNA-PKcs decreased in the knockdown group after radiotherapy, suggesting that cancer-IgG could affect radiotherapy resistance by mediating double-strand breaks damage repair in LUAD cells through the PI3K/AKT/DNA-PKcs pathway.

Conclusions: This study revealed that cancer-IgG regulates PI3K/AKT/DNA-PKcs signaling pathways to affect radioresistance of LUAD and associated with poor prognosis.
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http://dx.doi.org/10.3389/fonc.2021.675397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208032PMC
June 2021

Gastrointestinal Motility and Gut Hormone Secretion in response to Shenhuang Plaster in a Postoperative Ileus Rat Model.

Evid Based Complement Alternat Med 2021 1;2021:8859579. Epub 2021 Jun 1.

The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310018, China.

Postoperative ileus (POI), a gastrointestinal function disorder, is a complication that arises from surgery. Shenhuang plaster (SHP) application to the Shenque acupoint (CV8) to promote the recovery of gastrointestinal function has achieved definite curative effects in clinical settings; however, the underlying pharmacological mechanism remains unknown. In this study, we evaluated the effects of SHP using a Sprague Dawley rat POI model. Then, gastrointestinal transit in different rat groups was evaluated by the movement of fluorescein-labelled dextran. Ghrelin, obestatin, motilin (MTL), and vasoactive intestinal peptide (VIP) plasma concentrations were measured via a radioimmunoassay. The expression of the ghrelin and obestatin receptors (GHS-R1 and GPR39) in the intestinal muscularis of rats in different groups was comparatively identified via western blotting. The results indicated that SHP application improved gastrointestinal motility in POI model rats. SHP application significantly increased ghrelin concentration and the expression of its receptor and inhibited obestatin concentration and the expression of its receptor in blood. Further, ghrelin concentration and the capability of gastrointestinal transit were positively correlated. Simultaneously, SHP application also promoted the secretion of other gastrointestinal motility hormones, such as MTL and VIP. Hence, these results provide evidence that SHP can promote the recovery of gastrointestinal transmission in POI rat models through regulation of ghrelin and other intestinal hormones.
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http://dx.doi.org/10.1155/2021/8859579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189788PMC
June 2021

Adiponectin protects obesity-related glomerulopathy by inhibiting ROS/NF-κB/NLRP3 inflammation pathway.

BMC Nephrol 2021 Jun 10;22(1):218. Epub 2021 Jun 10.

Department of Endocrinology, The Third Affiliated Hospital of Soochow University, No.185 Bureau Front Street, 213003, Changzhou City, China.

Background: Adiponectin is an adipocytokine that plays a key regulatory role in glucose and lipid metabolism in obesity. The prevalence of obesity has led to an increase in the incidence of obesity-related glomerulopathy (ORG). This study aimed to identify the protective role of adiponectin in ORG.

Methods: Small-interfering RNA (siRNA) against the gene encoding adiponectin was transfected into podocytes. The oxidative stress level was determined using a fluorometric assay. Apoptosis was analyzed by flow cytometry. The expressions of podocyte markers and pyrin domain containing protein 3 (NLRP3) inflammasome-related proteins were measured by qRT-PCR, immunohistochemistry, and Western blot.

Results: Podocytes treated with palmitic acid (PA) showed downregulated expressions of podocyte markers, increased apoptosis, upregulated levels of NLRP3 inflammasome-related proteins, increased production of inflammatory cytokines (IL-18 and IL-1β), and induced activation of NF-κB as compared to the vehicle-treated controls. Decreased adiponectin expression was observed in the serum samples from high fat diet (HFD)-fed mice. Decreased podocin expression and upregulated NLRP3 expression were observed in the kidney samples from high fat diet (HFD)-fed mice. Treatment with adiponectin or the NLRP3 inflammasome inhibitor, MCC950, protected cultured podocytes against podocyte apoptosis and inflammation. Treatment with adiponectin protected mouse kidney tissues against decreased podocin expression and upregulated NLRP3 expression. The knockout of adiponectin gene by siRNA increased ROS production, resulting in the activation of NLRP3 inflammasome and the phosphorylation of NF-κB in podocytes. Pyrrolidine dithiocarbamate, an NF-κB inhibitor, prevented adiponectin from ameliorating FFA-induced podocyte injury and NLRP3 activation.

Conclusions: Our study showed that adiponectin ameliorated PA-induced podocyte injury in vitro and HFD-induced injury in vivo via inhibiting the ROS/NF-κB/NLRP3 pathway. These data suggest the potential use of adiponectin for the prevention and treatment of ORG.
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http://dx.doi.org/10.1186/s12882-021-02391-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191043PMC
June 2021

In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα.

Sci Rep 2021 Jun 3;11(1):11663. Epub 2021 Jun 3.

Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, Canada.

The interaction of platelet GPIbα with von Willebrand factor (VWF) is essential to initiate platelet adhesion and thrombosis, particularly under high shear stress conditions. However, no drug targeting GPIbα has been developed for clinical practice. Here we characterized anfibatide, a GPIbα antagonist purified from snake (Deinagkistrodon acutus) venom, and evaluated its interaction with GPIbα by surface plasmon resonance and in silico modeling. We demonstrated that anfibatide interferds with both VWF and thrombin binding, inhibited ristocetin/botrocetin- and low-dose thrombin-induced human platelet aggregation, and decreased thrombus volume and stability in blood flowing over collagen. In a single-center, randomized, and open-label phase I clinical trial, anfibatide was administered intravenously to 94 healthy volunteers either as a single dose bolus, or a bolus followed by a constant rate infusion of anfibatide for 24 h. Anfibatide inhibited VWF-mediated platelet aggregation without significantly altering bleeding time or coagulation. The inhibitory effects disappeared within 8 h after drug withdrawal. No thrombocytopenia or anti-anfibatide antibodies were detected, and no serious adverse events or allergic reactions were observed during the studies. Therefore, anfibatide was well-tolerated among healthy subjects. Interestingly, anfibatide exhibited pharmacologic effects in vivo at concentrations thousand-fold lower than in vitro, a phenomenon which deserves further investigation.Trial registration: Clinicaltrials.gov NCT01588132.
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http://dx.doi.org/10.1038/s41598-021-91165-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175443PMC
June 2021

Computed tomography image fusion, Coaxial guidewire technique, Fast intraprocedural cortisol testing technique improves success rate and decreases radiation exposure, procedure time, and contrast use for adrenal vein sampling.

J Hypertens 2021 Sep;39(9):1918-1925

Department of Endocrinology.

Background: Adrenal vein sampling (AVS) is recommended for discriminating patients with unilateral primary aldosteronism from bilateral disease. However, it is a technically demanding procedure that is markedly underused. We developed a computed tomography image fusion, coaxial guidewire technique, fast intraprocedural cortisol testing (CCF) technique to improve AVS success rate, which combines CT image fusion, coaxial guidewire technique, and fast intraprocedural cortisol testing.

Objective: To evaluate the effectiveness and safety of the AVS--CCF technique.

Methods: We retrospectively evaluated 105 patients who undervent AVS from June 2016 to October 2020. There were 51 patients in the AVS--CCF group and 54 patients in the AVS group. We compared two groups with technical success rate, procedure time, radiation exposure, volume of contrast medium, and complications (adrenal vein rupture, dissection, infarction, or thrombosis; intraglandular or periadrenal hematoma; and contrast-induced nephropathy).

Results: The technical success rate was higher for AVS--CCF than for AVS without CCF (98 vs. 83.3% for bilateral adrenal veins, P = 0.016). AVS--CCF was associated with a shorter procedure time (63.6 ± 24.6 vs. 94.8 ± 40.8 min, P < 0.001), shorter fluoroscopy time (15.6 ± 12.6 vs. 20.4 ± 15.0 min, P = 0.043), and lower contrast medium volume (25.10 ± 21.82 vs. 44.1 ± 31.0 ml, P < 0.001). There were no significant differences between groups with respect to the time for cannulating the left or right adrenal vein or the peak skin radiation dose. Adrenal vein rupture occurred in 14 patients and intraglandular hematoma in 1 patient.

Conclusion: The CCF technique during AVS not only contributed to improved technical success rates but also associated with decreased procedure time, radiation exposure, and contrast medium volume.
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http://dx.doi.org/10.1097/HJH.0000000000002852DOI Listing
September 2021

Detecting the Mechanism behind the Transition from Fixed Two-Dimensional Patterned Sika Deer () Dermal Papilla Cells to Three-Dimensional Pattern.

Int J Mol Sci 2021 Apr 29;22(9). Epub 2021 Apr 29.

School of Life Sciences, Jilin University, Changchun 130012, China.

The hair follicle dermal papilla is critical for hair generation and de novo regeneration. When cultured in vitro, dermal papilla cells from different species demonstrate two distinguishable growth patterns under the conventional culture condition: a self-aggregative three dimensional spheroidal (3D) cell pattern and a two dimensional (2D) monolayer cell pattern, correlating with different hair inducing properties. Whether the loss of self-aggregative behavior relates to species-specific differences or the improper culture condition remains unclear. Can the fixed 2D patterned dermal papilla cells recover the self-aggregative behavior and 3D pattern also remains undetected. Here, we successfully constructed the two growth patterns using sika deer () dermal papilla cells and proved it was the culture condition that determined the dermal papilla growth pattern. The two growth patterns could transit mutually as the culture condition was exchanged. The fixed 2D patterned sika deer dermal papilla cells could recover the self-aggregative behavior and transit back to 3D pattern, accompanied by the restoration of hair inducing capability when the culture condition was changed. In addition, the global gene expressions during the transition from 2D pattern to 3D pattern were compared to detect the potential regulating genes and pathways involved in the recovery of 3D pattern and hair inducing capability.
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http://dx.doi.org/10.3390/ijms22094715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124381PMC
April 2021

Efficacy and safety of Reduning injection in the treatment of COVID-19: a randomized, multicenter clinical study.

Ann Palliat Med 2021 May 9;10(5):5146-5155. Epub 2021 Apr 9.

Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine, Beijing, China.

Background: Reduning injection is a traditional Chinese medicine (TCM) with known efficacy against a variety of viral infections, but there is no data about its efficacy against coronavirus disease 2019 (COVID-19).

Methods: To explore the efficacy and safety of Reduning injection in the treatment of COVID-19, a randomized, open-labeled, multicenter, controlled trial was conducted from 12 general hospitals between 2020.02.06 and 2020.03.23. Patients with COVID-19 who met the diagnostic criteria of the "Diagnosis and Treatment Program for Novel Coronavirus Infection Pneumonia (Trial Fifth Edition)". Patients were randomized to routine treatment with or without Reduning injection (20 mL/day for 14 days) (ChiCTR2000029589). The primary endpoint was the rate of achieving clinical symptom recovery on day 14 of treatment.

Results: There were 77 and 80 participants in the Reduning and control groups. The symptom resolution rate at 14 days was higher in the Reduning injection than in controls [full-analysis set (FAS): 84.4% vs. 60.0%, P=0.0004]. Compared with controls, the Reduning group showed shorter median time to resolution of the clinical symptoms (143 vs. 313.5 h, P<0.001), shorter to nucleic acid test turning negative (146.5 vs. 255.5 h, P<0.001), shorter hospital stay (14.1 vs. 18.1 days, P<0.001), and shorter time to defervescence (29 vs. 71 h, P<0.001). There was no difference in AEs (3.9% vs. 8.8%, P=0.383).

Conclusions: This preliminary trial suggests that Reduning injection might be effective and safe in patients with symptomatic COVID-19.
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http://dx.doi.org/10.21037/apm-20-2121DOI Listing
May 2021

Titin mutation in circulatory tumor DNA is associated with efficacy to immune checkpoint blockade in advanced non-small cell lung cancer.

Transl Lung Cancer Res 2021 Mar;10(3):1256-1265

Institute of Cancer, Xinqiao Hospital, The Army Medical University, Chongqing, China.

Background: Only a fraction of patients with advanced non-small cell lung cancer (NSCLC) respond well to immune checkpoint blockade (ICB) therapy. Here, we investigated whether Titin () mutation, which has been demonstrated to be a predictive biomarker in tissue-based analysis, can identify patients with a greater likelihood in response to ICB based on circulatory tumor DNA (ctDNA) sequencing.

Methods: In this retrospective analysis, 92 patients with advanced NSCLC from two independent cohorts who received ICB treatment were included. A probe panel covering all exons of TTN was developed and validated to detect mutation in ctDNA. Baseline plasma samples were collected and subjected to ctDNA sequencing with the probe panel.

Results: Of the 92 patients, 28.3% harbored mutation in their baseline ctDNA. Progression-free survival was significantly improved in patients with the mutated (212 days and 334.5 days for cohort 1 and 2) compared to those without the mutation (113 days and 147 days for cohort 1 and 2). Objective response to ICB treatment (40% for TTN and 15.8% for TTN in cohort 1; 50% for TTN and 23.4% for TTN in cohort 2) was common in patients with mutated . Stratified analysis showed a generally predictive potential of mutation in patients with advanced NSCLC.

Conclusions: The presence of mutated in pre-treatment peripheral blood was associated with favorable objective response and survival with ICB administration. Therefore, circulatory mutation may be applicable for guiding ICB immunotherapy in patients with NSCLC.
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http://dx.doi.org/10.21037/tlcr-20-1118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044474PMC
March 2021

DUSP16 promotes cancer chemoresistance through regulation of mitochondria-mediated cell death.

Nat Commun 2021 04 16;12(1):2284. Epub 2021 Apr 16.

Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.
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http://dx.doi.org/10.1038/s41467-021-22638-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052345PMC
April 2021

Antibiotic Use Among Hospitalized Children and Neonates in China: Results From Quarterly Point Prevalence Surveys in 2019.

Front Pharmacol 2021 29;12:601561. Epub 2021 Mar 29.

Department of Pediatrics, Lishui Maternal and Child Health Care Hospital, Lishui, China.

Antimicrobial resistance is a significant clinical problem in pediatric practice in China. Surveillance of antibiotic use is one of the cornerstones to assess the quality of antibiotic use and plan and assess the impact of antibiotic stewardship interventions. We carried out quarterly point prevalence surveys referring to WHO Methodology of Point Prevalence Survey in 16 Chinese general and children's hospitals in 2019 to assess antibiotic use in pediatric inpatients based on the WHO AWaRe metrics and to detect potential problem areas. Data were retrieved via the hospital information systems on the second Monday of March, June, September and December. Antibiotic prescribing patterns were analyzed across and within diagnostic conditions and ward types according to WHO AWaRe metrics and Anatomical Therapeutic Chemical (ATC) Classification. A total of 22,327 hospitalized children were sampled, of which 14,757 (66.1%) were prescribed ≥1 antibiotic. Among the 3,936 sampled neonates (≤1 month), 59.2% ( = 2,331) were prescribed ≥1 antibiotic. A high percentage of combination antibiotic therapy was observed in PICUs (78.5%), pediatric medical wards (68.1%) and surgical wards (65.2%). For hospitalized children prescribed ≥1 antibiotic, the most common diagnosis on admission were lower respiratory tract infections (43.2%, = 6,379). WHO Watch group antibiotics accounted for 70.4% of prescriptions ( = 12,915). The most prescribed antibiotic ATC classes were third-generation cephalosporins (41.9%, = 7,679), followed by penicillins/β-lactamase inhibitors (16.1%, = 2,962), macrolides (12.1%, = 2,214) and carbapenems (7.7%, = 1,331). Based on these data, overuse of broad-spectrum Watch group antibiotics is common in Chinese pediatric inpatients. Specific interventions in the context of the national antimicrobial stewardship framework should aim to reduce the use of Watch antibiotics and routine surveillance of antibiotic use using WHO AWaRe metrics should be implemented.
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http://dx.doi.org/10.3389/fphar.2021.601561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039455PMC
March 2021

Use of Shenhuang paste on Shenque point improves chemotherapy induced gastrointestinal toxicity in breast cancer: A protocol for randomized controlled trial.

Medicine (Baltimore) 2021 Apr;100(15):e25097

Zhejiang Provincial Hospital of Chinese Medicine.

Background: Breast cancer, a malignant disorder, occurs in the epithelial tissue of the breast gland. Chemotherapy is the standard treatment for breast cancer, however, the side effect, especially gastrointestinal dysfunction, due to chemotherapy still remain major problems. Traditional Chinese Medicine has been proven therapeutically effective on reducing adverse effects caused by chemotherapy. Shenhuang Plaster.

Methods: The study is a randomized, placebo-controlled, blind trial. A total of 160 Chinese breast cancer patients will be enrolled and randomly allocated into the experimental group and control group in a 1:1 ratio. Patients in the experimental group will be prescribed Shenhuang plaster application on shenque point (CV8) plus chemotherapy treatment. Patients in the control group will be prescribed placebo plaster application on CV8 plus chemotherapy treatment. The acupoint application will last 3 days. The primary outcome will be the form of faces every day, and the secondary outcomes the symptom score of traditional Chinese medicine, the changes of fecal bacteria and metabolites, serum motilin, gastrin and ghrelin levels.

Discussion: This study is to observe therapeutic effects with Shenhuang plaster application on CV8 to regulate chemotherapy-induced gastrointestinal toxicity in breast cancer patients.

Trial Registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=55262) No. ChiCTR2000034313. Registered on July 2, 2020.
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http://dx.doi.org/10.1097/MD.0000000000025097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052020PMC
April 2021

MicroRNA-139-5p inhibits inflammatory and oxidative stress responses of Salmonella-infected macrophages through modulating TRAF6.

Pathog Dis 2021 04;79(4)

Department of Laboratory Medicine, Sanmen People's Hospital, 15 Taihe road, Binhai new town, Sanmen county, Taizhou, Zhejiang 317100, China.

Evidence indicates that macrophages play an important role in the immune system. Therefore, research involving inflammatory and oxidative stress responses in macrophages is of great significance. Many factors contribute to inflammation and oxidative stress, including Salmonella. We investigated the effect of the miR-139-5p/TRAF6 axis on the inflammatory and oxidative stress responses of Salmonella -infected macrophages. Our findings revealed that miR-139-5p decreased IL-1β and TNF-α levels to inhibit Salmonella-induced inflammatory responses in the RAW264.7 macrophage cell line. Furthermore, miR-139-5p inhibited Salmonella-induced oxidative stress by strengthening SOD, CAT and GSH-PX activity, as well as lowering the malondialdehyde level in the RAW264.7 macrophages cell line. Subsequently, it was verified that TRAF6 was a downstream target of miR-139-5p in RAW264.7 cells. Rescue assays indicated that the over-expression of miR-139-5p inhibits the effects of TRAF6 on inflammatory and oxidative stress responses including Salmonella infection in RAW264.7 cells. To our knowledge, this study is the first to verify that miR-139-5p inhibits inflammatory and oxidative stress responses of Salmonella-infected macrophages through regulating TRAF6. This discovery may offer new insights on inflammatory and oxidative stress responses in macrophages.
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http://dx.doi.org/10.1093/femspd/ftab018DOI Listing
April 2021

Electric-Field Reversible Switching of the Exchange Spring and Exchange Bias Effect in SrCoO/LaSrMnO Heterostructures.

ACS Appl Mater Interfaces 2021 Apr 26;13(13):15774-15782. Epub 2021 Mar 26.

School of Chemistry and Materials Science, Key Laboratory of Magnetic Molecules and Magnetic Information Materials, Ministry of Education, Shanxi Normal University, Linfen 041004, P. R. China.

The technique of electrical field to manipulate physicochemical properties of oxide heterostructures has ample potential in electronic and ionitronic devices. SrCoO is a famous "sponge" material displaying topotactic structural phase transition from perovskite (0 ≤ ≤ 0.25) to brownmillerite ( = 0.5) accompanied by the magnetic phase transition from ferromagnetism to antiferromagnetism, which can be controlled reversibly by electric field via the ionic liquid gating method. Here, the exchange spring effect can be observed at the perovskite SrCoO (P-SCO)/LaSrMnO (LSMO) bilayer, while the exchange bias effect is received at the brownmillerite SrCoO (B-SCO)/LSMO bilayer. The reversible and nonvolatile switching of the exchange spring and exchange bias effect can be achieved in these SCO/LSMO bilayers by utilizing ionic liquid gating to control the annihilation or generation of oxygen vacancies. In addition, the variations in the stacking orders of these SCO/LSMO bilayers are investigated because the previous SCO layer always acts as the cover layer. It is worth noting that LSMO/SCO bilayer magnetization is strongly suppressed when the SCO layer is used as the bottom layer. Combined with the X-ray line dichroism measurements, it is suggested that the bottom SCO layer would induce the spin arrangements in the LSMO layer to have the tendency toward the out-of-plane orientation. This is the reason for the sharp decrease in magnetization of LSMO/SCO bilayers. Our investigations accomplish a reversible control of the exchange coupling transition in all-oxide bilayers and provide the foundation for further electric-field control of magnetic properties.
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http://dx.doi.org/10.1021/acsami.0c22254DOI Listing
April 2021

How do employees appraise challenge and hindrance stressors? Uncovering the double-edged effect of conscientiousness.

J Occup Health Psychol 2021 Jun 25;26(3):243-257. Epub 2021 Mar 25.

Department of Psychology.

The challenge-hindrance model deems primary appraisal the central mechanism underlying the effects of challenge and hindrance stressors on employee outcomes. However, the literature has reported conflicting findings on the relationships between challenge/hindrance stressors and challenge/hindrance appraisals. Drawing upon transactional theory (Lazarus & Folkman, 1984), the current study aims to address these conflicting findings by investigating the moderating effect of conscientiousness on stressor-appraisal relationships. On this basis, we further demonstrate when challenge and hindrance appraisals mediate the effects of challenge and hindrance stressors on work motivation (i.e., work engagement) and job strain (i.e., job-related anxiety). We conducted two substudies to examine the research model at the between-person level (Study 1) and the within-person level (Study 2). The results of both studies were highly convergent. Challenge stressors were more positively related to both challenge and hindrance appraisals for employees high in conscientiousness. Hindrance stressors were also more positively related to hindrance appraisal for employees high in conscientiousness. By exacerbating the stressor-appraisal relationships, conscientiousness was found to strengthen the indirect relationship of challenge stressors with work engagement via challenge appraisal and the indirect relationships of challenge and hindrance stressors with job-related anxiety via hindrance appraisal. We conclude that conscientiousness functions as a double-edged sword in the process of making primary appraisals. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/ocp0000275DOI Listing
June 2021

Identification of primordial germ cell-like cells as liver metastasis initiating cells in mouse tumour models.

Cell Discov 2020 Mar 24;6(1):15. Epub 2020 Mar 24.

Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.

Liver metastasis, characterized by the spread of tumors to the liver from other areas, represents a deadly disease with poor prognosis. Currently, there is no effective therapeutic strategies and/or agents to combat liver metastasis primarily due to the insufficient understanding of liver metastasis. To develop a promising strategy for targeting liver metastasis, understanding of a cell origin responsible for liver metastasis and how this cell can be pharmacologically eliminated are therefore crucial. Using diverse tumor models including p53 genetic mouse model and syngeneic tumor models, we identified primordial germ cell (PGC)-like tumor cells, which are enriched in earliest liver micro-metastasis (up to 99%), as a cell origin of liver metastasis. PGC-like tumor cells formed earliest micro-metastasis in liver and gradually differentiated into non-PGC-like tumor cells to constitute late macro-metastasis in the course of tumor metastasis. The liver metastasis-initiating cells (PGC-like tumor cells) display cell renewal and differentiation capabilities, resemble primordial germ cells (PGCs) in morphology and PGC marker gene expression, and express higher level of the genes linked to metastasis and immune escape compared with non-PGC-like tumor cells. Of note, Stellar PGC-like tumor cells, but not Stellar non-PGC-like cells, sorted from primary tumors of p53 mice readily form liver metastasis. Depletion of PGC-like tumor cells through genetic depletion of any of key germ cell genes impairs liver metastasis, while increased PGC-like tumor cells by SMAD2 knockout is correlated with markedly enhanced liver metastasis. Finally, we present the proof of principle evidence that pharmacologically targeting BMP pathways serves as a promising strategy to eliminate PGC-like tumor cells leading to abrogating liver metastasis. Collectively, our study identifies PGC-like tumor cells as a cell origin of liver metastasis, whose depletion by genetically targeting core PGC developmental genes or pharmacologically inhibiting BMP pathways serves a promising strategy for targeting liver metastasis.
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http://dx.doi.org/10.1038/s41421-020-0145-3DOI Listing
March 2020

Normotensive presentation in primary aldosteronism: A report of two cases.

J Renin Angiotensin Aldosterone Syst 2021 Jan-Dec;22(1):14703203211003780

Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.

Normotensive patients with primary aldosteronism (PA) are relatively rare. Herein, we report two patients with normotensive PA and present a literature review to improve an understanding of the disease. Patient 1, a 56-year-old man, presented with recurrent hypokalemia that lasted for more than 2 years. Patient 2 was a 33-year-old man who presented with sexual dysfunction and was diagnosed with a prolactinoma combined with adrenal insufficiency and hypogonadism. Neither of these patients had hypertension that was detectable on repeated manual measurements. In both patients, a typical biological profile of PA was demonstrated that included hypokalemia with kaliuresis, elevated plasma aldosterone concentration (PAC), suppressed plasma renin concentration, and a high aldosterone-to-renin ratio. Both patients did not have sufficiently suppressed PAC on the saline infusion test, confirming the diagnosis of PA. Computed tomography of the adrenal gland and adrenal venous sampling suggested an aldosteronoma, which was confirmed by lateralized hypersecretion of aldosterone. After removal of the benign adenoma, the biochemical abnormalities were corrected. As hypertension is not necessarily a sign of PA, we propose that all patients with hypokalemia should be screened for PA in order to prevent cardiovascular complications while balancing economics and effectiveness.
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http://dx.doi.org/10.1177/14703203211003780DOI Listing
March 2021

Self-Assembled Micelles Improve the Oral Bioavailability of Dihydromyricetin and Anti-Acute Alcoholism Activity.

AAPS PharmSciTech 2021 Mar 21;22(3):111. Epub 2021 Mar 21.

Institute of Materia Medica, School of Pharmacy, Chengdu Medical College, No. 783 Xindu Avenue, Chengdu, 610500, China.

Dihydromyricetin (DMY) is highly effective in counteracting acute alcohol intoxication. However, its poor aqueous solubility and permeability lead to the low oral bioavailability and limit its clinic application. The aim of this work is to use Solutol®HS15 (HS 15) as surfactant to develop novel micelle to enhance the oral bioavailability of DMY by improving its solubility and permeability. The DMY-loaded Solutol®HS15 micelles (DMY-Ms) were prepared by the thin-film hydration method. The particle size of DMY-Ms was 13.97 ± 0.82 nm with an acceptable polydispersity index of 0.197 ± 0.015. Upon entrapped in micelles, the solubility of DMY in water was increased more than 25-fold. The DMY-Ms had better sustained release property than that of pure DMY. In single-pass intestinal perfusion models, the absorption rate constant (Ka) and permeability coefficient (Papp) of DMY-Ms were 5.5-fold and 3.0-fold than that of pure DMY, respectively. The relative bioavailability of the DMY-Ms (AUC) was 205% compared with that of pure DMY (AUC), indicating potential for clinical application. After administering DMY-Ms, there was much lower blood alcohol level and shorter duration of the loss of righting relax (LORR) in drunk animals compared with that treated by pure DMY. In addition, the oral administration of DMY-Ms greatly reduced oxidative stress, and significantly defended liver and gastric mucosa from alcoholic damages in mice with alcohol-induced tissue injury. Taken together, HS 15-based micelle system greatly improves the bioavailability of DMY and represents a promising strategy for the management of acute alcoholism. Graphical abstract.
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http://dx.doi.org/10.1208/s12249-021-01983-2DOI Listing
March 2021

Nanoscale Magnetization Reversal by Magnetoelectric Coupling Effect in GaFeO Multiferroic Thin Films.

ACS Appl Mater Interfaces 2021 Apr 19;13(15):18194-18201. Epub 2021 Mar 19.

School of Chemistry and Materials Science of Shanxi Normal University & Key Laboratory of Magnetic Molecules and Magnetic Information Materials of Ministry of Education, Shanxi Normal University, Linfen 041004, China.

The control of magnetism by electric means in single-phase multiferroic materials is highly desirable for the realization of next-generation magnetoelectric (ME) multifunctional devices. Nevertheless, most of these materials reveal either low working temperature or antiferromagnetic nature, which severely limits the practical applications. Herein, we selected room-temperature multiferroic GaFeO (GFO) with ferrimagnetism to study electric-field-induced nanoscale magnetic domain reversal. The GFO thin film fabricated on the (111)-orientated Nb-doped SrTiO single-crystal substrate was obtained through the pulsed laser deposition method. The test results indicate that the thin film not only exhibits ferroelectricity but also ferrimagnetism at room temperature. More importantly, reversible and nonvolatile nanoscale magnetic domains reversal under pure electrical fields is further demonstrated by taking advantage of its ME coupling effect with dependent origins based on iron ions. When providing an appropriate applied voltage, clear magnetic domain structures with large size can be easily manipulated. Meanwhile, the change ratio of the electrically induced magnetizations in the defined areas can reach up to 72%. These considerable merits of the GFO thin film may provide a huge potential in the ME multifunctional devices, such as the multi-value, low-energy-consuming, and nonvolatile memory and beyond.
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http://dx.doi.org/10.1021/acsami.0c21659DOI Listing
April 2021

The Role of a Dipeptide Transporter in the Virulence of Human Pathogen, .

Front Microbiol 2021 25;12:633166. Epub 2021 Feb 25.

Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.

harbors a dipeptide (Dpp) transporter consisting of a substrate-binding protein (DppA), two permeases (DppB and C), and two ATPases (DppD and F). The Dpp transporter is responsible for the transportation of dipeptides and short peptides. We found that its expression is important for the growth of . . To understand the role of the Dpp transporter in the pathogenesis of . , the expression of virulence factors and . -induced IL-8 production were investigated in wild-type and isogenic Dpp transporter mutants. We found that expression of CagA was downregulated, while expression of type 4 secretion system (T4SS) components was upregulated in Dpp transporter mutants. The DppA mutant strain expressed higher levels of outer membrane proteins (OMPs), including BabA, HopZ, OipA, and SabA, and showed a higher adhesion level to gastric epithelial AGS cells compared with the . 26695 wild-type strain. After infection of AGS cells, . Δ induced a higher level of NF-κB activation and IL-8 production compared with wild-type. These results suggested that in addition to supporting the growth of . , the Dpp transporter causes bacteria to alter the expression of virulence factors and reduces . -induced NF-κB activation and IL-8 production in gastric epithelial cells.
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http://dx.doi.org/10.3389/fmicb.2021.633166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959749PMC
February 2021

Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity.

Genome Biol 2021 03 4;22(1):73. Epub 2021 Mar 4.

Department of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.

Background: Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained.

Results: Analyzing single-cell RNA sequencing from Alzheimer's disease (AD) and Huntington's disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/- cells, a model for autism spectrum disorder.

Conclusions: Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.
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http://dx.doi.org/10.1186/s13059-021-02301-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934477PMC
March 2021

LINC00460 facilitated tongue squamous cell carcinoma progression via the miR-320b/IGF2BP3 axis.

Oral Dis 2021 Mar 4. Epub 2021 Mar 4.

Department of Stomatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Objective: We aimed to explore the role of long intergenic non-protein coding RNA 460 (LINC00460) in tongue squamous cell carcinoma (TSCC).

Methods: We enrolled 27 TSCC patients to explore LINC00460 expression in clinical TSCC samples. RT-qPCR measured expression of molecules in this research. Loss-of-function assays explored biological function of LINC00460 in TSCC cells. RNA pull-down assay, luciferase reporter assay, and RIP assay investigated mechanism of LINC00460 underlying TSCC cells.

Results: TSCC tissues and cell lines both showed high expression of LINC00460. Functionally, LINC00460 downregulation inhibited TSCC cell growth and promoted TSCC cell apoptosis. Additionally, LINC00460 silencing suppressed tumor growth in vivo. Mechanistically, LINC00460 bound with microRNA 320b (miR-320b) in TSCC cells. MiR-320b overexpression suppressed TSCC cell growth and promoted TSCC cell apoptosis. Moreover miR-320b targeted insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) 3'untranslated region in TSCC cells. Furthermore, IGF2BP3 silencing suppressed TSCC cell growth and promoted TSCC cell apoptosis. IGF2BP3 upregulation countervailed effects of silenced LINC00460 on TSCC cells. The LINC00460/miR-320b/IGF2BP3 axis was associated with lymph node metastasis of TSCC patients.

Conclusion: Our research illustrated that LINC00460 facilitated TSCC progression via the miR-320b/IGF2BP3 axis, highlighting a potential insight for the treatment of TSCC.
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http://dx.doi.org/10.1111/odi.13828DOI Listing
March 2021
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