Publications by authors named "Yin Gao"

82 Publications

Improving robustness of a deep learning-based lung-nodule classification model of CT images with respect to image noise.

Phys Med Biol 2021 Nov 24. Epub 2021 Nov 24.

Department of Radiation Oncology, UT Southwestern Medical Center, 6363 Forest Park Rd. BL10.202G, MC9315, Dallas, Texas, 75390-9315, UNITED STATES.

Objective: Robustness is an important aspect to consider, when developing methods for medical image analysis. This study investigated robustness properties of deep neural networks (DNNs) for a lung nodule classification problem based on CT images and proposed a solution to improve robustness.

Approach: We firstly constructed a class of four DNNs with different widths, each predicting an output label (benign or malignant) for an input CT image cube containing a lung nodule. These networks were trained to achieve Area Under the Curve of 0.891-0.914 on a testing dataset. We then added to the input CT image cubes noise signals generated randomly using a realistic CT image noise model based on a noise power spectrum at 100 mAs, and monitored the DNN's output change. We defined $SAR_{5} (\%)$ to quantify the robustness of the trained DNN model, indicating that for $5\%$ of CT image cubes, the noise can change the prediction results with a chance of at least $SAR_{5} (\%)$. To understand robustness, we viewed the information processing pipeline by the DNN as a two-step process, with the first step using all but the last layers to extract representations of the input CT image cubes in a latent space, and the second step employing the last fully-connected layer as a linear classifier to determine the position of the sample representations relative to a decision plane. To improve robustness, we proposed to retrain the last layer of the DNN with a Supporting Vector Machine (SVM) hinge loss function to enforce the desired position of the decision plane.

Main Results: $SAR_{5}$ ranged in $47.0\sim 62.0\%$ in different DNNs. The unrobustness behavior may be ascribed to the unfavorable placement of the decision plane in the latent representation space, which made some samples be perturbed to across the decision plane and hence susceptible to noise. The DNN-SVM model improved robustness over the DNN model and reduced $SAR_{5}$ by $8.8\sim 21.0\%$.

Significance: This study provided insights about the potential reason for the unrobustness behavior of DNNs and the proposed DNN-SVM model improved model robustness.
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http://dx.doi.org/10.1088/1361-6560/ac3d16DOI Listing
November 2021

Transferrin-Pep63-liposomes accelerate the clearance of Aβ and rescue impaired synaptic plasticity in early Alzheimer's disease models.

Cell Death Discov 2021 Sep 21;7(1):256. Epub 2021 Sep 21.

NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, 221004, Xuzhou, Jiangsu, China.

Alzheimer's disease (AD) is characterized by aberrant accumulation of extracellular β-amyloid (Aβ) peptides in the brain. Soluble Aβ oligomers are thought to be the most neurotoxic species and are correlated with cognitive dysfunction in early AD. However, there is still no effective treatment so far. We determined that Pep63, a small peptide, had a neuroprotective effect on synaptic plasticity and memory in our previous study. Here, we developed novel and multifunctional liposomes targeting both Aβ oligomers and fibrils based on a liposome delivery system. Transferrin-Pep63-liposomes (Tf-Pep63-Lip), possessing the ability for blood-brain barrier targeting, were also incorporated with phosphatidic acid (PA) and loaded with neuroprotective Pep63. We discovered that administration of Tf-Pep63-Lip could significantly reduce the Aβ burden in the hippocampus, and improve cognitive deficits in 6-month-old APP/PS1 mice in the Morris-Water maze task and fear-conditioning test with the combined effects of PA and Pep63. Tf-Pep63-Lip could capture Aβ oligomers or fibrils and then facilitated microglial chemotaxis nearby for clearance. Simultaneously, Tf-Pep63-Lip hindered Aβ1-42 aggregation and disaggregated Aβ1-42 assembly due to multivalent PA-Aβ. Pep63 effectively inhibited the binding between EphB2 and Aβ oligomers after release from liposomes and rescued NMDA receptors trafficking, the basis of synaptic plasticity. No side effects were observed in either APP/PS1 or wild-type mice, indicating that Tf-Pep63-Lip might be safe under the dosing regimen used in our experiment. Taken together, our results suggested that Tf-Pep63-Lip may serve as a safe and efficient agent for AD combination therapy.
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http://dx.doi.org/10.1038/s41420-021-00639-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455582PMC
September 2021

dCA1-NAc shell glutamatergic projection mediates context-induced memory recall of morphine.

Pharmacol Res 2021 10 28;172:105857. Epub 2021 Aug 28.

NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address:

Opioid relapse is generally caused by the recurrence of context-induced memory reinstatement of reward. However, the internal mechanisms that facilitate and modify these processes remain unknown. One of the key regions of the reward is the nucleus accumbens (NAc) which receives glutamatergic projections from the dorsal hippocampus CA1 (dCA1). It is not yet known whether the dCA1 projection to the NAc shell regulates the context-induced memory recall of morphine. Here, we used a common model of addiction-related behavior conditioned place preference paradigm, combined with immunofluorescence, chemogenetics, optogenetics, and electrophysiology techniques to characterize the projection of the dCA1 to the NAc shell, in context-induced relapse memory to morphine. We found that glutamatergic neurons of the dCA1 and gamma aminobutyric acidergic (GABA) neurons of the NAc shell are the key brain areas and neurons involved in the context-induced reinstatement of morphine memory. The dCA1-NAc shell glutamatergic input pathway and the excitatory synaptic transmission of the dCA1-NAc shell were enhanced via the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) when mice were re-exposed to environmental cues previously associated with drug intake. Furthermore, chemogenetic and optogenetic inactivation of the dCA1-NAc shell pathway decreased the recurrence of long- and short-term morphine-paired context memory in mice. These results provided evidence that the dCA1-NAc shell glutamatergic projections mediated the context-induced memory recall of morphine.
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http://dx.doi.org/10.1016/j.phrs.2021.105857DOI Listing
October 2021

Efficaciousness of dexmedetomidine in children undergoing cleft lip and palate repair: a systematic review and meta-analysis.

BMJ Open 2021 08 16;11(8):e046798. Epub 2021 Aug 16.

Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

Objective: To systematically assess the efficacy and safety of dexmedetomidine as an anaesthesia adjuvant for cleft lip and palate (CLP) repair in children.

Design: Systematic review and meta-analysis.

Data Sources: PubMed, Embase, Cochrane, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP) and Wanfang (up to October 2020). Studies in languages other than English and Chinese were excluded.

Eligibility Criteria For Selecting Studies: Randomised controlled trials (RCTs) evaluating the impact of dexmedetomidine on emergence agitation (EA), the need for postoperative rescue analgesics, postoperative nausea and vomiting (PONV), and other adverse events in paediatric patients during CLP repair.

Data Extraction And Synthesis: The quality of evidence was assessed by using the Cochrane Review Methods and the Grading of Recommendations Assessment, Development and Evaluation approach. Data were screened, extracted and assessed by two independent authors. Outcomes were reported as a risk ratio (RR) with a 95% CI. A random-effect model was used when heterogeneity was detected.

Results: Thirteen studies including 1040 children met the inclusion criteria. The incidence of EA was significantly decreased in the dexmedetomidine group (RR, 0.19; 95% CI 0.10 to 0.36; p<0.00001; I=56%) as compared with the control group. Paediatric patients receiving dexmedetomidine had lower postoperative analgesic requirements (RR, 0.27; 95% CI 0.10 to 0.73; p=0.01; I=84%) and a lower incidence of respiratory adverse events (RR, 0.49; 95% CI 0.31 to 0.78; p=0.003; I=0%). There were no significant differences in the risk of PONV and cardiovascular adverse events.

Conclusions: There was a lack of high-quality studies in this field. Perioperative administration of dexmedetomidine reduced the need for postoperative rescue analgesics and the incidence of EA in children without side effects undergoing CLP repair. However, further verification with larger samples and higher-quality RCTs is needed.
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http://dx.doi.org/10.1136/bmjopen-2020-046798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370512PMC
August 2021

The critical role of B4GALT4 in promoting microtubule spindle assembly in HCC through the regulation of PLK1 and RHAMM expression.

J Cell Physiol 2021 Jul 16. Epub 2021 Jul 16.

Department of Biochemistry, Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, China.

Beta 1,4-galactosyltransferase (B4GALT)-family glycosyltransferases are involved in multiple biological processes promoting cancer progression, regulating the dynamic network of cancer cell proliferation and apoptosis, and are associated with metastasis. However, their roles in the dysregulation of expressions and functions in hepatocellular carcinoma (HCC) remain unclear. Herein, bioinformatic approaches have been applied to investigate their expression profiles, and to obtain correlations between gene expressions and clinicopathological parameters as well as downstream target genes in HCC. Multiple databases were used to screen the expressions of B4GALT family members in tumor tissues, and to evaluate their prognostic value among HCC patients in different aspects. Results indicated an overall upregulation of B4GALTs' transcription levels in tumor tissues and a strong correlation with poor prognosis. Through Gene Ontology analysis, gene set enrichment analysis, and verification of single-cell RNA sequencing data, we established a connection between the B4GALT family and microtubule spindle assembly, which particularly highlighted the role of B4GALT4 in this phenomenon. B4GALT4 knockdown downregulated the production of lumican, and repressed the expressions of polo-like kinase 1 and RHAMM by regulating the transforming growth factor-beta pathway, thus suggesting that B4GALT4 is a critical promotor for HCC. We believe that these studies will provide valuable insight into the role of B4GALT family members in HCC and lead to the development of new strategies to improve the outcomes for patients with HCC.
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http://dx.doi.org/10.1002/jcp.30531DOI Listing
July 2021

Role of Glycans on Key Cell Surface Receptors That Regulate Cell Proliferation and Cell Death.

Cells 2021 05 19;10(5). Epub 2021 May 19.

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L3N6, Canada.

Cells undergo proliferation and apoptosis, migration and differentiation via a number of cell surface receptors, most of which are heavily glycosylated. This review discusses receptor glycosylation and the known roles of glycans on the functions of receptors expressed in diverse cell types. We included growth factor receptors that have an intracellular tyrosine kinase domain, growth factor receptors that have a serine/threonine kinase domain, and cell-death-inducing receptors. - and -glycans have a wide range of functions including roles in receptor conformation, ligand binding, oligomerization, and activation of signaling cascades. A better understanding of these functions will enable control of cell survival and cell death in diseases such as cancer and in immune responses.
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http://dx.doi.org/10.3390/cells10051252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159107PMC
May 2021

TREM1 Blockade Ameliorates Lipopolysaccharide-Induced Acute Intestinal Dysfunction through Inhibiting Intestinal Apoptosis and Inflammation Response.

Biomed Res Int 2021 16;2021:6635452. Epub 2021 Apr 16.

Wuxi Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine Affiliated Wuxi Hospital, Wuxi, 214071 Jiangsu, China.

Objective: The lipopolysaccharide- (LPS-) induced acute intestinal dysfunction model has been widely applied in recent years. Here, our aim was to investigate the effect of triggering receptor expressed on myeloid cells-1 (TREM1) inhibitor in LPS-induced acute intestinal dysfunction.

Methods: Male rats were randomly assigned into normal (saline injection), model (LPS and saline injection), and LP17 (LPS and LP17 (a synthetic TREM1 inhibitor) injection) groups. The levels of intestinal TREM1 expression were evaluated by immunohistochemistry and western blot. Intestinal permeability and apoptosis were separately assessed by the lactulose/mannitol (L/M) ratio and TUNEL assay. The levels of soluble TREM1 (sTREM1), TNF-, IL-6, and IL-1 were measured in the plasma and intestinal tissues by ELISA. The expression levels of NF-B, high-mobility group box 1 (HMGB1), and toll-like receptor 4 (TLR-4) were measured with RT-qPCR and western blot. After transfection with si-TREM1 in LPS-induced intestinal epithelium-6 (IEC-6) cells, p-p65 and p-IB levels were detected by western blot.

Results: LP17-mediated TREM1 inhibition alleviated the intestine tissue damage in rats with LPS-induced acute intestinal dysfunction. LP17 attenuated the LPS-induced increase in sTREM1, TNF-, IL-6, and IL-1 levels in the plasma and intestinal tissues. Furthermore, intestine permeability and epithelial cell apoptosis were ameliorated by LP17. LP17 attenuated the LPS-induced increase in the expression of TREM1, HMGB1, TLR-4, and NF-B in the intestine tissues. In vitro, TREM1 knockdown inactivated the NF-B signaling in LPS-induced IEC-6 cells.

Conclusion: LP17 could ameliorate LPS-induced acute intestinal dysfunction, which was associated with inhibition of intestinal apoptosis and inflammation response.
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http://dx.doi.org/10.1155/2021/6635452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068534PMC
May 2021

Systematic analysis reveals a lncRNA-miRNA-mRNA network associated with dasatinib resistance in chronic myeloid leukemia.

Ann Palliat Med 2021 Feb 2;10(2):1727-1738. Epub 2020 Dec 2.

The First Clinical School of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China; Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China; Department of Biomedical Engineering, Basic Medicine School, Guangzhou Medical University, Guangzhou, China.

Background: Chronic myelogenous leukemia (CML) is a malignant tumor formed by the clonal proliferation of bone marrow hematopoietic stem cells. CML is a relatively rare disease, mainly affecting elderly patients, but the prevalence of CML is expected to increase dramatically. The tyrosine kinase inhibitors (TKIs) have changed the CML patients' treatment patterns and improved its treatment effect, but drug resistance still remains a significant problem to be solved. Therefore, the identification of biomarkers of CML resistance involved therein is essential for treatment and prognosis prediction.

Methods: Bioinformatics was used to analyze and construct a lncRNA-miRNA-mRNA network of CML resistance to dasatinib and predict key lncRNAs.

Results: By screening differentially expressed genes in CML resistant to dasatinib and comprehensively analyzing their functions and signal pathways, the core genes in these differential genes were found, and by predictive analysis of the upstream targets of these core genes. Finally, a network diagram containing lncRNA, miRNA, and mRNA was constructed.

Conclusions: MALAT1 as a lncRNA may be a tumor suppressor in patients with CML. According to our data, MALAT1 may have potential role as a molecular biomarker for the occurrence and development of CML resistance to dasatinib.
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http://dx.doi.org/10.21037/apm-20-343DOI Listing
February 2021

The expression and functional analysis of the sialyl-T antigen in prostate cancer.

Glycoconj J 2020 08 24;37(4):423-433. Epub 2020 Jun 24.

Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, 130012, Changchun, China.

Aberrant glycosylation is a featured characteristic of cancer and plays a role in cancer pathology; thus an understanding of the compositions and functions of glycans is critical for discovering diagnostic biomarkers and therapeutic targets for cancer. In this study, we used MALDI-TOF-MS analysis to determine the O-glycan profiles of prostate cancer cells metastasized to bone (PC-3), brain (DU145), lymph node (LNCaP), and vertebra (VCaP) in comparison to immortalized RWPE-1 cells derived from normal prostatic tissue. Prostate cancer (CaP) cells exhibited an elevation of simple/short O-glycans, with a reduction of complex O-glycans, increased O-glycan sialylation and decreased fucosylation. Core 1 sialylation was increased dramatically in all CaP cells, and especially in PC-3 cells. The expression of Neu5Acα2-3Galβ1-3GalNAc- (sialyl-3T antigen) which is the product of α2,3-sialyltransferase-I (ST3Gal-I) was substantially increased. We therefore focused on exploring the possible function of ST3Gal-I in PC-3 cells. ST3Gal-I silencing studies showed that ST3Gal-I was associated with PC-3 cell proliferation, migration and apoptosis. Further in vivo studies demonstrated that down regulation of ST3Gal-I reduced the tumor size in xenograft mouse model, indicating that sialyl-3T can serve as a biomarker for metastatic prostate cancer prognosis, and that ST3Gal-I could be a target for therapeutic intervention in cancer treatment.
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http://dx.doi.org/10.1007/s10719-020-09927-xDOI Listing
August 2020

Simultaneous measurement of phenols by three-way fluorescence spectroscopy: A comparison of N-PLS/RBL, U-PLS/RBL and PARAFAC.

Spectrochim Acta A Mol Biomol Spectrosc 2020 Oct 21;239:118511. Epub 2020 May 21.

Key Laboratory of Environmental Optics and Technology, Anhui Institute of Optics and Fine Mechanics, Chinese Academy of Sciences, Hefei, 230031, China.

Phenol, o-cresol, p-cresol, catechol and resorcinol are five phenolic compounds with extremely similar structure. Their fluorescence spectra are hard to be analyzed because of the serious spectral overlaps between any two of the five phenolic components in the mixture system. In this experiment, multi-dimensional partial least-squares (N-PLS), unfolded partial least-squares (U-PLS) with residual bilinearization (RBL) and parallel factor analysis (PARAFAC) are employed to analyze the three-way fluorescence spectra aiming to achieve quantitative results. Meanwhile, a contrast of these three methods is given. The experiment results show that N-PLS/RBL and U-PLS/RBL algorithms are superior to PARARFAC in terms of analysis of highly overlapping three-way fluorescence spectra for concentration determination.
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http://dx.doi.org/10.1016/j.saa.2020.118511DOI Listing
October 2020

LncRNA NEAT1 sponges miR-214 to regulate M2 macrophage polarization by regulation of B7-H3 in multiple myeloma.

Mol Immunol 2020 01 12;117:20-28. Epub 2019 Nov 12.

Department of Hematology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, P.R. China; Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha 410003, Hunan Province, P.R. China. Electronic address:

Background: LncRNA NEAT1 was associated with the tumorigenesis of multiple myeloma (MM). However, the mechanisms of M2 macrophage polarization involved with NEAT1 in MM are still unknown.

Methods: Bone marrow samples, multiple myeloma cells RPMI 8226 and monocyte cell line THP-1 were used in this study. The expression of NEAT1 and miR-214 was modified by transfection with the shNEAT1 or miR-214 inhibitor. The expression of NEAT1, miR-214 and B7-H3 in MM patient tissues and cells was analyzed by RT-qPCR. ELISA assay was used to determine the release of B7-H3 in the supernatant of cell culture. The patient survival curve was analyzed using Kaplan-Meier method. The macrophage polarization markers were examined by RT-qPCR and western blotting. The interaction between NEAT1, miR-214 and B7-H3 was analyzed by Dual-Luciferase reporter and RIP assays. AG490 was used to block the JAK2/STAT3 signaling. Co-culture of THP-1 and RPMI 8226 cells was used for macrophage polarization.

Results: NEAT1 and B7-H3 were up-regulated, but miR-214 was obviously down-regulated in MM patients. B7-H3, NEAT1 and miR-214 were associated with overall survival time of MM patients. NEAT1 silencing induced miR-214 and inhibited the expression and release of B7-H3 and then suppressed M2 macrophage polarization via inhibiting the JAK2/STAT3 signaling. NEAT1 directly targeted miR-214, and miR-214 directly bound to B7-H3. MiR-214 inhibitor reversed the down-regulation and release of B7-H3 and M2 macrophage polarization caused by shNEAT1. The specific JAK2/STAT3 signaling inhibitor AG490 abrogated M2 macrophage polarization.

Conclusion: NEAT1 promoted M2 macrophage polarization by sponging miR-214 and then regulating B7-H3, thus accelerating MM progression via the JAK2/STAT3 signaling pathway. Our study revealed novel mechanisms of M2 macrophage polarization and provided new potential clinical therapeutic targets for MM.
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http://dx.doi.org/10.1016/j.molimm.2019.10.026DOI Listing
January 2020

-Butyrylated hyaluronic acid ameliorates gout and hyperuricemia in animal models.

Pharm Biol 2019 Dec;57(1):717-728

Division of Rheumatology, Department of Medicine, Queen's University , Kingston , Canada.

Hyaluronic acid (HA) plays critical roles in the structural skeleton, joint lubrication, renal function and cell signaling. We previously showed that partially -butyrylated, low molecular weight, hyaluronic acid (BHA) exhibited an anti-inflammatory effect in cultured human macrophage, where inflammation was induced either by a TL-4 agonist or the low molecular weight HA itself, in dose-dependent fashion. To investigate the anti-inflammatory, antioxidative, and antihyperuricemic effects of BHA using animal models of acute gouty arthritis and hyperuricemia. The anti-inflammatory effect of articular BHA (10 and 50 μg) injections was evaluated by measuring joint swelling and the serum levels of inflammatory cytokines in a model of acute gouty arthritis induced by intra-articular injection of monosodium urate crystals in Wistar rats ( = 10/group), in comparison to the control group with saline injection. Antioxidative and antihyperuricemic activities were investigated using intraperitoneal injections of oteracil potassium and yeast extract hyperuricemic Balb/C mice, which were treated with intraperitoneal injection of BHA at day 6-8 in the model. In the gouty arthritis rat model, BHA at a higher dosage (50 μg) demonstrated a strong anti-inflammatory effect by reducing the degree of articular swelling and the serum levels of IL-1β, IL-8, IFN-γ, and MCP-1 by 5.56%, 6.55%, 15.58% and 33.18%. In the hyperuricemic mouse model, lower dosage BHA (10 μg) was sufficient to provide antioxidative activities by significantly decreasing the ROS levels in both serum and liver by 14.87% and 8.04%, while improving liver SOD by 12.77%. Intraperitoneal injection of BHA suppressed uric acid production through reducing liver XO activity by 19.78% and decreased the serum uric acid level in hyperuricemic mice by 30.41%. : This study demonstrated for the first time that BHA exhibits anti-inflammatory, antioxidative and antihyperuricemic effects , suggesting a potential therapeutic application of BHA in gouty arthritis and hyperuricemia.
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http://dx.doi.org/10.1080/13880209.2019.1672755DOI Listing
December 2019

A Low Molecular Weight Hyaluronic Acid Derivative Accelerates Excisional Wound Healing by Modulating Pro-Inflammation, Promoting Epithelialization and Neovascularization, and Remodeling Collagen.

Int J Mol Sci 2019 Jul 30;20(15). Epub 2019 Jul 30.

Departments of Medicine (Div. of Rheumatology), and of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.

Recent knowledge of the cellular and molecular mechanisms underlying cutaneous wound healing has advanced the development of medical products. However, patients still suffer from the failure of current treatments, due to the complexity of healing process and thus novel therapeutic approaches are urgently needed. Previously, our laboratories produced a range of low molecular weight hyaluronic acid (LMW-HA) fragments, where a proportion of the glucosamine moieties were chemically N-acyl substituted. Specifically, -butyrylation results in anti-inflammatory properties in a macrophage system, and we demonstrate the importance of N-acyl substituents in modulating the inflammatory response of LMW-HA. We have set up an inter-institutional collaborative program to examine the biomedical applications of the -butyrylated LMW-HA (BHA). In this study, the potentials of BHA for dermal healing are assessed in vitro and in vivo. Consequently, BHA significantly promotes dermal healing relative to a commercial wound care product. By contrast, the "parent" partially de-acetylated LMW-HA (DHA) and the re-acetylated DHA (AHA) significantly delays wound closure, demonstrating the specificity of this N-acylation of LMW-HA in wound healing. Mechanistic studies reveal that the BHA-mediated therapeutic effect is achieved by targeting three phases of wound healing (i.e., inflammation, proliferation and maturation), demonstrating the significant potential of BHA for clinical translation in cutaneous wound healing.
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http://dx.doi.org/10.3390/ijms20153722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695899PMC
July 2019

Docetaxel-loaded human serum albumin (HSA) nanoparticles: synthesis, characterization, and evaluation.

Biomed Eng Online 2019 Jan 31;18(1):11. Epub 2019 Jan 31.

Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, No.2699, Qianjin Street, Changchun, 130012, China.

Background: Docetaxel (DTX) is an anticancer drug that is currently formulated with polysorbate 80 and ethanol (50:50, v/v) in clinical use. Unfortunately, this formulation causes hypersensitivity reactions, leading to severe side-effects, which have been primarily attributed to polysorbate 80.

Methods: In this study, a DTX-loaded human serum albumin (HSA) nanoparticle (DTX-NP) was designed to overcome the hypersensitivity reactions that are induced by polysorbate 80. The methods of preparing the DTX-NPs have been optimized based on factors including the drug-to-HSA weight ratio, the duration of HSA incubation, and the choice of using a stabilizer. Synthesized DTX-NPs were characterized with regard to their particle diameters, drug loading capacities, and drug release kinetics. The morphology of the DTX-NPs was observed via scanning electron microscopy (SEM) and the successful preparation of DTX-NPs was confirmed via differential scanning calorimetry (DSC). The cytotoxicity and cellular uptake of DTX-NPs were investigated in the non-small cell lung cancer cell line A549 and the maximum tolerated dose (MTD) of DTX-NPs was evaluated via investigations with BALB/c mice.

Results: The study showed that the loading capacity and the encapsulation efficiency of DTX-NPs prepared under the optimal conditions was 11.2 wt% and 63.1 wt%, respectively and the mean diameter was less than 200 nm, resulting in higher permeability and controlled release. Similar cytotoxicity against A549 cells was exhibited by the DTX-NPs in comparison to DTX alone while higher maximum tolerated dose (MTD) with the DTX-NPs (75 mg/kg) than with DTX (30 mg/kg) was demonstrated in mice, suggesting that the DTX-NPs prepared with HSA yielded similar anti-tumor activity but were accompanied by less systemic toxicity than solvent formulated DTX.

Conclusions: DTX-NPs warrant further investigation and are promising candidates for clinical applications.
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http://dx.doi.org/10.1186/s12938-019-0624-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357434PMC
January 2019

[Expression of miR-146a in saliva of chronic periodontitis patients and its influence on gingival crevicular inflammation and MMP-8/TIMP-1 levels].

Authors:
Yin Gao Chen-di Hao

Shanghai Kou Qiang Yi Xue 2018 Jun;27(3):309-312

Department of Stomatology, the Sixth Affiliated Hospital of Wenzhou Medical University, People's Hospital of Lishui City. Lishui 323000, Zhejiang Province, China.

Purpose: To study the expression of miR-146a in saliva of chronic periodontitis patients and its influence on gingival crevicular inflammation and MMP-8/TIMP-1 levels.

Methods: Sixty-eight patients with chronic periodontitis treated in our hospital during March 2015 to January 2017 were chosen as the experimental group, while 50 healthy volunteers for physical examination were chosen as the control group. The level of miR-146a in saliva and inflammatory factors, MMP-8/TIMP-1 in gingival crevicular fluid were detected. Pearson test was used to assess the correlation between expression of miR-146a in saliva and the severity of disease with SPSS24.0 software package.

Results: The expression of miR-146a in saliva in the experimental group was significantly higher than that in the control group(P<0.05). The level of inflammatory cytokines (IL-1β, IL-6 and IL- 35, TNF-α), the indexes of periodontal clinical symptoms (PD, AL, PLI, BI) in the experimental group were significantly higher than those in the control group (P<0.05); and MMP-8 and TIMP-1 in gingival crevicular fluid in the experimental group were significantly higher than those in the control group(P<0.05). Pearson test found that the expression of miR-146a in saliva of patients with chronic periodontitis was positively correlated with the degree of gingival inflammation, the severity of periodontal symptoms and the level of MMP-8/TIMP-1.

Conclusions: The expression of miR-146a in saliva of chronic periodontitis patients is abnormally high, and the specific expression is consistent with the degree of gingival inflammation and periodontal injury.
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June 2018

Recent advances in single-cell analysis by mass spectrometry.

Analyst 2019 Jan;144(3):824-845

Research Institute of Translational Medicine, The First Hospital of Jilin University, Jilin University, Dongminzhu Street, Changchun 130061, PR China.

Cells are the most basic structural units that play vital roles in the functioning of living organisms. Analysis of the chemical composition and content of a single cell plays a vital role in ensuring precise investigations of cellular metabolism, and is a crucial aspect of lipidomic and proteomic studies. In addition, structural knowledge provides a better understanding of cell behavior as well as the cellular and subcellular mechanisms. However, single-cell analysis can be very challenging due to the very small size of each cell as well as the large variety and extremely low concentrations of substances found in individual cells. On account of its high sensitivity and selectivity, mass spectrometry holds great promise as an effective technique for single-cell analysis. Numerous mass spectrometric techniques have been developed to elucidate the molecular profiles at the cellular level, including electrospray ionization mass spectrometry (ESI-MS), secondary ion mass spectrometry (SIMS), laser-based mass spectrometry and inductively coupled plasma mass spectrometry (ICP-MS). In this review, the recent advances in single-cell analysis by mass spectrometry are summarized. The strategies of different ionization modes to achieve single-cell analysis are classified and discussed in detail.
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http://dx.doi.org/10.1039/c8an01190gDOI Listing
January 2019

Antitumor effect of a liposome-encapsulated β1,4-galactosyltransferase inhibitor.

Int J Pharm 2018 Dec 6;552(1-2):388-393. Epub 2018 Oct 6.

School of Life Sciences, Jilin University, Changchun 130012, China. Electronic address:

Galactosyltransferases are a family of enzymes responsible for the synthesis of glycan chains which are involved in cell proliferation, adhesion and apoptosis. A recently synthesized galactosyltransferase inhibitor, 2-naphthyl 2-butanamido-2-deoxy-1-thio-β-D-glucopyranoside (612), has been found to selectively inhibit β1,4-galactosyltransferase over β1,3-galactosyltransferase and, therefore, has potential to suppress the synthesis of cancer associated epitopes. However, the application of this inhibitory activity in biological systems remains unknown. In this study, 612 was introduced into a cationic liposome (LP) delivery system, and the anti-proliferative effects of both free and the LP-incorporated 612 (612-LP) were investigated in A549 lung cancer cells, which actively express anionic sialic acid moieties on the surfaces of cells. The anti-proliferative effects were evaluated via MTT assays. The results revealed that free 612 and empty LP impose neither anti-proliferative nor apoptotic effects on cancer cells at low doses, whereas the 612-LP system inhibited cancer cell growth at a concentration as low as 0.1 μg/mL after 3 days of incubation, suggesting that this formulation enabled efficient delivery of 612 into cells and promoted the anti-proliferative activity of 612 against cancer cells. Therefore, this highly specific inhibitor 612 has the potential for development as an effective anti-cancer agent and merits further investigation.
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http://dx.doi.org/10.1016/j.ijpharm.2018.10.010DOI Listing
December 2018

[Electrothermal acupuncture in the prevention and treatment of chemotherapy-induced nausea and vomiting:a randomized controlled trial].

Zhongguo Zhen Jiu 2017 Apr;37(4):355-359

Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China.

Objective: To observe the effectiveness and safety of electrothermal acupuncture in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in the cancerous patients of phlegm-stasis interaction in cisplatin-containing chemotherapy.

Methods: Sixty cases of phlegm-stasis interaction in cisplatin-containing chemotherapy were randomized into a trial group and a control group, 30 cases in each one. In the control group, the intravenous drip of granisetron hydrochloride injection was adopted, 3 mg before and after cisplatin-containing chemotherapy 30 min, continuously for 3 days. 43 to 45℃ electrothermal acupuncture at zusanli(ST 36) for 30 min was used on the basis of the treatment as the control group in the trial group,once a day for 3 days. CINV, anti-nausea effects, Karnofsky score, the syndrome score of phlegm-stasis interaction, and relevant indices of safety were observed on the 1st and 7th days of cisplatin-containing chemotherapy separately.

Results: 1.Regarding CINV and anti-nausea effect, CINV did not occur before chemotherapy in the patients of the two groups. On the 1st and 7th days of chemotherapy, CINV in the trial group were milder than those in the control group (both <0.05).The anti-nausea effects in the trail group were better than those of the control group.2.Regarding Karnofsky score and the syndrome score of phlegm-stasis interaction, the improvements on the 7th days of chemotherapy in the trial group were better than those in the control group, indicating the significant differences (both <0.05). 3.Regarding the safety indies, there was no adverse reaction during the treatment in the two groups.

Conclusions: The electrothermal acupuncture effectively relieves CINV, and improves self-care dbility and the symptoms of phlegm-stasis interaction.
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http://dx.doi.org/10.13703/j.0255-2930.2017.04.003DOI Listing
April 2017

Solid-State N and O NMR Studies of S-Nitrosothiols.

J Phys Chem B 2017 08 20;121(30):7311-7317. Epub 2017 Jul 20.

Department of Chemistry, Queen's University , 90 Bader Lane, Kingston, Ontario K7L 3N6, Canada.

We report a solid-state N and O NMR study of two representative S-nitrosothiols (RSNO): S-nitroso N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO). The N and O NMR tensors are experimentally determined for the first time for this important class of nitric-oxide (NO)-related compounds. The observed NMR characteristics for RSNO include large N and O chemical shift anisotropies and large O quadrupole coupling constants. Quantum chemical calculations are also performed for the N and O NMR tensors in two simple RSNO models: t-BuSNO and MeSNO. On the basis of computational results, we have identified the molecular orbitals that are responsible for the observed large chemical shift anisotropies in RSNO compounds.
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http://dx.doi.org/10.1021/acs.jpcb.7b05685DOI Listing
August 2017

Analysis of therapeutic monoclonal antibody glycoforms by mass spectrometry for pharmacokinetics study.

Talanta 2017 Apr 11;165:664-670. Epub 2017 Jan 11.

CAS Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.

Monoclonal antibodies (mAbs), are one of the most important protein drugs have attracted increasing attention. However, the pharmacokinetics of mAbs has not been fully investigated due to the complexity of protein drugs. Traditonal immuno-based approaches can not recognize the proteoforms of mAbs because of the long development cycles, prohibitive cost, and interactions between different proteins. Therefore, reliable qualitative and quantitative analysis of the proteoforms of mAbs in biological samples is of crucial importance. Herein, a novel method was developed for absolute quantitation of mAbs and their glycoforms in complex biological samples such as serum and tissues. With the combination of HILIC enrichment and parallel reaction monitoring by high resolution mass spectrometry, most of the glycoforms can be accurately quantified at the fmol level through the use of the model mAb of bevacizumab. More importantly, the structural confirmation can be achieved simultaneously without the need for additional experiments. This strategy can be readily applied to the pharmacokinetic study of glycosylation modification and biomarker discovery for clinical applications.
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http://dx.doi.org/10.1016/j.talanta.2017.01.023DOI Listing
April 2017

Effects of Yishengukang decoction on expression of bone-specific alkaline phosphatase, carboxyterminal propeptide of type Ⅰ procollagen, and carboxyterminal cross-linked telepeptide of type Ⅰ collagen in malignant tumor patients with bone metastasis.

J Tradit Chin Med 2017 02;37(1):30-4

Objective: To investigate the effect of Yishengukang decoction on the expression of the metabolic bone markers, bone-specific alkaline phosphatase (BAP), carboxyterminal propeptide of type Ⅰ procollagen (PICP), and arboxyterminal cross-linked telepeptide of type Ⅰ collagen (ICTP), in cancer patients with bone metastasis.

Methods: Patients (n = 180) were divided into three groups: (a) bone metastasis patients treated with Yishengukang and pamidronate disodium injection (treatment group, n = 60); (b) bone metastasis patients treated with pamidronate disodium injection alone (control group, n = 60); (c) cancer patients without metastatic bone lesion (non-bone metastasis group, n = 60). Serum levels of the metabolic markers BAP, PICP, and ICTP were detected by enzyme-linked immunosorbent assay pre- and post-therapy.

Results: A significant decrease in serum BAP level was observed in the treatment group compared with the control group. However there were no significant differences in serum levels of PICP and ICTP before or after treatment compared with the control group.

Conclusion: Yishengukang decoction combined with pamidronate disodium injection reduced serum BAP level to a greater extent that pamidronate disodium injection alone. Furthermore, the combined therapy was more beneficial in regulating imbalanced bone metabolism after bone metastasis, and may represent the molecular mechanism underpinning the effects of Yishengukang decoction.
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http://dx.doi.org/10.1016/s0254-6272(17)30023-7DOI Listing
February 2017

[The expression and clinical significance of pepsin and pepsinogen in patients with otitis media with effusion].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2015 Jul;29(14):1252-5

Objective: To analyze the role and significance of pepsin and pepsinogen in the pathogenesis of OME in children.

Method: Pediatric patients with otitis media aged 2-8 years who enrolled in our department of the hospital from May of 2012 to December of 2012 were set as experimental group (38 cases, 48 ears) which should be underwent tympanic membrane puncture/tube insertion. Meanwhile, pediatric patients waiting for cochlear implant without otitis media (10 ears), were set as control group. Middle ear lavage fluid and plasma samples from the two groups were collected and detected using enzyme-linked immune method for pepsin and pepsinogen.

Result: The concentrations of pepsin and pepsinogen in the middle ear lavage fluid of OME group [(48.8 ± 415.99) ng/ml and 676.32 ± 336.71)ng/ml] were significantly higher than those in the control group [(8.20 ± 4.59)ng/ml and (77.27 ± 50.33) ng/ml] (P < 0.01). Meanwhile, the concentration of pepsinogen in the middle ear lavage of OME patients was significantly higher than that of plasma (P < 0.01). The concentration of pepsin in the middle ear lavage fluid from the dry ear subgroup was lower than those in the serum ear and mucous ear subgroups (P < 0.01), but there was no significant difference about concentrations of pepsinogen among the dry ear, serum ear and mucous ear subgroups (P > 0.05).

Conclusion: Pepsin and pepsinogen in the middle ear cavity of OME patients maybe originated from laryngopharyngeal reflux (LPR), indicating that LPR is associated with the pathogenesis of OME in children.
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July 2015

Enhanced delivery of Paclitaxel using electrostatically-conjugated Herceptin-bearing PEI/PLGA nanoparticles against HER-positive breast cancer cells.

Int J Pharm 2016 Jan 23;497(1-2):78-87. Epub 2015 Nov 23.

School of Life Sciences, Jilin University, Qianjin Street No.2699, Changchun, Jilin Province 130012, China. Electronic address:

We have developed a novel nanoparticle delivery system fabricated from polyethylenimine (PEI) and poly(d,l-lactide-co-glycolide) (PLGA), which were able to deliver the chemotherapeutic agent Paclitaxel, while the biomacromolecule Herceptin acted as a targeting ligand that was conjugated onto the surfaces of the nanoparticles via electrostatic interactions. In this study, these electrostatically-conjugated Herceptin-bearing PEI/PLGA nanoparticles (eHER-PPNs) were optimized and employed as vectors to target HER2-positive breast cancer cells. The eHER-PPNs had an average diameter of ∼ 280 nm and a neutral surface charge (1.00 ± 0.73 mV), which remained stable under physiological conditions. The anticancer effects of eHER-PPNs were investigated in HER2-positive BT474 cells and HER2-negative MCF7 cells. The eHER-PPNs showed enhanced cytotoxicity that was dependent on the receptor expression levels and the incubation time. These conjugated nanoparticles deliver Paclitaxel more efficiently (p<0.001) than unmodified PPNs, Herceptin and the combined effects of these two monotherapies. Furthermore, the chemically-conjugated Herceptin-bearing PEI/PLGA nanoparticles (cHER-PPNs) were fabricated as a comparison. The eHER-PPNs exhibited lower cell viability (46.7%) than that of cHER-PPNs (65.1%). The targeting ability of eHER-PPNs was demonstrated through confocal microscopy images and flow cytometry, which showed that eHER-PPNs displayed higher cellular uptake efficiency (p<0.001) in comparison with cHER-PPNs. Therefore, eHER-PPNs could provide promising platforms for the delivery of therapeutic drugs against HER2-positive breast cancers.
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http://dx.doi.org/10.1016/j.ijpharm.2015.11.033DOI Listing
January 2016

Direct NMR detection of the unstable "red product" from the reaction between nitroprusside and 2-mercaptosuccinic acid.

Dalton Trans 2015 Dec 17;44(47):20338-43. Epub 2015 Nov 17.

Department of Chemistry, Queen's University, 90 Bader Lane, Kingston, Ontario, Canada K7L 3N6.

The reaction between nitroprusside (NP, [Fe(II)(CN)5NO](2-)) and organic thiolates (RS(-)) in aqueous solution has long been known to produce an unstable red intermediate thus often being referred to as the "red product" (RP) in the literature. While RP has always been formulated as [Fe(II)(CN)5N(O)SR](3-), it is rather difficult to study it in aqueous solution because it is not only unstable but also exhibits rapid ligand exchange. All previous studies of RP have relied on UV-vis, IR, kinetics measurements, and analysis of decomposed products. Herein we report the first comprehensive multinuclear ((1)H, (13)C, (15)N, and (17)O) NMR characterization of the RP produced from the reaction between NP and 2-mercaptosuccinic acid (MSA). The NMR chemical shifts obtained for the RP are compared with those from the free ligand (S-nitrosothiol, RS-N=O) prepared in situ by the reaction of MSA with NaNO2. We also showed that useful thermodynamic and kinetic properties of RP formation can be readily obtained from (1)H NMR studies.
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http://dx.doi.org/10.1039/c5dt04029aDOI Listing
December 2015

[The therapeutic effect of proton pump inhibitor on alleviation of hoarseness symptoms in patients with laryngopharyngeal reflux].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2015 Jun;29(11):997-1001

Objective: To analyze the therapeutic effect of proton pump inhibitor(PPI) on alleviation of hoarseness symptoms in patients with laryngopharyngeal reflux(LPR).

Method: The LPR outpatients in ENT department of our hospital(60 cases)complained of hoarseness were enrolled in the study from August of 2013 to October of 2014. All of them were randomly divided into group A and B. The individuals in group A (30 cases) taked golden voice capsule to treat for 3 months, while the individuals in group B (30 cases) taked golden voice capsule and omeprazole to treat for 3 months. The data about reflux symptom index (RSI), reflux finding score (RFS) and voice handicap index (VHI)from the first month to the third month after treatment were recorded and compared group A with group B.

Result: The scores of RSI and RFS in patients (60 cases) before treatment were significantly correlated with their VHI (r=0. 823, P<0. 01; r=0. 873, P<0. 01). The score changes of RSI and VHI from the first to the third month after treatment in group B were significantly higher than those in group A (P<0. 01). Meanwhile, the score changes of RFS from the third month after treatment in group B were significantly higher than those in group A (t=8. 307, P<. 01), but the differences were not significant for RFS from the first to the second month after treatment between group A and group B(t=1. 128, P>0. 05; t=0. 376, P> 0. 05).

Conclusion: PPI therapy could significantly alleviate the hoarseness symptom in LPR patients.
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June 2015

Solving the 170-Year-Old Mystery About Red-Violet and Blue Transient Intermediates in the Gmelin Reaction.

Chemistry 2015 Nov 28;21(48):17172-7. Epub 2015 Sep 28.

Department of Chemistry, Queen's University, Kingston, Ontario, K7L 3N6 (Canada).

The Gmelin reaction between nitroprusside and sulfides in aqueous solution is known to produce two transient intermediates with distinct colors: an initial red-violet intermediate that subsequently converts into a blue intermediate. In this work, we use a combination of multinuclear ((17) O, (15) N, (13) C) NMR, UV/Vis, IR spectroscopic techniques and quantum chemical computation to show unequivocally that the red-violet intermediate is [Fe(CN)5 N(O)S](4-) and the blue intermediate is [Fe(CN)5 N(O)SS)](4-) . While the formation of [Fe(CN)5 N(O)S](4-) has long been postulated in the literature, this study provides the most direct proof of its structure. In contrast, [Fe(CN)5 N(O)SS)](4-) represents the first example of any metal coordination complex containing a perthionitro ligand. The new reaction pathways found in this study not only provide clues for the mode of action of nitroprusside for its pharmacological activity, but also have broader implications to the biological role of H2 S, potential reactions between H2 S and nitric oxide donor compounds, and the possible biological function of polysulfides.
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http://dx.doi.org/10.1002/chem.201503353DOI Listing
November 2015

Fungal-specific subunits of the Candida albicans mitochondrial complex I drive diverse cell functions including cell wall synthesis.

Cell Microbiol 2015 Sep 16;17(9):1350-64. Epub 2015 Apr 16.

Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA.

Our published research has focused on the role of Goa1p, an apparent regulator of the Candida albicans mitochondrial complex I (CI). Lack of Goa1p affects optimum cell growth, CI activity and virulence. Eukaryotic CI is composed of a core of 14 alpha-proteobacterial subunit proteins and a variable number of supernumerary subunit proteins. Of the latter group of proteins, one (NUZM) is fungal specific and the other (NUXM) is found in fungi, algae and plants, but is not a mammalian CI subunit protein. We have established that NUXM is orf19.6607 and NUZM is orf19.287 in C. albicans. Herein, we validate both subunit proteins as NADH:ubiquinone oxidoreductases (NUO) and annotate their gene functions. To accomplish these objectives, we compared null mutants of each with wild type (WT) and gene-reconstituted strains. Genetic mutants of genes NUO1 (orf19.6607) and NUO2 (orf19.287), not surprisingly, each had reduced oxygen consumption, decreased mitochondrial redox potential, decreased CI activity, increased reactive oxidant species (ROS) and decreased chronological ageing in vitro. Loss of either gene results in disassembly of CI. Transcriptional profiling of both mutants indicated significant down-regulation of genes of carbon metabolism, as well as up-regulation of mitochondrial-associated gene families that may occur to compensate for the loss of CI activity. Profiling of both mutants also demonstrated a loss of cell wall β-mannosylation but not in a conserved CI subunit (ndh51Δ). The profiling data may indicate specific functions driven by the enzymatic activity of Nuo1p and Nuo2p. Of importance, each mutant is also avirulent in a murine blood-borne, invasive model of candidiasis associated with their reduced colonization of tissues. Based on their fungal specificity and roles in virulence, we suggest both as drug targets for antifungal drug discovery.
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http://dx.doi.org/10.1111/cmi.12438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677794PMC
September 2015

Determination of thymopentin in beagle dog blood by liquid chromatography with tandem mass spectrometry and its application to a preclinical pharmacokinetic study.

J Sep Sci 2015 May 4;38(8):1351-7. Epub 2015 Mar 4.

College of Life Science, Jilin University, Changchun, P. R. China.

The pentapeptide thymopentin (Arg-Lys-Asp-Val-Tyr, RKDVY) corresponds to amino acids 32-36 of the 49 amino acid immunomodulatory polypeptide, thymopoietin, whose biological activity is partially reproduced. Thymopentin is widely used in the clinic and represents a promising target for drug design but bioanalytical and pharmacokinetic data are limited due to its enzymatic instability. This paper reports a rapid and sensitive method based on liquid chromatography with tandem mass spectrometry for the determination of thymopentin in beagle dog blood. To inactivate peptidases and stabilize thymopentin, acetonitrile was added to blood samples immediately after collection followed by addition of stable isotope-labeled thymopentin as internal standard and washing with dichloromethane. Chromatography was carried out on an Ascentis Express Peptide ES-C18 column using gradient elution with methanol and aqueous 0.1% formic acid at a flow rate of 0.6 mL/min. Positive electrospray ionization mass spectrometry with selected reaction monitoring achieved linearity in the range of 1.5-800 ng/mL with good accuracy/precision and minimal matrix effects. The method was successfully applied to a pharmacokinetic study in beagle dogs after intravenous administration of 0.2 mg/kg thymopentin.
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http://dx.doi.org/10.1002/jssc.201401198DOI Listing
May 2015

Acidity and hydrogen exchange dynamics of iron(II)-bound nitroxyl in aqueous solution.

Angew Chem Int Ed Engl 2014 Oct 9;53(43):11547-51. Epub 2014 Sep 9.

Department of Chemistry, Queen's University, Kingston, Ontario, K7L 3N6 (Canada).

Nitroxyl-iron(II) (HNO-Fe(II)) complexes are often unstable in aqueous solution, thus making them very difficult to study. Consequently, many fundamental chemical properties of Fe(II)-bound HNO have remained unknown. Using a comprehensive multinuclear ((1)H, (15)N, (17)O) NMR approach, the acidity of the Fe(II)-bound HNO in [Fe(CN)5(HNO)](3-) was investigated and its pK(a) value was determined to be greater than 11. Additionally, HNO undergoes rapid hydrogen exchange with water in aqueous solution and this exchange process is catalyzed by both acid and base. The hydrogen exchange dynamics for the Fe(II)-bound HNO have been characterized and the obtained benchmark values, when combined with the literature data on proteins, reveal that the rate of hydrogen exchange for the Fe(II)-bound HNO in the interior of globin proteins is reduced by a factor of 10(6).
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http://dx.doi.org/10.1002/anie.201407018DOI Listing
October 2014

Increased urinary interleukin 22 binding protein levels correlate with lupus nephritis activity.

J Rheumatol 2014 Sep 1;41(9):1793-800. Epub 2014 Aug 1.

From the Department of Rheumatology, Second Affiliated Hospital, College of Medicine, and Department of Immunology, Institute of Basic Medical Sciences, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.X.Y. Yang, MD; Y. Gao, MD, Department of Rheumatology; H.Y. Wang, MD, PhD, Department of Allergy and Clinical Immunology; X.Y. Zhao, MD, Department of Hematology; X.B. Gong, MD, Laboratory of Bone Marrow, Second Affiliated Hospital, College of Medicine, Zhejiang University; Q.Q. Wang, MD, PhD, Department of Immunology, Institute of Basic Medical Sciences; X.F. Zhang, MD, Department of Clinical Epidemiology and Biostatistics, Second Affiliated Hospital, College of Medicine, Zhejiang University.

Objective: Interleukin 22 (IL-22) plays an important role in the promotion of antimicrobial immunity. However, dysregulated IL-22 action leads to inflammation and is involved in autoimmune diseases, including systemic lupus erythematosus (SLE). IL-22 binding protein (IL-22BP) is a soluble inhibitory IL-22 receptor and may represent a crucial regulator of IL-22. We investigated the expression and potential significance of serum and urinary IL-22BP levels in patients with SLE.

Methods: A total of 112 patients with SLE and healthy control subjects participated in our study. Patients were classified according to kidney involvement and disease activity based on clinical and laboratory measures such as urinary sediment, proteinuria, kidney function, complement factor 3 (C3), C4, anti-dsDNA, disease activity index, and renal SLE disease activity index. The concentrations of IL-22BP and IL-22 were measured by ELISA. The expression of IL-22BP in the renal tissue was detected by immunohistochemistry.

Results: Patients with active renal disease had urinary levels of IL-22BP higher than (1) patients with active SLE but no renal involvement, (2) patients with a history of lupus nephritis in remission with no systemic disease activity and no history of renal involvement, and (3) control subjects. There was no difference in serum levels of IL-22BP among the groups. Urinary levels of IL-22BP in patients with active renal disease were positively correlated with SLE Disease Activity Index, Systemic Lupus International Collaborating Clinics renal activity score, and histological activity index. IL-22BP was highly expressed in renal tissue of patients with active renal disease. After 6 months of treatment, urinary IL-22BP levels decreased significantly in patients with complete response, but remained unchanged in those with partial or no response.

Conclusion: Urinary but not serum IL-22BP levels were associated with active renal disease. Urinary levels of IL-22BP might be a potential marker for the presence of renal involvement in patients with SLE.
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http://dx.doi.org/10.3899/jrheum.131292DOI Listing
September 2014
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