Publications by authors named "Yanwei Wu"

31 Publications

Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD.

Cell Rep 2021 Aug;36(8):109581

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55902, USA. Electronic address:

Loss-of-function mutations in the progranulin gene (GRN), which encodes progranulin (PGRN), are a major cause of frontotemporal dementia (FTD). GRN-associated FTD is characterized by TDP-43 inclusions and neuroinflammation, but how PGRN loss causes disease remains elusive. We show that Grn knockout (KO) mice have increased microgliosis in white matter and an accumulation of myelin debris in microglial lysosomes in the same regions. Accumulation of myelin debris is also observed in white matter of patients with GRN-associated FTD. In addition, our findings also suggest that PGRN insufficiency in microglia leads to impaired lysosomal-mediated clearance of myelin debris. Finally, Grn KO mice that are deficient in cathepsin D (Ctsd), a key lysosomal enzyme, have augmented myelin debris and increased neuronal TDP-43 pathology. Together, our data strongly imply that PGRN loss affects microglial activation and lysosomal function, resulting in the accumulation of myelin debris and contributing to TDP-43 pathology.
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http://dx.doi.org/10.1016/j.celrep.2021.109581DOI Listing
August 2021

Directing Group Enables Electrochemical Selectively -Bromination of Pyridines under Mild Conditions.

J Org Chem 2021 Jun 15. Epub 2021 Jun 15.

Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, People's Republic of China.

Without the use of catalysts and oxidants, a facile and sustainable electrochemical bromination protocol was developed. By introducing the directing groups, the regioselectivity of pyridine derivatives could be controlled at the -position utilizing the inexpensive and safe bromine salts at room temperature. A variety of brominated pyridine derivatives were obtained in 28-95% yields, and the reaction could be readily performed at a gram scale. By combining the installation and removing the directing group, the concept of -bromination of pyridines could be verified.
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http://dx.doi.org/10.1021/acs.joc.1c00923DOI Listing
June 2021

Triptolide analog LLDT-8 ameliorates psoriasis-like dermatitis in BALB/c mice via suppressing the IL-36α signaling pathway.

Pharmacol Res 2021 Jul 17;169:105678. Epub 2021 May 17.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address:

Triptolide has shown a good immunosuppressive effect on autoimmune diseases. However, the toxicity limited its widely clinical practice. In this study, we investigated the effects and underlying mechanisms of (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, on a murine psoriasis-like dermatitis model and related cell lines. Here, we showed that LLDT-8 significantly attenuated symptoms of psoriasis-like dermatitis induced by imiquimod (IMQ, a TLR7 agonist) by reducing the psoriasis area and severity index (PASI) score and inflammatory parameters. The action of LLDT-8 was involved in down-regulated interleukin (IL)-36α expression and blocked IL-36α pathway by LC-MS-based label-free quantitative (LFQ) proteomic approach and further experiments. Meanwhile, we observed that LLDT-8 significantly inhibited the expression of IL-36α in R837-treated bone marrow-derived dendritic cells (BMDCs). In conclusion, LLDT-8 notably alleviated IMQ-induced psoriasis-like skin inflammation via suppressing the IL-36α signaling pathway, suggesting LLDT-8 might be a potential drug for the treatment of psoriasis.
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http://dx.doi.org/10.1016/j.phrs.2021.105678DOI Listing
July 2021

A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage.

Metabolism 2021 Jul 10;120:154797. Epub 2021 May 10.

Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address:

Objective: Obeticholic acid (OCA) has been proved to play potential therapeutic effect on nonalcoholic steatohepatitis (NASH). Up to now, the study of OCA on NLRP3 inflammasome activation in macrophage is still blank and merits great attention. Here, we aimed to better characterize the role and mechanism of OCA on NASH treatment focusing on NLRP3 inflammasome activation in macrophages.

Methods: The effects of OCA on inflammasome activation were investigated in BMDM, Kupffer cell, BMDC and LX2 cell. Preconditioned media from BMDM culture was used to treat primary hepatocytes to explore the effects of macrophage NLRP3 inflammasome activation on the function of hepatocytes. In vivo, high fat diet plus CCl (DIO + CCl) induced murine NASH model and choline-deficient and amino acid-defined (CDA) diet-induced NASH mice were used to verify the inhibitory effect of OCA on inflammasome activation in liver macrophages and recapitulate its protective role on NASH progressing. To clear up the effect of OCA on macrophage is FXR dependent or not, FXR siRNA was introduced into BMDMs.

Results: OCA blockaded NLRP3 inflammasome in BMDMs by impacting on the activation stage and disrupting ASC oligomerization. Preconditioned supernatant from LPS + ATP treated BMDMs increased mRNA expression of lipogenic enzymes and lipid content, whereas preconditioned supernatant from OCA treated BMDM blocked these effects in both normal and the FXR knockdown hepatocytes. In DIO + CCl mice, the population of inflammatory myeloid lineage cells in livers was decreased upon OCA treatment. Accordingly, the level of IL-1β and IL-18 in liver, the hepatic expression of ASC, pro-caspase-1 and active caspase-1, the expression of caspase 1 p20 in liver macrophages were also reduced. Similar results were obtained in CDA diet-fed mice. Furthermore, OCA maintained the inhibition on NLRP3 inflammasome activation in FXR knockdown BMDMs, suggesting FXR could be dispensable in this effect.

Conclusions: This finding brings up a new mechanism of OCA on NASH treatment, suggested by direct inhibition on NLRP3 inflammasome activation in macrophage, further suppression on inflammasome activation-elicited hepatic lipid accumulation, and contributing to the amelioration of NASH.
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http://dx.doi.org/10.1016/j.metabol.2021.154797DOI Listing
July 2021

Financial Self-Efficacy and General Life Satisfaction: The Sequential Mediating Role of High Standards Tendency and Investment Satisfaction.

Front Psychol 2021 17;12:545508. Epub 2021 Mar 17.

School of Psychology, South China Normal University, Guangzhou, China.

Important strides have been made toward understanding the relationship between self-efficacy and life satisfaction. However, existing studies have largely focused on work and academic domains, leaving self-efficacy in the finance domain less frequently investigated. The present study applied the self-efficacy construct to the finance domain, namely "financial self-efficacy" (FSE), and tested the sequential mediating roles of high standards tendency and investment satisfaction in the relationship between FSE and general life satisfaction. A total of 323 employees from finance-related businesses completed anonymous questionnaires regarding FSE, high standards tendency, investment satisfaction, and general life satisfaction. Results indicated that FSE influenced general life satisfaction through investment satisfaction, and sequentially through high standards tendency and investment satisfaction. These results provide contributions to the current literature on life satisfaction, and positive psychology literature by shedding light on the roles of high standards tendency and investment satisfaction in the relation between FSE and general life satisfaction.
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http://dx.doi.org/10.3389/fpsyg.2021.545508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009975PMC
March 2021

IDH1 gene mutation activates Smad signaling molecules to regulate the expression levels of cell cycle and biological rhythm genes in human glioma U87‑MG cells.

Mol Med Rep 2021 05 24;23(5). Epub 2021 Mar 24.

Department of Pathology, School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China.

Isocitrate dehydrogenase1 (IDH1) mutation is the most important genetic change in glioma. The most common IDH1 mutation results in the amino acid substitution of arginine 132 (Arg/R132), which is located at the active site of the enzyme. IDH1 Arg132His (R132H) mutation can reduce the proliferative rate of glioma cells. Numerous diseases follow circadian rhythms, and there is growing evidence that circadian disruption may be a risk factor for cancer in humans. Dysregulation of the circadian clock serves an important role in the development of malignant tumors, including glioma. Brain‑Muscle Arnt‑Like protein 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) are the main biological rhythm genes. The present study aimed to further study whether there is an association between IDH1 R132H mutation and biological rhythm in glioma, and whether this affects the occurrence of glioma. The Cancer Genome Atlas (TCGA) database was used to detect the expression levels of the biological rhythm genes BMAL1 and CLOCK in various types of tumor. Additionally, U87‑MG cells were infected with wild‑type and mutant IDH1 lentiviruses. Colony formation experiments were used to detect cell proliferation in each group, cell cycle distribution was detected by flow cytometry and western blotting was used to detect the expression levels of wild‑type and mutant IDH1, cyclins, biological rhythm genes and Smad signaling pathway‑associated genes in U87‑MG cells. TCGA database results suggested that BMAL1 and CLOCK were abnormally expressed in glioma. Cells were successfully infected with wild‑type and mutant IDH1 lentiviruses. Colony formation assay revealed decreased cell proliferation in the IDH1 R132H mutant group. The cell cycle distribution detected by flow cytometry indicated that IDH1 gene mutation increased the G phase ratio and decreased the S phase ratio in U87‑MG cells. The western blotting results demonstrated that IDH1 R132H mutation decreased the expression levels of the S phase‑associated proteins Cyclin A and CDK2, and increased the expression levels of the G phase‑associated proteins Cyclin D3 and CDK4, but did not significantly change the expression levels of the G/M phase‑associated protein Cyclin B1. The expression levels of the positive and negative rhythm regulation genes BMAL1, CLOCK, period (PER s (PER1, 2 and 3) and cryptochrom (CRY)s (CRY1 and 2) were significantly decreased, those of the Smad signaling pathway‑associated genes Smad2, Smad3 and Smad2‑3 were decreased, and those of phosphorylated (p)‑Smad2, p‑Smad3 and Smad4 were increased. Therefore, the present results suggested that the IDH1 R132H mutation may alter the cell cycle and biological rhythm genes in U87‑MG cells through the TGF‑β/Smad signaling pathway.
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http://dx.doi.org/10.3892/mmr.2021.11993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974315PMC
May 2021

Heme supplementation ameliorates lupus nephritis through rectifying the disorder of splenocytes and alleviating renal inflammation and oxidative damage.

Int Immunopharmacol 2021 May 24;94:107482. Epub 2021 Feb 24.

Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China. Electronic address:

Heme is an important iron-containing porphyrin molecule expressed ubiquitously in organisms. Recently, this endogenous molecule has been widely reported to be involved in the pathogenesis of numerous diseases such as sepsis, atherosclerosis and inflammatory bowel disease. However, the role of heme during systemic lupus erythematosus (SLE) pathogenesis has not been previously evaluated. Herein, we have measured the levels of heme in lupus-prone mice and explored the influence of heme on the pathogenesis of lupus. We revealed that heme levels in serum, kidney and spleen lymphocytes are all negatively associated with the levels of proteinuria in lupus-prone mice. Heme supplementation at 15 mg/kg could significantly ameliorate the syndromes of lupus in MRL/lpr mice, extending lifespan, reducing the level of proteinuria and alleviating splenomegaly and lymphadenopathy. Further study demonstrated that heme replenishment corrected the abnormal compartment of T cell subsets, plasma cells and macrophages in the spleen and alleviates inflammation and oxidative damage in kidney of MRL/lpr mice. Our study well defined heme as a relevant endogenous molecule in the etiology of SLE, as well as a potential therapeutic target for treating this autoimmune disease. Meanwhile, heme replenishment might be a new choice to therapeutically modulate immune homeostasis and prevent SLE.
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http://dx.doi.org/10.1016/j.intimp.2021.107482DOI Listing
May 2021

Downregulation of microRNA‑25‑3p inhibits the proliferation and promotes the apoptosis of multiple myeloma cells via targeting the PTEN/PI3K/AKT signaling pathway.

Int J Mol Med 2021 03 15;47(3). Epub 2021 Jan 15.

Department of Hematology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China.

Numerous studies have confirmed that microRNAs (miRNAs or miRs) have important roles in cancer biogenesis and development including multiple myeloma (MM). MicroRNA‑25‑3p (miR‑25‑3p) has been proven to promote cancer progression, whereas its functions in MM has not yet been reported, at least to the best of our knowledge. Therefore, the present study aimed to investigate the function of miR‑25‑3p in MM and to identify the potential underlying mechanistic pathway. Herein, it was found that miR‑25‑3p expression was significantly increased in MM tissues and cell lines. The upregulation of miR‑25‑3p was closely associated with anemia, renal function impairment international staging system (ISS) staging and Durie‑Salmon (D‑S) staging. A high level of miR‑25‑3p was predictive of a poor prognosis of patients with MM. , the knockdown of miR‑25‑3p suppressed the proliferation and promoted the apoptosis of RPMI‑8226 and U266 cells, while the overexpression of miR‑25‑3p exerted opposite effects. In addition, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a well‑known tumor suppressor, was confirmed as a target of miR‑25‑3p in MM cells. Moreover, it was found that the PTEN expression levels were decreased, and inversely correlated with miR‑25‑3p expression levels in MM tissues. Further analyses revealed that the overexpression of PTEN exerted effects similar to those of miR‑25‑3p knockdown, whereas the knockdown of PTEN partially abolished the effects of miR‑25‑3p inhibitor on MM cells. Accompanied by PTEN induction, miR‑25‑3p promoted PI3K/AKT signaling pathway activation in MM cells. Collectively, these findings demonstrate critical roles for miR‑25‑3p in the pathogenesis of MM, and suggest that miR‑25‑3p may serve as a novel prognostic biomarker and therapeutic target of MM.
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http://dx.doi.org/10.3892/ijmm.2020.4841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834966PMC
March 2021

LncRNA Regulates the Progress of Acute Myeloid Leukemia Through miR183-5p-FOXO1 Axis.

Onco Targets Ther 2020 17;13:12943-12954. Epub 2020 Dec 17.

Central Laboratory, First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China.

Purpose: At present, there is a lack of precise knowledge on acute myeloid leukemia (AML) at the molecular level, and understanding its occurrence at the genetic level is conducive to the development of targeted therapies. Therefore, in this study the relationship between the lncRNA -miR183-5p-FOXO1 axis and AML was explored.

Methods: Expression of lncRNA and miR183-5p was quantified by quantitative real-time PCR, and the level of FOXO1 and other proteins was measured by Western blot. Expression vectors of lncRNA , miR183-5p, and FOXO1 were constructed to assess effects of the three on cell proliferation and apoptosis. MTT reduction assays were employed for cell proliferation, flow cytometry for cell cycle and apoptosis, and dual luciferase-reporter assays for the targeting relationship between lncRNA and miR183-5p and miR183-5p and FOXO1.

Results: lncRNA was highly expressed in peripheral blood/leukemia cell lines of patients with AML compared with normal human peripheral blood/peripheral blood mononuclear cells. miR183-5p was the target of lncRNA and the target gene of miR183-5p rather than lncRNA SNHG16. Absence of lncRNA led to upregulation of miR183-5p, promotion of apoptosis, and inhibition of proliferation. Suppression of miR183-5p accelerated cell proliferation and hindered apoptosis. miR183-5p negatively regulated FOXO1, and FOXO1 promoted proliferation and inhibited apoptosis. Inhibition of miR183-5p counteracted the changes caused by lncRNA absence.

Conclusion: lncRNA regulates the progress of AML via the miR183-5p-FOXO1 axis.
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http://dx.doi.org/10.2147/OTT.S258684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751589PMC
December 2020

poly(GR) aggregation induces TDP-43 proteinopathy.

Sci Transl Med 2020 09;12(559)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by GC repeat expansions in the gene (c9FTD/ALS). Providing mechanistic insight into the link between mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded GC repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 inclusion formation. Moreover, in GFP-(GR) mice, poly(GR) caused the mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins. These mislocalization events resulted in the aberrant accumulation of endogenous TDP-43 in the cytoplasm where it co-aggregated with poly(GR). Last, we demonstrated that treating GC repeat-expressing mice with repeat-targeting antisense oligonucleotides lowered poly(GR) burden, which was accompanied by reduced TDP-43 pathology and neurodegeneration, including lowering of plasma neurofilament light (NFL) concentration. These results contribute to clarification of the mechanism by which poly(GR) drives TDP-43 proteinopathy, confirm that GC-targeted therapeutics reduce TDP-43 pathology in vivo, and demonstrate that alterations in plasma NFL provide insight into the therapeutic efficacy of disease-modifying treatments.
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http://dx.doi.org/10.1126/scitranslmed.abb3774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989020PMC
September 2020

Polycomb-like 2 regulates PRC2 components to affect proliferation in glioma cells.

J Neurooncol 2020 Jun 21;148(2):259-271. Epub 2020 May 21.

Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technological Enterprise (BRITE), North Carolina Central University, Durham, NC, USA.

Introduction: The Polycomb group (PcG) is an important family of transcriptional regulators that controls growth and tumorigenesis. The PcG mainly consists of two complexes, PRC1 and Polycomb Repressive Complex 2 (PRC2). Polycomb-like 2 (PCL2) is known to interact with the PRC2 protein. The role of PCL2 in the development and progression of glioma is unclear.

Methods: We use The Cancer Genome Atlas (TCGA) database to detect the expression of PCL2 in various tumors. 117 cases of clinical glioma (WHOI-IV) were collected, and PCL2 expression and localization were detected by immunohistochemical staining. Glioma cells U87/U251 were infected with overexpressed and interfered PCL2. CCK8 assay, colony formation assay, EdU method, cell cycle and apoptosis were used to detect cell proliferation and apoptosis. Western blot was used to detect the expression of PRC2-related core proteins. After DZNeP intervention, PRC2 protein expression was again measured to discuss the mechanism of PCL2 action.

Results: TCGA database results and immunohistochemical staining results suggest that PCL2 is highly expressed in gliomas. We found that the PCL2 gene promoted tumor cell proliferation, enhanced the colony formation ability, and increased S phase in the cell cycle. The overexpression of PCL2 upregulated the expression levels of EZH2 and EED (two core members of PRC2), decreased the expression of SUZ12, increased the level of H3K27 trimethylation (H3K27me3), H3K4 dimethylation (H3K4me2), and decreased H3K9 dimethylation (H3K9me2). The result after interfering with PCL2 was the opposite.

Conclusions: As an important accessory protein of PRC2, PCL2 can not only change the expression of PRC2 components, but also affect the expression level of Histone methylation. Therefore, PCL2 may be an important hub for regulating the synergy among PRC2 members. This study revealed PCL2 as a new target for tumor research and open up a new avenue for future research in glioma.
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http://dx.doi.org/10.1007/s11060-020-03538-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316845PMC
June 2020

Heme protects intestinal mucosal barrier in DSS-induced colitis through regulating macrophage polarization in both HO-1-dependent and HO-1-independent way.

FASEB J 2020 06 17;34(6):8028-8043. Epub 2020 Apr 17.

Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Hemoglobin-derived heme was reported to play protective roles in hemorrhagic diseases by modulating the macrophages toward recovery. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases (IBD). However, whether heme provides anti-inflammatory profiles in macrophages, thus contributing to the intestinal mucosal barrier protection, is unclear. In the current study, we investigated the beneficial effects of heme on DSS-induced colitis mice and explored the underlying mechanisms. In vivo, systemic heme supplementation by hemin injection relieved intestinal inflammation and remedied intestinal mucosal barrier damage by correcting abnormal intestinal macrophage polarization. In vitro, we confirmed the reciprocally regulating effects of hemin on M1/M2 macrophage polarization in BMDM. Intriguingly, with knockdown of HO-1, the inhibiting effects of hemin on M1 polarization were maintained, while the promoting effects on M2 polarization were reversed. Further research proved that hemin repressed the inflammatory profiles in macrophages through inhibiting the translocation of NF-κB p65 by disrupting IRF5-NF-κB p65 complex formation in Spi-C-dependent way. In conclusion, these results showed that the modification of colon tissue microenvironment with heme supplementation plays a protective role in DSS-induced colitis mice through regulating the macrophage polarization in both HO-1-dependent and HO-1-independent way, indicating a new choice to therapeutically modulate the macrophage function and prevent IBD.
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http://dx.doi.org/10.1096/fj.202000313RRDOI Listing
June 2020

Tunable Electrochemical C-N versus N-N Bond Formation of Nitrogen-Centered Radicals Enabled by Dehydrogenative Dearomatization: Biological Applications.

Angew Chem Int Ed Engl 2020 07 23;59(28):11583-11590. Epub 2020 Apr 23.

Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, P. R. China.

Herein, an environmentally friendly electrochemical approach is reported that takes advantage of the captodative effect and delocalization effect to generate nitrogen-centered radicals (NCRs). By changing the reaction parameters of the electrode material and feedstock solubility, dearomatization enabled a selective dehydrogenative C-N versus N-N bond formation reaction. Hence, pyrido[1,2-a]benzimidazole and tetraarylhydrazine frameworks were prepared through a sustainable transition-metal- and exogenous oxidant-free strategy with broad generality. Bioactivity assays demonstrated that pyrido[1,2-a]benzimidazoles displayed antimicrobial activity and cytotoxicity against human cancer cells. Compound 21 exhibited good photochemical properties with a large Stokes shift (approximately 130 nm) and was successfully applied to subcellular imaging. A preliminary mechanism investigation and density functional theory (DFT) calculations revealed the possible reaction pathway.
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http://dx.doi.org/10.1002/anie.202001510DOI Listing
July 2020

DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models.

Arthritis Res Ther 2019 12 16;21(1):290. Epub 2019 Dec 16.

Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Background: Systemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is designed to investigate the therapeutic potentiality of DZ2002 for experimental systemic sclerosis models.

Methods: The anti-inflammatory and anti-fibrotic features of DZ2002 and its mechanisms were investigated in a bleomycin (BLM)-induced dermal fibrosis mice model. The effects of DZ2002 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. Simultaneously, the effects of DZ2002 on macrophage activation and endothelial cell adhesion molecule expression were also evaluated.

Results: DZ2002 significantly attenuated dermal fibrosis in BLM-induced mice. Consistently, DZ2002 inhibited the expression of various molecules associated with dermal fibrosis, including transforming growth factor β1, connective tissue growth factor, tumor necrosis factor-α, interferon-γ, IL-1β, IL-4, IL-6, IL-10, IL-12p40, IL-17A, and monocyte chemotactic protein 1 in the lesional skin of BLM-induced mice. Furthermore, DZ2002 decreased the proportion of macrophages, neutrophils, and T cells (especially T helper cells) in the skin tissue of BLM-induced mice. In addition, DZ2002 attenuated both M1 macrophage and M2 macrophage differentiation in vivo and in vitro. Importantly, DZ2002 directly reversed the profibrotic phenotype of transforming growth factor-β1-treated dermal fibroblasts and suppressed ICAM-1, VCAM-1, VEGF, bFGF, and ET-1 expression in endothelial cells. Finally, our investigations showed that DZ2002 relieved systemic sclerosis by regulating fibrosis TGF-β/Smad signaling pathway.

Conclusions: DZ2002 prevents the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a potential drug for the treatment of systemic sclerosis.
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http://dx.doi.org/10.1186/s13075-019-2074-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916442PMC
December 2019

RIPK1 inhibitor ameliorates colitis by directly maintaining intestinal barrier homeostasis and regulating following IECs-immuno crosstalk.

Biochem Pharmacol 2020 02 16;172:113751. Epub 2019 Dec 16.

Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address:

Background: The receptor-interacting protein kinase 1 (RIPK1) has emerged as a key upstream regulator that controls the inflammatory response via its kinase-dependent and independent functions, which makes it an attractive target for developing new drugs against inflammation-related diseases. Growing evidences illustrate that RIPK1 is certainly associated with pathogenesis of multiple tissue-damage diseases. However, what are intricate regulatory codes of RIPK1 inhibitor in diseases is still obscure.

Methods: We used DSS-induced colitis model in vivo to study the therapeutic effects and the mechanisms of RIPK1 inhibitor. We next characterized the barrier function and the interaction between intestinal epithelial cells (IECs) and immunocytes both in vivo and in vitro. As a candidate in clinical study, GSK2982772 is the most well-developed drug of RIPK1 inhibitors, and we chose it as our study object.

Results: We demonstrated that RIPK1 inhibitor could ameliorate the intestinal barrier injury by reducing tight junctions' disruption and accompanying oxidative stress. Moreover, the release of chemokines and adhesion molecules from damaged IECs was suppressed by RIPK1 inhibitor treatment. And these protective effects were not only dependent on the suppression of necroptosis but also on the compromised activity of NF-κB. Taken together, RIPK1 inhibitor exerts suppressive function in intestinal inflammatory response possibly via protecting the intestinal epithelial barrier and maintaining the homeostasis of immune microenvironments. Eventually, the positive feedback immune response which triggered progressive epithelial cells injury could be restrained.
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http://dx.doi.org/10.1016/j.bcp.2019.113751DOI Listing
February 2020

Heme Catabolic Pathway in Inflammation and Immune Disorders.

Front Pharmacol 2019 24;10:825. Epub 2019 Jul 24.

Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

In recent years, the heme catabolic pathway is considered to play an important regulatory role in cell protection, apoptosis, inflammation, and other physiological and pathological processes. An appropriate amount of heme forms the basic elements of various life activities, while when released in large quantities, it can induce toxicity by mediating oxidative stress and inflammation. Heme oxygenase (HO) -1 can catabolize free heme into carbon monoxide (CO), ferrous iron, and biliverdin (BV)/bilirubin (BR). The diverse functions of these metabolites in immune systems are fascinating. Decades work shows that administration of degradation products of heme such as CO and BV/BR exerts protective activities in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS) and other immune disorders. This review elaborates the molecular and biochemical characterization of heme catabolic pathway, discusses the signal transduction and immunomodulatory mechanism in inflammation and summarizes the promising therapeutic strategies based on this pathway in inflammatory and immune disorders.
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http://dx.doi.org/10.3389/fphar.2019.00825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667928PMC
July 2019

Inhibition of phosphodiesterase-4 attenuates murine ulcerative colitis through interference with mucosal immunity.

Br J Pharmacol 2019 07 17;176(13):2209-2226. Epub 2019 May 17.

Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Background And Purpose: Ulcerative colitis (UC) is an aetiologically refractory inflammatory disease, accompanied by dysfunction of the epithelial barrier and intestinal inflammation. Phosphodiesterase-4 (PDE4) serves as an intracellular proinflammatory enzyme, hydrolyzing and inactivating cAMP. Though PDE4 inhibitors have been approved for pulmonary and dermatological diseases, the role of PDE4 inhibition in modulating mucosal immunity in the intestine remains ill-defined. This study was designed to explore whether PDE4 inhibition by apremilast exerts protective effects in dextran sulfate sodium-induced murine UC.

Experimental Approach: Intestinal inflammation and disease severity were evaluated by morphological, histopathological and biochemical assays, and in vivo imaging. Expression of inflammatory mediators, components of PDE4-mediated pathways in colon and macrophages were determined using quantitative real-time PCR, ELISA, Luminex assay, immunostaining, or western blotting, along with siRNA knockdown. Immune cells in mesenteric lymph nodes and colonic lamina propria were analysed by flow cytometry.

Key Results: Apremilast attenuated clinical features of UC, suppressing microscopic colon damage, production of inflammatory mediators, oxidative stresses, and fibrosis. Apremilast also promoted epithelial barrier function and inhibited infiltration of immune cells into inflamed tissues, through decreasing expression of chemokines and chemokine receptors. Furthermore, in UC, PDE4A, PDE4B, and PDE4D were highly expressed in colon. Apremilast not only inhibited PDE4 isoform expression but also activated PKA-CREB and Epac-Rap1 pathways and subsequently suppressed MAPK, NF-κB, PI3K-mTOR, and JAK-STAT-SOCS3 activation.

Conclusion And Implications: Inhibition of PDE4 by apremilast protected against UC, by interfering with mucosal immunity. These findings represent a promising strategy for regulating intestinal inflammation.
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http://dx.doi.org/10.1111/bph.14667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555859PMC
July 2019

Heterochromatin anomalies and double-stranded RNA accumulation underlie poly(PR) toxicity.

Science 2019 02;363(6428)

Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, and Chan Zuckerberg Biohub, San Francisco, CA, USA.

How hexanucleotide GGGGCC (GC) repeat expansions in cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded GC repeats. The expression of green fluorescent protein-conjugated (PR) (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of -associated FTD and ALS.
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http://dx.doi.org/10.1126/science.aav2606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524780PMC
February 2019

Apatinib monotherapy for advanced VEGFR-2-negative nasopharyngeal carcinoma: A case report.

Medicine (Baltimore) 2019 Jan;98(1):e13491

Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.

Rationale: Due to the anatomical and biological characteristics of nasopharyngeal carcinoma (NPC), radiotherapy is the standard treatment of choice. Recent advances in small molecule therapies targeting tumor angiogenesis also hold promise for the treatment of advanced NPC.

Patient Concerns: The patient's symptoms, including nasal obstruction, nasal bleeding, and headache, reappeared periodically and eventually became so severe that the patient's vision became impaired. In January 2016, the patient presented with blurred vision, diplopia, language impairment, left temporal paralysis, and bilateral eyelid ptosis.

Diagnosis: Advanced NPC without metastasis in a 55-year-old man.

Interventions: The patient refused treatment with radiotherapy or chemotherapy and was treated with Chinese herbal medicines. Following a worsening of symptoms, the patient was subsequently treated with apatinib monotherapy (0.25 g, once daily).

Outcomes: Symptom improvement, including decreased nasal bleeding and headache, was observed after 1 week of apatinib treatment. After 100 days of treatment, the patient was nearly asymptomatic with stable disease and improved quality of life.

Lessons: For patients with advanced NPC who refuse standard radiotherapy and chemotherapy, apatinib monotherapy may be a suitable treatment option to improve symptoms and quality of life even in those with vascular endothelial growth factor receptor-negative tumors.
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http://dx.doi.org/10.1097/MD.0000000000013491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344178PMC
January 2019

Analysis of weighted subspace fitting and subspace-based eigenvector techniques for frequency estimation for the coherent Doppler lidar.

Appl Opt 2017 Nov;56(33):9268-9276

Since the periodogram maximum (PM) algorithm fails to provide consistent estimates, more robust techniques are developed, especially in a low signal-to-noise ratio (SNR) regime. The methods are formulated in a subspace fitting-based framework, such as the eigenvector (EV) method and the proposed weighted subspace fitting (WSF) method by introducing an optimal weighting matrix, which exploits the low-rank properties of the covariance matrix of the coherent Doppler lidar echo data. Simulation results reveal that the number of the reliable estimates by the WSF method is more than the other two methods, and the standard deviation is the smallest. Furthermore, the predicted best-fit Gaussian model for the probability density function of the estimates has a narrower spectral width than that of PM and EV methods. Experimental results also validate the simulation results, which show that the WSF approach outperforms the PM and EV algorithms in the furthest detectable range. The proposed method improves the detection range approximately up to 14.2% and 26.6% when compared to the EV method and the PM method, respectively. In conclusion, the proposed method can reduce the statistical uncertainties and enhance the accuracy in wind estimation specifically for a low SNR regime.
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http://dx.doi.org/10.1364/AO.56.009268DOI Listing
November 2017

Wind profiling for a coherent wind Doppler lidar by an auto-adaptive background subtraction approach.

Appl Opt 2017 Apr;56(10):2705-2713

Auto-adaptive background subtraction (AABS) is proposed as a denoising method for data processing of the coherent Doppler lidar (CDL). The method is proposed specifically for a low-signal-to-noise-ratio regime, in which the drifting power spectral density of CDL data occurs. Unlike the periodogram maximum (PM) and adaptive iteratively reweighted penalized least squares (airPLS), the proposed method presents reliable peaks and is thus advantageous in identifying peak locations. According to the analysis results of simulated and actually measured data, the proposed method outperforms the airPLS method and the PM algorithm in the furthest detectable range. The proposed method improves the detection range approximately up to 16.7% and 40% when compared to the airPLS method and the PM method, respectively. It also has smaller mean wind velocity and standard error values than the airPLS and PM methods. The AABS approach improves the quality of Doppler shift estimates and can be applied to obtain the whole wind profiling by the CDL.
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http://dx.doi.org/10.1364/AO.56.002705DOI Listing
April 2017

The lysosomal membrane protein SCAV-3 maintains lysosome integrity and adult longevity.

J Cell Biol 2016 Oct 17;215(2):167-185. Epub 2016 Oct 17.

National Institute of Biological Sciences, Beijing 102206, China

Lysosomes degrade macromolecules and recycle metabolites as well as being involved in diverse processes that regulate cellular homeostasis. The lysosome is limited by a single phospholipid bilayer that forms a barrier to separate the potent luminal hydrolases from other cellular constituents, thus protecting the latter from unwanted degradation. The mechanisms that maintain lysosomal membrane integrity remain unknown. Here, we identified SCAV-3, the Caenorhabditis elegans homologue of human LIMP-2, as a key regulator of lysosome integrity, motility, and dynamics. Loss of scav-3 caused rupture of lysosome membranes and significantly shortened lifespan. Both of these phenotypes were suppressed by reinforced expression of LMP-1 or LMP-2, the C. elegans LAMPs, indicating that longevity requires maintenance of lysosome integrity. Remarkably, reduction in insulin/insulin-like growth factor 1 (IGF-1) signaling suppressed lysosomal damage and extended the lifespan in scav-3(lf) animals in a DAF-16-dependent manner. Our data reveal that SCAV-3 is essential for preserving lysosomal membrane stability and that modulation of lysosome integrity by the insulin/IGF-1 signaling pathway affects longevity.
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http://dx.doi.org/10.1083/jcb.201602090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084646PMC
October 2016

Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation.

Cell Mol Immunol 2016 05 16;13(3):379-90. Epub 2015 Mar 16.

Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

We previously reported that SM934, a water-soluble artemisinin derivative, was a viable treatment in murine lupus models. In the current study, we further investigated the therapeutic effects of a modified dosage regimen of SM934 on lupus-prone MRL/lpr mice and explored its effects on B cell responses, a central pathogenic event in systemic lupus erythematosus (SLE). When orally administered twice-daily, SM934 significantly prolonged the life-span of MRL/lpr mice, ameliorated the lymphadenopathy symptoms and decreased the levels of serum anti-nuclear antibodies (ANAs) and of the pathogenic cytokines IL-6, IL-10 and IL-21. Furthermore, SM934 treatment restored the B-cell compartment in the spleen of MRL/lpr mice by increasing quiescent B cell numbers, maintaining germinal center B-cell numbers, decreasing activated B cell numbers and reducing plasma cell (PC) numbers. Ex vivo, SM934 suppressed the Toll-like receptor (TLR)-triggered activation and proliferation of B cells, as well as antibody secretion. Moreover, the present study demonstrated that SM934 interfered with the B-cell intrinsic pathway by downregulating TLR7/9 mRNA expression, MyD88 protein expression and NF-κB phosphorylation. In human peripheral blood mononuclear cells (PBMCs), consistent with the results in MRL/lpr mice, SM934 inhibited TLR-associated B-cell activation and PC differentiation. In conclusion, a twice daily dosing regimen of SM934 had therapeutic effects on lupus-prone MRL/lpr mice by suppressing B cell activation and plasma cell formation.
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http://dx.doi.org/10.1038/cmi.2015.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856803PMC
May 2016

PI3P phosphatase activity is required for autophagosome maturation and autolysosome formation.

EMBO Rep 2014 Sep 14;15(9):973-81. Epub 2014 Aug 14.

National Institute of Biological Sciences, Beijing, China

Autophagosome formation is promoted by the PI3 kinase complex and negatively regulated by myotubularin phosphatases, indicating that regulation of local phosphatidylinositol 3-phosphate (PtdIns3P) levels is important for this early phase of autophagy. Here, we show that the Caenorhabditis elegans myotubularin phosphatase MTM-3 catalyzes PtdIns3P turnover late in autophagy. MTM-3 acts downstream of the ATG-2/EPG-6 complex and upstream of EPG-5 to promote autophagosome maturation into autolysosomes. MTM-3 is recruited to autophagosomes by PtdIns3P, and loss of MTM-3 causes increased autophagic association of ATG-18 in a PtdIns3P-dependent manner. Our data reveal critical roles of PtdIns3P turnover in autophagosome maturation and/or autolysosome formation.
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http://dx.doi.org/10.15252/embr.201438618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198041PMC
September 2014

Autophagy genes coordinate with the class II PI/PtdIns 3-kinase PIKI-1 to regulate apoptotic cell clearance in C. elegans.

Autophagy 2013 Dec 21;9(12):2022-32. Epub 2013 Oct 21.

Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing, China; National Institute of Biological Sciences; Beijing, China.

Phagocytosis and autophagy are two lysosome-mediated cellular degradation pathways designed to eliminate extracellular and intracellular constituents, respectively. Recent studies suggest that these two processes intersect. Several autophagy proteins have been shown to participate in clearance of apoptotic cells, but whether and how the autophagy pathway is involved is unclear. Here we showed that loss of function mutations in 19 genes acting at overlapping or distinct stages of autophagy caused increased numbers of cell corpses in C. elegans embryos. In contrast, genes that mediate specific clearance of P granules or protein aggregates through autophagy are dispensable for cell corpse removal. We showed that defective autophagy impairs phagosome maturation and that autophagy genes act in parallel to the class II phosphoinositide (PI)/phosphatidylinositol (PtdIns) 3-kinase PIKI-1 to regulate phagosomal PtdIns3P in a similar manner as VPS-34. Our data indicate that autophagy may coordinate with PIKI-1 to promote phagosome maturation, thus ensuring efficient clearance of apoptotic cells.
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http://dx.doi.org/10.4161/auto.26323DOI Listing
December 2013

[Determination of taxol in taxol injection using near infrared transmission spectroscopy].

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2009 Oct;26(5):982-4

Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China.

The objective of this study was to develop a method for the determination of taxol injection using near infrared transmission spectroscopy, turning out redetermination for injection from hospital pharmacy before using. Near infrared spectra (NIR) in the range of 12 000 approximation 4 000cm(-1) were recorded for the taxol injection manufactured during recent 24 months with different time. Calibration models were established using the partial least squares (PLS). Comparing different spectra pretreatments methods, dimension and spectra range, The study showed that spectra information cab be extracted thoroughly by delete a line method with dimension 6, spectra range 9002.5 approximately 4597.7cm(-1) ,standard error of the calibration sets(SEC) 0.035 and standard error of the prediction sets(SEP) 0. 059. Percent of prediction sets sample is less than +/- 2%. Results indicate that near infrared transmission spectroscopy method can be used to rapidly analyze the frequent and important drugs from hospital pharmacy.
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October 2009

Identification and functional analysis of a CDE/CHR element in the POLD1 promoter.

Sci China C Life Sci 2009 Jun 26;52(6):551-9. Epub 2009 Jun 26.

Key Laboratory of Cell Proliferation and Regulation of Ministry of Education, Beijing Normal University, Beijing 100875, China.

DNA polymerase delta is encoded by the POLD1 gene, the transcription of which is strictly cell cycle-dependent. However, the means by which POLD1 transcription is regulated by the cell cycle mechanism is currently unknown. We discovered a novel element in the POLD1 promoter known as a CDE(cell cycle-dependent element)/CHR(cell cycle gene homology region) element. A series of luciferase reporter constructs containing various POLD1 promoter mutations were used to investigate the role of the CDE/CHR element in POLD1 transcription. When the CDE/CHR element was mutated, the promoter activity was up-regulated, and the cell-cycle related factors E2F1 and p21 stopped regulating the promoter. Furthermore, cell cycle-dependent changes in the promoter activity required the integrative CDE/CHR element. Electrophoretic mobility shift assay (EMSA) revealed the presence of at least three types of DNA/protein complexes binding to the CDE/CHR element. Our findings provide strong evidence that the CDE/CHR-like sequence is an active functional element in the POLD1 promoter, which is important for the cell cycle regulation of the POLD1 gene.
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http://dx.doi.org/10.1007/s11427-009-0077-5DOI Listing
June 2009

Attitudes and behavioral response toward key tobacco control measures from the FCTC among Chinese urban residents.

BMC Public Health 2007 Sep 18;7:248. Epub 2007 Sep 18.

Center for Tobacco Control Research, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Background: The Chinese National People's Congress ratified the WHO Framework Convention on Tobacco Control (FCTC) on 27 August 2005, signaling China's commitment to implement tobacco control policies and legislation consistent with the treaty. This study was designed to examine attitudes towards four WHO FCTC measures among Chinese urban residents.

Methods: In a cross-sectional design study, survey data were collected from two Chinese urban cities involving a sample of 3,003 residents aged 15 years or older. Through a face-to-face interview, respondents were asked about attitudes toward four tobacco control measures developed by the WHO FCTC. Data on the four dependent measures were analyzed using multivariate logistic regression analyses. Using descriptive statistics, potential change in smoking behavior that smokers might make in response to increasing cigarette prices is also reported.

Results: 81.8% of the respondents in the study sample supported banning smoking in public places, 68.8% favored increasing the cigarette tax, 85.1% supported health warnings on cigarette packages, and 85.7% favored banning tobacco advertising. The likelihood to support these measures was associated with gender, educational level, and personal income. Smokers were less likely to support these measures than non-smokers, with decreased support expressed by daily smokers compared to occasional smokers, and heavy smokers compared to light smokers. The proportion of switching to cheaper cigarette brands, decreasing smoking, and quitting smoking altogether with increased cigarette prices were 29.1%, 30.90% and 40.0% for occasional smokers, respectively; and 30.8%, 32.7% and 36.5% for daily smokers, respectively.

Conclusion: Results from this study indicate strong public support in key WHO FCTC measures and that increases in cigarette price may reduce tobacco consumption among Chinese urban residents. Findings from this study have implications with respect to policymaking and legislation for tobacco control in China.
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http://dx.doi.org/10.1186/1471-2458-7-248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194773PMC
September 2007

Stochastic resonance is applied to quantitative analysis for weak chromatographic signal of roxithromycin in beagle dog plasma.

J Chromatogr B Analyt Technol Biomed Life Sci 2006 Feb 4;831(1-2):307-12. Epub 2006 Jan 4.

Center for Instrumental Analysis of China Pharmaceutical University, Nanjing 210009, China.

Based on the theory of stochastic resonance, the signal to noise ratio (SNR) of HPLC/UV chromatographic signal of roxithromycin is enhanced by cooperation of signal, noise and nonlinear system. A simple new method for the determination of low concentration of roxithromycin in beagle dog plasma is presented. Using signal enhancement by stochastic resonance, this method extends the limit of quantitation from the reported 0.5 to 0.1 microg/ml. During validation of the new method, HPLC/MS was used as a comparison technique. The results indicate that the recovery and low concentrations of roxithromycin in beagle dog plasma were equivalent between the two methods (P>0.05). Stochastic resonance may be a promising tool for improving detection limits in trace analysis.
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http://dx.doi.org/10.1016/j.jchromb.2005.12.014DOI Listing
February 2006

Determination of nifuratel in human plasma by HPLC and study on its pharmacokinetics.

J Chromatogr Sci 2005 Apr;43(4):179-82

China Pharmaceutical University, Center for Instrumental Analysis, Nanjing 210009, China.

A simple and sensitive reversed-phase high-performance liquid chromatography method using UV detection is established for the determination of nifuratel in human plasma and applied to a study of its pharmacokinetics. Plasma samples are extracted with ethyl acetate. A C(18) column and a mobile phase of 0.01 M (pH 7) phosphate buffer (KH(2)PO(4)) and acetonitrile (61:39, v/v) are used. Analysis is run at a flow rate of 1.0 mL/min with the detector operated at a wavelength of 367 nm. The calibration curve is linear over a concentration range of 0.2-40 ng/mL with a correlation coefficient of 0.9996. The limit of detection is 0.1 ng/mL. The mean absolute recovery value is greater than 80%. The intraday precision (relative standard deviation) ranges from 1.89% to 7.32%, and the interday precision ranges from 1.71% to 7.83%. The results show that the area under the plasma concentration-time curve, time to maximum observed plasma concentration, maximum concentration reached in the concentration profile, and elimination half-life between the testing tablets and reference tablets have no significant difference (P > 0.05). Relative bioavailability is 104.0% +/- 16.5%.
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April 2005
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