48 results on '"Lei, Xiaoyong"'
Search Results
2. Variance state propagation for uplink channel estimation in LEO satellite systems.
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Lei, Xiaoyong, Zhang, Mingchen, Liu, Yilun, and Zhang, Yong
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CHANNEL estimation , *ORTHOGONAL frequency division multiplexing , *DOPPLER effect , *ITERATIVE learning control - Abstract
This paper, considers the channel estimation problem of the uplink low Earth orbit (LEO) satellite orthogonal frequency division multiplexing (OFDM) system. By exploiting the channel structured sparsity in the delay‐Doppler‐angle domain, the channel estimation problem is formulated as a block‐sparse signal recovery problem. The variance state propagation (VSP) framework is extended to solve such a problem. Considering that the delay, Doppler shift, and angle of departure (AoD) of each propagation path may not exactly fall on the presumed discrete grid points, an expectation maximization (EM) based parameter learning scheme in VSP to iteratively update the grid parameters is introduced. Simulation results demonstrate that the proposed approach achieves a substantial performance gain over the existing methods. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Emerging role of competing endogenous RNA in lung cancer drug resistance.
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Wu, Shijie, Luo, Ting, Lei, Xiaoyong, and Yang, Xiaoyan
- Abstract
AbstractLung cancer remains one of the most common malignant cancers worldwide, and its survival rate is extremely low. Chemotherapy, the mainstay of lung cancer treatment, is not as effective as it could be due to the development of cellular resistance. The molecular mechanisms of drug resistance in lung cancer remain to be elucidated. Accumulating evidence suggests that ceRNAs are involved in various carcinogenesis and development. CeRNA is a transcript that regulates each other through competition with miRNA. However, the relationship between ceRNAs and chemoresistance in lung cancer remains unclear. In this narrative review, we provided a summary of treatment approaches that focus on ceRNA networks to overcome drug resistance. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Ca2+-independent phospholipase A2β-derived PGE2 contributes to osteogenesis.
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Hancock, William D., Lei, Xiaoyong, Clines, Gregory A., Tusing, Ying G., Nozell, Susan E., and Ramanadham, Sasanka
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MESENCHYMAL stem cells , *BONE growth , *OSTEOINDUCTION , *PHOSPHOLIPASES , *CYCLOOXYGENASE 2 - Abstract
• iPLA 2 β-derived PGE 2 is important for optimal bone formation. • iPLA 2 β-derived PGE 2 induces osteogenic factors. • Select inhibitors of iPLA 2 β and EP4 receptor mitigate induction of osteogenic factors and osteogenesis. • Roles for iPLA 2 β-derived PGE 2 include induction of Runx2 and also iPLA 2 β. • First demonstration of iPLA 2 β regulation by downstream products of its activation. Bone modeling can be modulated by lipid signals such as arachidonic acid (AA) and its cyclooxygenase 2 (COX2) metabolite, prostaglandin E 2 (PGE 2), which are recognized mediators of optimal bone formation. Hydrolysis of AA from membrane glycerophospholipids is catalyzed by phospholipases A 2 (PLA 2 s). We reported that mice deficient in the Ca2+- independent PLA 2 beta (iPLA 2 β), encoded by Pla2g6 , exhibit a low bone phenotype, but the cause for this remains to be identified. Here, we examined the mechanistic and molecular roles of iPLA 2 β in bone formation using bone marrow stromal cells and calvarial osteoblasts from WT and iPLA 2 β-deficient mice, and the MC3T3-E1 osteoblast precursor cell line. Our data reveal that transcription of osteogenic factors (Bmp2 , Alpl , and Runx2) and osteogenesis are decreased with iPLA 2 β-deficiency. These outcomes are corroborated and recapitulated in WT cells treated with a selective inhibitor of iPLA 2 β (10 μM S -BEL), and rescued in iPLA 2 β-deficient cells by additions of 10 μM PGE 2. Further, under osteogenic conditions we find that PGE 2 production is through iPLA 2 β activity and that this leads to induction of Runx2 and iPLA 2 β transcription. These findings reveal a strong link between osteogenesis and iPLA 2 β-derived lipids and raise the intriguing possibility that iPLA 2 β-derived PGE 2 participates in osteogenesis and in the regulation of Runx2 and also iPLA 2 β. [ABSTRACT FROM AUTHOR]
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- 2022
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5. Alterations in β-Cell Sphingolipid Profile Associated with ER Stress and iPLA 2 β: Another Contributor to β-Cell Apoptosis in Type 1 Diabetes.
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Ali, Tomader, Lei, Xiaoyong, Barbour, Suzanne E., Koizumi, Akio, Chalfant, Charles E., and Ramanadham, Sasanka
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TYPE 1 diabetes , *CELL death , *CELL survival , *APOPTOSIS , *SPHINGOLIPIDS , *CERAMIDES - Abstract
Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca2+-independent phospholipase A2 beta (iPLA2β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLA2β-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA2β on sphingolipids (SLs), we characterized their profile in β-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student's t-test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLA2β-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) β-cells. As expected, iPLA2β induction was greater in the OE and AK cells in comparison with V and WT cells. We report here that ER stress led to elevations in pro-apoptotic and decreases in pro-survival sphingolipids and that the inactivation of iPLA2β restores the sphingolipid species toward those that promote cell survival. In view of our recent finding that the SL profile in macrophages—the initiators of autoimmune responses leading to T1D—is not significantly altered during T1D development, we posit that the iPLA2β-mediated shift in the β-cell sphingolipid profile is an important contributor to β-cell death associated with T1D. [ABSTRACT FROM AUTHOR]
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- 2021
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6. Group VIA Ca2+-independent phospholipase A2 (iPLA2β) and its role in β-cell programmed cell death
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Lei, Xiaoyong, Barbour, Suzanne E., and Ramanadham, Sasanka
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PHOSPHOLIPASE A2 , *CELL death , *CERAMIDES , *GENE expression , *LABORATORY mice , *DIAGNOSIS of diabetes , *CELLULAR signal transduction - Abstract
Abstract: Activation of phospholipases A2 (PLA2s) leads to the generation of biologically active lipid mediators that can affect numerous cellular events. The Group VIA Ca2+-independent PLA2, designated iPLA2β, is active in the absence of Ca2+, activated by ATP, and inhibited by the bromoenol lactone suicide inhibitor (BEL). Over the past 10–15 years, studies using BEL have demonstrated that iPLA2β participates in various biological processes and the recent availability of mice in which iPLA2β expression levels have been genetically-modified are extending these findings. Work in our laboratory suggests that iPLA2β activates a unique signaling cascade that promotes β-cell apoptosis. This pathway involves iPLA2β dependent induction of neutral sphingomyelinase, production of ceramide, and activation of the intrinsic pathway of apoptosis. There is a growing body of literature supporting β-cell apoptosis as a major contributor to the loss of β-cell mass associated with the onset and progression of Type 1 and Type 2 diabetes mellitus. This underscores a need to gain a better understanding of the molecular mechanisms underlying β-cell apoptosis so that improved treatments can be developed to prevent or delay the onset and progression of diabetes mellitus. Herein, we offer a general review of Group VIA Ca2+-independent PLA2 (iPLA2β) followed by a more focused discussion of its participation in β-cell apoptosis. We suggest that iPLA2β-derived products trigger pathways which can lead to β-cell apoptosis during the development of diabetes. [Copyright &y& Elsevier]
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- 2010
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7. Recent advances in pyruvate dehydrogenase kinase inhibitors: Structures, inhibitory mechanisms and biological activities.
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Li, Yiyang, Xie, Zhizhong, Lei, Xiaoyong, Yang, Xiaoyan, Huang, Sheng, Yuan, Weixi, Deng, Xiangping, Wang, Zhe, and Tang, Guotao
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PYRUVATE dehydrogenase kinase , *KINASE inhibitors , *PYRUVATE dehydrogenase complex , *PYRUVATE kinase , *METABOLIC reprogramming , *PHARMACEUTICAL chemistry , *CANCER cells - Abstract
[Display omitted] Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Long non-coding RNA GAS5 in human cancer.
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Yang, Xiaoyan, Xie, Zhizhong, Lei, Xiaoyong, and Gan, Runliang
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RENAL cancer , *BLADDER cancer , *LUNG cancer , *PROSTATE cancer , *GROWTH arrest-specific 5 - Abstract
Long non-coding RNAs (lncRNAs) constitute a group of >200-nucleotide ncRNA molecules. lncRNAs regulate several cell functions, such as proliferation, apoptosis, invasion and metastasis. Meanwhile, lncRNAs are abnormally expressed in human malignancies, where they suppress or promote tumor growth. The present study focused on growth arrest-specific transcript 5 (GAS5), a well-known lncRNA that acts as a tumor suppressor but is suppressed in multiple types of cancer, including mammary carcinoma, prostate cancer, colorectal cancer, gastric cancer, melanoma, esophageal squamous cell carcinoma, lung cancer, ovarian cancer, cervical cancer, gliomas, osteosarcoma, pancreatic cancer, bladder cancer, kidney cancer, papillary thyroid carcinoma, neuroblastoma, endometrial cancer and liver cancer. Notably, GAS5 is overexpressed in liver cancer, potentially functioning as an oncogene. In the present study, the diagnostic and therapeutic roles of GAS5 in different tumors were reviewed, with a summary of the potential clinical application of the lncRNA, which may help identify novel study directions for GAS5. [ABSTRACT FROM AUTHOR]
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- 2020
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9. Identification of Proteins Regulated During ER Stress-Induced β-Cell Apoptosis by Quantitative Proteomic Profiling using SILAC.
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Song, Haowei, Lei, Xiaoyong, Zhang, Sheng, Turk, John, and Ramanadham, Sasanka
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PROTEINS , *APOPTOSIS , *PHOSPHOLIPASES , *DIABETES , *AMINO acids , *CELL culture , *GLYCOSYLTRANSFERASES - Abstract
We previously reported that a bromoenol lactone (BEL) suicide inhibitor of the Group VIA Ca[sup 2+]-independent phospholipase A[sub 2] (iPLA[sub 2]β) suppresses ER stress-induced β-cell apoptosis, suggesting that iPLA[sub 2]β plays a role in this process. To gain a better understanding of the mechanism of involvement of iPLA[sub 2]β during ER stress, stable isotope labeling with amino acids in cell culture (SILAC) experiment were performed in empty-vector (V) transfected and iPLA[sub 2]β-overexpressing (OE) cells INS-1 β-cells. cells cultured in isotope-labeled (heavy) amino acids medium were treated with DMSO vehicle and Cells cultured in regular media were treated with thapsigargin (1 µM) to induce ER stress. After 24h, the vehicle- and thapsigargin-treated homogenate protein from each were combined in a 1:1 ratio, separated by SDS-PAGE (7.5%), digested with trypsin, and analyzed by LC/MS/MS mass spectrometry. ER stress induced no change in tubulin in either V or OE INS-1 cells, an increase in iPLA[sub 2]β in the OE cells, and dysregulation of several cytosolic-, mitochondrial-, and ER-associated proteins that participate in apoptosis in both V and OE INS-1 cells. While ubiquitin-like 1 activating enzyme E1A was up-regulated less in the OE than in the V INS-1 cells; GRP 78, Trap 1, Erp 61, hypoxia up-regulated 1, and UDP-glucose ceramide glucosyltransferase-like 1 were down-regulated more in the OE than in the V INS-1 cells. Thus, the SILAC protocol allowed identification of differentially-regulated proteins in β-cells undergoing ER stress, generation a dataset of proteins that might participate in ER stress-induced β-cell apoptosis, and assessment of the role of iPLA[sub 2]β in this process. Our findings indicate that induction of ER stress in β-cells leads to recruitment of the mitochondria and that both organelles, in concert with iPLA[sub 2]β, contribute to ER stress-induced β-cell apoptosis. [ABSTRACT FROM AUTHOR]
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- 2007
10. Design, synthesis, and antitumor evaluation of trimethoxyflavonoid with arylurea structure against hepatocellular carcinoma.
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Sun, Xueyan, Zhao, Yin, Zhao, Jingduo, Xie, Zhizhong, Lei, Xiaoyong, Liu, Xingyun, Li, Yong, Huang, Sheng, Wang, Zhe, and Tang, Guotao
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BIOSYNTHESIS , *VASCULAR endothelial growth factors , *HEPATOCELLULAR carcinoma , *LIVER tumors , *LIVER cells - Abstract
Simultaneous targeting of tumor vasculature and inhibitors of tumor cell glycolysis may be a promising antitumor strategy. Here, we reported the total synthesis and biological evaluation of A‐ring arylurea flavonoid derivatives with B‐ring trimethoxy group, which exhibited potent antitumor activity against a variety of tumor cells in vitro. Most of the derivatives showed in vitro antitumor activity on HepG‐2, HGC‐27, MDA‐MB‐231, and A549 cells. Among them, compounds 8e, 8f, 8g, 8h, 8j, and 8l also exhibited significant anti‐proliferation effects on liver tumor cell subtypes BEL‐7402 and SMMC‐7721. Compound 8l had the lowest IC50 value (5.61 ± 0.39 μM) on HepG‐2 cells, and showed the effects of inhibiting colony formation, arresting the cell cycle in G0/G1 phase, and inducing apoptosis in a concentration‐dependent manner. In addition, the toxicity of compound 8l on human normal cells LO2 and GES‐1 was lower than that of sorafenib. The inhibitory effects of compound 8l on the expression of glycolytic rate‐limiting enzymes HKII, PFK‐1, PKM2 and vascular endothelial growth factor were further evaluated. Corresponding reduction in intracellular lactate was also detected after compound 8 treatment. Our results support an antitumor strategy targeting tumor vasculature and glycolysis to discover and develop a new generation of antitumor drugs. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Advances in antitumor research of HIF-1α inhibitor YC-1 and its derivatives.
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Ouyang, Chenglin, Zhang, Jing, Lei, Xiaoyong, Xie, Zhizhong, Liu, Xingyun, Li, Yong, Huang, Sheng, Wang, Zhe, and Tang, Guotao
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STRUCTURE-activity relationships , *ANTINEOPLASTIC agents , *DRUG derivatives , *AZOLES , *LEAD compounds - Abstract
[Display omitted] • Main anti-tumor mechanisms of YC-1 are summarized. • The research progress of YC-1 derivatives as HIF-1α inhibitors and antitumor drugs is reviewed. • Some unique insights have been made into the further development of YC-1 derivatives as anti-tumor drugs. Generally, hypoxia-inducible factor-1α (HIF-1α) is highly expressed in solid tumors, it plays a key role in the occurrence and development of tumors, hindering cancer treatment in various ways. The antitumor activity and pharmacological mechanism of YC-1 [3-(5′-hydroxymethyl-2′-furyl)-1‑benzyl indazole], an HIF-1α inhibitor, and the design and synthesis of its derivatives have attracted tremendous attention in the field of antitumor research. YC-1 is a potential drug candidate and a lead compound for tumor therapy. Hence, the multifaceted mechanism of action of YC-1 and the structure activity relationship (SAR) of its derivatives are important factors to be considered for the development of HIF-1α inhibitors. Therefore, this review aimed to provide a comprehensive overview of the various antitumor mechanisms of YC-1 in antitumor research and an in-depth summary of the SAR for the development of its derivatives. A full understanding and discussion of these aspects are expected to provide potential ideas for developing novel HIF-1α inhibitors and antitumor drugs belonging to the YC-1 class. The review also highlighted the application prospects of the YC-1 class of potential antitumor candidates, and provided some unique insights about these antitumor agents. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Discovery of a Potential Multi-Target Anti-Tumor Agent via Structural Modification on Flavonoid.
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Deng, Xiangping, Zou, Yang, Liu, Renbo, Peng, Yijiao, Ouyang, Chenglin, Peng, Junmei, Lei, Xiaoyong, Xie, Zhizhong, Li, Chong, and Tang, Guotao
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ANTINEOPLASTIC agents , *ANNEXINS , *FLAVONOIDS , *DRUG development , *CANCER cells , *TUBULINS , *BENZIMIDAZOLES - Abstract
A series of flavonoid derivatives bearing trimethoxyphenyl and benzimidazole were designed, synthesized and evaluated as potential anti-tumor agents. Compound 5g showed remarkable inhibitory activity against SGC-7901, HGC-27 and MCF-7 (IC50 values of 20.5 ± 5.93, 3.3 ± 2.53 and 16.6 ± 0.75 μM, respectively), and had great selectivity to cancer cells. The results of Hoechst 33258 staining and Annexin V-FITC/PI dual staining confirmed that compound 5 g induced apoptosis of the HGC-27 cells in a concentration-dependent manner. After treatment with compound 5 g, the expression of HIF-1α, VEGF and PKM2 were down-regulated, accompanied by weakened the levels of lactate. Further research revealed that compound 5 g could obviously inhibit tubulin assembly. In summary, compound 5 g possessed a promising potential for further development into anti-tumor drug candidates. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Amazing roles of extrachromosomal DNA in cancer progression.
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Zhao, Leilei, Jiang, Yicun, Lei, Xiaoyong, and Yang, Xiaoyan
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EXTRACHROMOSOMAL DNA , *CANCER invasiveness , *TUMOR microenvironment , *DRUG resistance , *CANCER cells - Abstract
In cancers, extrachromosomal DNA (ecDNA) has gained renewed interest since its first discovery, presenting its roles in tumorigenesis. Because of the unique structure and genetic characteristics, extrachromosomal DNA shed new light on development, early diagnosis, treatment and prognosis of cancers. Occurs in cancer cells, extrachromosomal DNA, one dissociative circular extrachromosomal element, drives the amplification of oncogenes, promotes the transcription and lifts tumor heterogeneity to participate in tumorigenesis. Given its role act as messenger, extrachromosomal DNA is connected with drug resistance, tumor microenvironment, germline and aging. The diversity of space and time gives extrachromosomal DNA a crucial role in cancer progression that has been ignored for decades. Thus, in this review, we will focus on some unique information of extrachromosomal DNA and the regulation of oncogenes as well as its roles and possible mechanisms in tumorigenesis, which are of great significance for us to understand extrachromosomal DNA comprehensively in carcinogenic mechanism. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Overexpression of iPLA2γ in INS-1 Cells Protects Against Nitric Oxide-Induced Apoptosis by Reducing the ER Stress Response.
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Bao, Shunzhong, Lei, Xiaoyong, Jin, Wu, Ramanadham, Sasanka, and Turk, John
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DIABETES , *PANCREATIC beta cells , *CELL death , *CYTOKINES , *NITRIC oxide , *APOPTOSIS , *PHOSPHOLIPASE A2 , *CELLS - Abstract
In type I diabetes, beta cell death can result from cytokine-induced nitric oxide (NO) production and apoptosis, iPLA2γ is a recently recognized Group VI phospholipase A2 that is expressed in mitochondria and other subcellular loci, and it has been suggested to participate in the maintenance of mitochondrial membrane integrity. Here we demonstrate that overexpression of iPLA2γ in INS-1 insulinoma cells (OE cells) protects against apoptosis induced by the NO donor S-nitroso-N-acetylpenicillamine (SNAP), as assessed by TUNEL staining up to 11.5±2.5% of control INS-1 cells experienced apoptosis after exposure to SNAP for 16 hr, but only 5.6±1.4% (p<0.01) of OE cells did so. In addition, fewer OE cells than control cells experienced collapse of the mitochondrial membrane potential after SNAP exposure. SNAP strongly induced expression of the ER stress marker CHOP in control INS-1 cells before onset of apoptosis, and these responses were greatly blunted in OE cells. No differences between control and OE cells were observed with respect to activation of the Akt or GSK3ß signaling pathways induced by SNAP exposure. These findings suggest that iPLA2γ might act to reduce both mitochondrial injury upon exposure to NO and the associated generation of signals that induce ER stress and that these actions of iPLA2γ do not involve the Akt or GSK3B signaling pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2007
15. Roles of ABCA1 in cancer.
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Wu, Kun, Zou, Longwei, Lei, Xiaoyong, and Yang, Xiaoyan
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CHOLESTEROL metabolism , *CHOLESTEROL , *ANTINEOPLASTIC agents , *CANCER treatment - Abstract
Studies have indicated that anticancer drugs targeting cholesterol metabolism have clinical significance. From the perspective of the mechanism of cholesterol excretion from cells, ATP-binding cassette (ABC)A1 has an essential role that cannot be ignored. ABCA1 is located on the cell membrane and able to mediate the efflux of lipids, such as intracellular cholesterol, thereby initiating reverse cholesterol transport to reduce the intracellular cholesterol level. Therefore, inducing the expression of ABCA1 may become a new breakthrough point in cancer therapy. [ABSTRACT FROM AUTHOR]
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- 2022
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16. Research progress of PD‐L1 non‐glycosylation in cancer immunotherapy.
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Cao, Pu, Yang, Xiaoyan, Liu, Daquan, Ye, Simin, Yang, Wei, Xie, Zhizhong, and Lei, Xiaoyong
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PROGRAMMED death-ligand 1 , *PROGRAMMED cell death 1 receptors , *SMALL molecules , *GOLGI apparatus , *SYNTHETIC enzymes , *MOVEMENT disorders , *GLYCANS - Abstract
Cancer is the second leading cause of death among human diseases. Immunotherapy has opened a new chapter in cancer treatment. However, the emergence of immune escape mechanisms severely limited its application. The high expression of PD‐L1 on tumour cells is an important means for cancer cells to achieve immune escape via binding to PD‐1 on immune cells. Recent studies have shown that PD‐L1 expression in most cancer cells is over‐glycosylated. Glycosylation is a fundamental and extensive post‐translational modification of eukaryotic membrane‐binding proteins, which affects a variety of biological activities, including protein folding, solubility, stability and ligand‐receptor interactions. PD‐L1 glycosylation initiates in the endoplasmic reticulum (ER) and completes in the Golgi apparatus, which has a complex relationship with cancer development. Importantly, non‐glycosylated PD‐L1 attenuates protein stability and PD‐1 interactions. These processes are essential regulatory mechanisms that modulate immunosuppression and immune surveillance in cancer patients. Therefore, non‐glycosylated PD‐L1 may be a potentially promising strategy to improve the efficacy of checkpoint blockade therapy for cancer. In this review, we have described the PD‐L1 glycosylation processes and provided evidence for the role of non‐glycosylated PD‐L1 in anti‐tumour‐related signalling pathways. Furthermore, strategies for non‐glycosylation of PD‐L1 using small molecule inhibitors, gene therapy and various enzymes in the synthetic glycosylation pathway are discussed. Finally, the detection of PD‐L1 expression is enhanced by its deglycosylation, and we have summarized the development, application and clinical application potential of antibody therapies targeting PD‐1/PD‐L1 glycosylation. [ABSTRACT FROM AUTHOR]
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- 2022
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17. Discovery of novel small molecules targeting the USP21/JAK2/STAT3 axis for the treatment of triple-negative breast cancer.
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Long, Lin, Xu, Jiachi, Qi, Xiaowen, Pen, Yan, Wang, Chengkun, Jiang, Weifan, Peng, Xue, Hu, Zecheng, Yi, Wenjun, Xie, Liming, Lei, Xiaoyong, Wang, Zhen, and Zhuo, Linsheng
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TRIPLE-negative breast cancer , *SMALL molecules , *PACLITAXEL , *DEUBIQUITINATING enzymes , *TRYPTAMINE - Abstract
The deficiency in available targeted agents and frequency of chemoresistance are primary challenges in clinical management of triple-negative breast cancer (TNBC). The aberrant expression of USP21 and JAK2 represents a characterized mechanism of TNBC progression and resistance to paclitaxel (PTX). Despite its clear that high expression of USP21-mediated de-ubiquitination leads to increased levels of JAK2 protein, we lack regulator molecules to dissect the mechanisms that the interaction between USP21 and JAK2 contributes to the phenotype and resistance of TNBC. Here, we report a USP21/JAK2/STAT3 axis-targeting regulator 13c featuring a N -anthraniloyl tryptamine scaffold that showed excellent anti -TNBC potency and promising safety profile. Importantly, the therapeutic potential of using 13c in combination with PTX in PTX -resistant TNBC was demonstrated. This study showcases N -anthraniloyl tryptamine derivatives as a novel anti -TNBC chemotype with a pharmacological mode of action targeting the USP21/JAK2/STAT3 axis and provides a potential therapeutic target for the treatment of TNBC. [Display omitted] • The anti -TNBC potency of N -anthraniloyl tryptamine scaffold was well-identified. • Compound 13c showed excellent potency against MDA-MB-231 and HCC-1806 cell lines. • Compound 13c showed potential capability to regulate USP21/JAK2/STAT3 axis. • Compound 13c showed significant anti -TNBC efficacy in vivo. [ABSTRACT FROM AUTHOR]
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- 2024
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18. LINC01234 Accelerates the Progression of Breast Cancer via the miR-525-5p/Cold Shock Domain-Containing E1 Axis.
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Yu, Jia, Zhang, Xinxin, He, Rongfang, Yang, Xiaoyan, Hu, Juan, Tan, Fang, Yao, Jinyu, Lei, Xiaoyong, and Wen, Gebo
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REVERSE transcriptase polymerase chain reaction , *LINCRNA , *BREAST cancer , *FLUORESCENCE in situ hybridization , *CANCER invasiveness - Abstract
Backgrounds. Long noncoding RNAs (lncRNAs) are strongly associated with the development of breast cancer (BC). As yet, the function of LINC01234 in BC remains unknown. Methods. Using biological information, the potential lncRNA, miRNA, and target gene were predicted. LINC01234 and miR-525-5p expression in BC tissues was detected using quantitative real-time reverse transcription polymerase chain reaction. Fluorescence in situ hybridization was used to determine the distribution of LINC01234. Cell proliferation was analyzed using CCK-8 assay, colony formation, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and apoptosis evaluated using flow cytometry. Western blotting was used to evaluate protein expression. Dual-luciferase® reporter, RNA pull-down, and RNA immunoprecipitation assays were performed to analyze the binding relationships among LINC01234, miR-525-5p, and cold shock domain-containing E1 (CSDE1). Results. We screened out LINC01234, found to be significantly increased in BC tissues, associated with a poor prognosis, and positively correlated with tumor size of BC. Knockdown of LINC01234 suppressed BC cell growth and facilitated apoptosis. Dual-luciferase reporter®, RNA pull-down, and RNA immunoprecipitation assays confirmed that LINC01234 and CSDE1 directly interacted with miR-525-5p. Upregulation of miR-525-5p and suppression of CSDE1 inhibited BC cell growth and induced cell apoptosis. Conclusion. Upregulation of LINC01234 contributes to the development of BC through the miR-525-5p/CSDE1 axis. LINC01234 may be one of the potential diagnostic and treatment targets for BC. [ABSTRACT FROM AUTHOR]
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- 2022
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19. Small-molecule modulators of tumor immune microenvironment.
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Zhang, Jing, Yu, Jia, Liu, Meijing, Xie, Zhizhong, Lei, Xiaoyong, Yang, Xiaoyan, Huang, Sheng, Deng, Xiangping, Wang, Zhe, and Tang, Guotao
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IMMUNOMODULATORS , *TUMOR microenvironment , *IMMUNE checkpoint inhibitors , *IMMUNE checkpoint proteins , *STRUCTURE-activity relationships - Abstract
PD-L1, IDO1, and TGF-β immunosuppressive signaling pathways are upregulated in tumor cells. Small-molecule immune modulators are exhibited in the picture. [Display omitted] In recent years, tumor immunotherapy, aimed at increasing the activity of immune cells and reducing immunosuppressive effects, has attracted wide attention. Among them, immune checkpoint blocking (ICB) is the most commonly explored therapeutic approach. All approved immune checkpoint inhibitors (ICIs) are clinically effective monoclonal antibodies (mAbs). Compared with biological agents, small-molecule drugs have many unique advantages in tumor immunotherapy. Therefore, they also play an important role. Immunosuppressive signals such as PD-L1, IDO1, and TGF-β, etc. overexpressed in tumor cells form the tumor immunosuppressive microenvironment. In addition, the efficacy of multi-pathway combined immunotherapy has also been reported and verified. Here, we mainly reviewed the mechanism of tumor immunotherapy, analyzed the research status of small-molecule modulators, and discussed drug candidates' structure–activity relationship (SAR). It provides more opportunities for further research to design more immune small-molecule modulators with novel structures. [ABSTRACT FROM AUTHOR]
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- 2024
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20. pH regulators and their inhibitors in tumor microenvironment.
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Liao, Senyi, Wu, Guang, Xie, Zhizhong, Lei, Xiaoyong, Yang, Xiaoyan, Huang, Sheng, Deng, Xiangping, Wang, Zhe, and Tang, Guotao
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TUMOR microenvironment , *MONOCARBOXYLATE transporters , *CARBONIC anhydrase , *STRUCTURE-activity relationships , *LACTIC acid - Abstract
As an important characteristic of tumor, acidic tumor microenvironment (TME) is closely related to immune escape, invasion, migration and drug resistance of tumor. The acidity of the TME mainly comes from the acidic products produced by the high level of tumor metabolism, such as lactic acid and carbon dioxide. pH regulators such as monocarboxylate transporters (MCTs), carbonic anhydrase IX (CA IX), and Na+/H+ exchange 1 (NHE1) expel protons directly or indirectly from the tumor to maintain the pH balance of tumor cells and create an acidic TME. We review the functions of several pH regulators involved in the construction of acidic TME, the structure and structure-activity relationship of pH regulator inhibitors, and provide strategies for the development of small-molecule antitumor inhibitors based on these targets. [Display omitted] • Review of pH regulators related to tumor and their inhibitors. • Structure-activity relationship analysis. • The hypothesis of two interaction mode for MCT1 inhibitors. • Guide for future drug modification or drug design. [ABSTRACT FROM AUTHOR]
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- 2024
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21. HIV-protease inhibitors suppress skeletal muscle fatty acid oxidation by reducing CD36 and CPT1 fatty acid transporters
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Richmond, Scott R., Carper, Michael J., Lei, Xiaoyong, Zhang, Sheng, Yarasheski, Kevin E., and Ramanadham, Sasanka
- Subjects
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PROTEASE inhibitors , *FATTY acids , *OXIDATION , *HIV infections , *ANTIRETROVIRAL agents , *LIPID metabolism , *LIPOLYSIS - Abstract
Abstract: Infection with human immunodeficiency virus (HIV) and treatment with HIV-protease inhibitor (PI)-based highly active antiretroviral therapies (HAART) is associated with dysregulated fatty acid and lipid metabolism. Enhanced lipolysis, increased circulating fatty acid levels, and hepatic and intramuscular lipid accumulation appear to contribute to insulin resistance in HIV-infected people treated with PI-based HAART. However, it is unclear whether currently prescribed HIV-PIs directly alter skeletal muscle fatty acid transport, oxidation, and storage. We find that ritonavir (r, 5µmol/l) plus 20µmol/l of atazanavir (ATV), lopinavir (LPV), or darunavir (DRV) reduce palmitate oxidation(16–21%) in differentiated C2C12 myotubes. Palmitate oxidation was increased following exposure to high fatty acid media but this effect was blunted when myotubes were pre-exposed to the HIV-PIs. However, LPV/r and DRV/r, but not ATV/r suppressed palmitate uptake into myotubes. We found no effect of the HIV-PIs on FATP1, FATP4, or FABPpm but both CD36/FAT and carnitine palmitoyltransferase 1 (CPT1) were reduced by all three regimens though ATV/r caused only a small decrease in CPT1, relative to LPV/r or DRV/r. In contrast, sterol regulatory element binding protein-1 was increased by all 3 HIV-PIs. These findings suggest that HIV-PIs suppress fatty acid oxidation in murine skeletal muscle cells and that this may be related to decreases in cytosolic- and mitochondrial-associated fatty acid transporters. HIV-PIs may also directly impair fatty acid handling and partitioning in skeletal muscle, and this may contribute to the cluster of metabolic complications that occur in people living with HIV. [Copyright &y& Elsevier]
- Published
- 2010
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22. Evidence for proteolytic processing and stimulated organelle redistribution of iPLA2β
- Author
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Song, Haowei, Bao, Shunzhong, Lei, Xiaoyong, Jin, Chun, Zhang, Sheng, Turk, John, and Ramanadham, Sasanka
- Subjects
- *
PROTEOLYSIS , *ORGANELLES , *PHOSPHOLIPASES , *GENE expression , *GENE transfection , *MASS spectrometry - Abstract
Abstract: Over the past decade, important roles for the 84–88kDa Group VIA Ca2+-independent phospholipase A2 (iPLA2β) in various organs have been described. We demonstrated that iPLA2β participates in insulin secretion, insulinoma cells and native pancreatic islets express full-length and truncated isoforms of iPLA2β, and certain stimuli promote perinuclear localization of iPLA2β. To gain a better understanding of its mobilization, iPLA2β was expressed in INS-1 cells as a fusion protein with EGFP, enabling detection of subcellular localization of iPLA2β by monitoring EGFP fluorescence. Cells stably-transfected with fusion protein expressed nearly 5-fold higher catalytic iPLA2β activity than control cells transfected with EGFP cDNA alone, indicating that co-expression of EGFP does not interfere with manifestation of iPLA2β activity. Dual fluorescence monitoring of EGFP and organelle Trackers combined with immunoblotting analyses revealed expression of truncated iPLA2β isoforms in separate subcellular organelles. Exposure to secretagogues and induction of ER stress are known to activate iPLA2β in β-cells and we find here that these stimuli promote differential localization of iPLA2β in subcellular organelles. Further, mass spectrometric analyses identified iPLA2β variants from which N-terminal residues were removed. Collectively, these findings provide evidence for endogenous proteolytic processing of iPLA2β and redistribution of iPLA2β variants in subcellular compartments. It might be proposed that in vivo processing of iPLA2β facilitates its participation in multiple biological processes. [Copyright &y& Elsevier]
- Published
- 2010
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23. 111-OR: Macrophage IPLA2ß-Derived Lipid (iDL) Signaling Promote Type 1 Diabetes Development.
- Author
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ALMUTAIRI, ABDULAZIZ, GAI, YING, LEI, XIAOYONG Y., STEPHENSON, DANIEL, CHALFANT, CHARLES, and RAMANADHAM, SASANKA
- Abstract
Type 1 diabetes (T1D) is a consequence of autoimmune-mediated destruction of pancreatic β-cells, and the leading causes for this process are incompletely understood. Our previous work revealed that Ca2+-independent phospholipase A2β (iPLA2β), which hydrolyzes membrane phospholipids at the sn-2 position and releases bioactive lipids, modulates polarization of macrophages (MΦ). Several of the iPLA2β derived lipid signals (iDLs) are proinflammatory, which can initiate immune cell infiltration and β-cell damage. Our recent work suggests that MΦ-derived from spontaneous-T1D prone nonobese diabetic mice (NOD) produce a proinflammatory lipids including (PGE2, 5-HETEs, 20-HETEs, DHETs, LTB4) at the early stage of the disease (4 weeks), interestingly, the proinflammatory lipid signature is similar to a high-risk T1D individuals. Here, we examined the effects of MΦ-iPLA2β iDLs by generating a select conditional decrease in iPLA2β in NOD MΦ (NOD.cMiPLA2훽;;;;+/-). We found that (1) that the selective decrease of iPLA2β in MΦ significantly reduces T1D incidence and immune cell infiltration to the islets in the NOD mice. (2) NOD.cMiPLA2훽;;;;+/- bone marrow-derived (BMD) MΦ are skewed towards an anti-inflammatory phenotype in comparison to NOD BMD MΦ, favoring an anti-inflammatory phenotype. (4) Selective inhibition of (PGE2 and DHETs) shifted NOD MΦ towards an anti-inflammatory phenotype. These findings suggest that MΦ-iDLs contribute to T1D development, and inhibition of select iDLs production can be targeted to counter T1D development. Disclosure: A. Almutairi: None. Y. Gai: None. X. Y. Lei: None. D. Stephenson: None. C. Chalfant: None. S. Ramanadham: None. Funding: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110292); National Institute of Allergy and Infectious Diseases (R21AI146743) [ABSTRACT FROM AUTHOR]
- Published
- 2021
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24. Progress on the role of extrachromosomal DNA in tumor pathogenesis and evolution.
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Xing, Jichen, Ning, Qian, Tang, Diya, Mo, Zhongcheng, Lei, Xiaoyong, and Tang, Shengsong
- Subjects
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EXTRACHROMOSOMAL DNA , *GENE enhancers , *CENTROMERE , *GENES , *CANCER invasiveness , *TUMOR microenvironment , *DRUG resistance - Abstract
The amplification of oncogenes on extrachromosomal DNA (ecDNA) provides a new mechanism for cancer cells to adapt to the changes in the tumor microenvironment and accelerate tumor evolution. These extrachromosomal elements contain oncogenes, and their chromatin structures are more open than linear chromosomes and therefore have stronger oncogene transcriptional activity. ecDNA always contains enhancer elements, and genes on ecDNA can be reintegrated into the linear genome to regulate the selective expression of genes. ecDNA lacks centromeres, and the inheritance from the parent cell to the daughter cell is uneven. This non‐Mendelian genetic mechanism results in the increase of tumor heterogeneity with daughter cells that can gain a competitive advantage through a large number of copies of oncogenes. ecDNA promotes tumor invasiveness and provides a mechanism for drug resistance associated with poorer survival outcomes. Recent studies have demonstrated that the overall proportion of ecDNA in tumors is approximately 40%. In this review, we summarize the current knowledge of ecDNA in the field of tumorigenesis and development. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
25. Recent advances in Bcr‐Abl tyrosine kinase inhibitors for overriding T315I mutation.
- Author
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Liu, Juan, Zhang, Yuan, Huang, Honglin, Lei, Xiaoyong, Tang, Guotao, Cao, Xuan, and Peng, Junmei
- Subjects
- *
PROTEIN-tyrosine kinase inhibitors , *KINASE inhibitors , *PROTEIN-tyrosine kinases , *CHRONIC myeloid leukemia , *ENZYME inhibitors , *GENE fusion , *DASATINIB - Abstract
BCR‐ABL is a gene produced by the fusion of the bcr gene and the c‐abl proto‐oncogene and is considered to be the main cause of chronic myelogenous leukemia (CML) production. Therefore, the development of selective Bcr‐Abl kinase inhibitors is an attractive strategy for the treatment of CML. However, in the treatment of CML with a Bcr‐Abl kinase inhibitor, the T315I gatekeeper mutant disrupts the important contact interaction between the inhibitor and the enzyme, resistant to the first‐ and second‐generation drugs currently approved, such as imatinib, bosutinib, nilotinib, and dasatinib. In order to overcome this special resistance, several different strategies have been explored, and many molecules have been studied to effectively inhibit Bcr‐Abl T315I. Some of these molecules are still under development, and some are being studied preclinically, and still others are in clinical research. Herein, this review reports some of the major examples of third‐generation Bcr‐Abl inhibitors against the T315I mutation. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
26. 1664-P: Macrophage-Derived Lipid Signaling Contributes to Type 1 Diabetes Development.
- Author
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ALMUTAIRI, ABDULAZIZ, GAI, YING, LEI, XIAOYONG Y., PARK, MARGARET A., CHALFANT, CHARLES, RAMANADHAM, SASANKA, and STEPHENSON, DANIEL
- Abstract
Type 1 diabetes (T1D) is a consequence of autoimmune-mediated destruction of pancreatic β-cells and the leading causes for this process are incompletely understood. Our previous work suggests the involvement of lipid signaling from immune cells on T1D development. Relevant lipids were shown to be generated by the Ca2+-independent phospholipase A2β (iPLA2β), which is ubiquitously expressed and hydrolyzes membrane phospholipids at the sn-2 position to release bioactive lysophospholipids and free fatty acids such as arachidonic acid. Arachidonic acid can be metabolized to generate eicosanoids, many of which are pro-inflammatory. We found that iPLA2β activation promotes pro-inflammatory M1 macrophage phenotype and that selective inhibition of iPLA2β preserves β-cell mass and reduces T1D incidence and insulitis in the NOD mice. Herein, we report that NOD macrophages generate significantly higher pro-inflammatory lipids and reduced anti-inflammatory lipids than C57 macrophages during the prediabetic phase. Such changes in the lipidome are mitigated with reduced expression of iPLA2β. Specifically, lipidomics analyses revealed that NOD.iPLA2β+/- macrophage production of multiple pro-inflammatory lipids (PGE2, leukotrienes, 12-HETE, DHETs) is decreased, and of anti-inflammatory lipids increased, relative to NOD-derived macrophages. The mitigated inflammatory lipid signature during the prediabetic phase the NOD.iPLA2β+/- contributed to a reduced T1D incidence. These findings suggest a role for macrophage iPLA2β-derived lipids (iDLs) in T1D development. In support, adoptive transfer of NOD.iPLA2β+/- macrophages reduced T1D incidence and improved glucose tolerance; and conditional knockout of iPLA2β in macrophages reduced T1D incidence in the NOD mice. We hypothesize that iDLs produced by macrophages contribute to T1D development and that these could be targeted to prevent onset/progression of T1D. Disclosure: A. Almutairi: None. Y. Gai: None. X.Y. Lei: None. M.A. Park: None. C. Chalfant: None. S. Ramanadham: None. D. Stephenson: None. Funding: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110292); National Institute of Allergy and Infectious Diseases (R21AI146743) [ABSTRACT FROM AUTHOR]
- Published
- 2020
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27. Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) in autophagy-induced hepatocellular carcinoma.
- Author
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Zhou, Juan, Zhang, Xinxin, Tang, Huifang, Yu, Jia, Zu, Xuyu, Xie, Zhizhong, Yang, Xiaoyan, Hu, Juan, Tan, Fang, Li, Qing, and Lei, Xiaoyong
- Subjects
- *
HEPATOCELLULAR carcinoma , *PROTHROMBIN , *DRUG resistance in cancer cells , *DISEASE progression , *BINDING sites , *UBIQUITINATION , *METHYLATION - Abstract
• Nrf2 participates in HCC tumorigenesis by regulating ROS production, in which autophagy may contribute to oxidant metabolic reprogramming of HCC cells. • Nrf2 is participated in HCC proliferation, migration and invasion through autophagy. • Nrf2 exhibits chemoresistance through its binding sites in the promoter region of the target genes. Autophagy, an evolutionarily conserved catabolic process, is the most important pathogenic events in the development and progression of liver diseases. Deregulation of Nrf2 is proposed to play a key pathogenic role in hepatocellular carcinoma (HCC). Under certain pathophysiological conditions, such as oxidative stress, impaired autophagy is accompanied by the Nrf2 activation that leads to the detrimental effects favoring the proliferation and survival of HCC. Elucidating its role and potential mechanism is essential for understanding tumorigenesis and the development of effective clinical application. Nrf2 is participated in HCC proliferation, migration and invasion through autophagy pathways. These includes the negatively regulated-Nrf2 by Keap1 that participates in HCC tumorigenesis via regulating ROS production, in which autophagy may contribute to oxidant metabolic reprogramming of HCC cells. Post-transcriptional modifications, such as phosphorylation and ubiquitination of Nrf2, can be positively or negatively induced by multiple transcription factors. Nrf2 exhibits chemoresistance through its binding sites in the promoter region of the target genes. Nrf2 may be a valuable potential biomarker and therapeutic strategy for diagnostics, prognostics and treatment of HCC. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
28. iPLA2β and its role in male fertility, neurological disorders, metabolic disorders, and inflammation.
- Author
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Turk, John, White, Tayleur D., Nelson, Alexander J., Lei, Xiaoyong, and Ramanadham, Sasanka
- Subjects
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NEUROLOGICAL disorders , *METABOLIC disorders , *FERTILITY , *INFLAMMATION , *ORGANELLES - Abstract
Abstract The Ca2+-independent phospholipases, designated as group VI iPLA 2 s, also referred to as PNPLAs due to their shared homology with patatin, include the β, γ, δ, ε, ζ, and η forms of the enzyme. The iPLA 2 s are ubiquitously expressed, share a consensus GXSXG catalytic motif, and exhibit organelle/cell-specific localization. Among the iPLA 2 s, iPLA 2 β has received wide attention as it is recognized to be involved in membrane remodeling, cell proliferation, cell death, and signal transduction. Ongoing studies implicate participation of iPLA 2 β in a variety of disease processes including cancer, cardiovascular abnormalities, glaucoma, and peridonditis. This review will focus on iPLA 2 β and its links to male fertility, neurological disorders, metabolic disorders, and inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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- View/download PDF
29. Design, synthesis, and preliminary biological evaluation of 3′,4′,5′-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents.
- Author
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Deng, Xiangping, Liu, Renbo, Li, Junjian, Li, Zhongli, Liu, Juan, Xiong, Runde, Lei, Xiaoyong, Zheng, Xing, Xie, Zhizhong, and Tang, Guotao
- Subjects
- *
SALICYLATES , *ANTINEOPLASTIC agents , *CELL-mediated cytotoxicity - Abstract
According to the pharmacophore combination principle, a set of new 3′,4′,5′-trimethoxy flavonoid salicylate derivatives were designed, synthesized, and evaluated for biological activity. The cytotoxicity evaluation revealed that compound 10v exhibited higher potency than 5-Fu against HCT-116 cells. Preliminary biological activity studies showed that compound 10v could inhibit the colony formation and migration of HCT-116 cells. Besides, the Hoechst 33258 staining assay and flow cytometry revealed that treatment with compound 10v induced the apoptosis of HCT-116 cells in a concentration-dependent manner, while it had no effect on their cell cycle. The WB analysis suggested that HIF-1α, tubulin, HK-2, and PFK might be the potential pharmacophore targets of compound 10v. Tubulin was a potential drug target for compound 10v, which was explained by analyzing the crystal structure of compound 10v complexed with tubulin. These results indicated that compound 10v might be a promising anti-tumor agent candidate, deserving further optimization and evaluation. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
30. FS-7 inhibits MGC-803 cells growth in vitro and in vivo via down-regulating glycolysis.
- Author
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Deng, Xiangping, Li, Zhongli, Xiong, Runde, Liu, Juan, Liu, Renbo, Peng, Junmei, Chen, Yanming, Lei, Xiaoyong, Cao, Xuan, Zheng, Xing, Xie, Zhizhong, and Tang, Guotao
- Subjects
- *
SALICYLATES , *CELL growth , *EMIGRATION & immigration , *CELLS , *CELL lines , *ANTINEOPLASTIC agents - Abstract
Graphical abstract Highlights • FS-7 had potent anticancer activity in human gastric carcinoma MGC-803 cell line. • FS-7 had potent anticancer activity in vivo/vitro and was superior to 5-Fu. • FS-7 down-regulated glycolysis-related protein HIF-1α, HK-II and PFKP. Abstract In this study, we investigated the anticancer effects of FS-7, a flavonoid salicylate derivative, in human gastric carcinoma MGC-803 cell line and studied its preliminary anticancer effects. FS-7 displayed greater in vitro cytotoxicity against MGC-803 cell line compared with 5-Fu and had a certain extent of selectivity to cancer cells. The flow cytometry analysis revealed that FS-7 induced apoptosis MGC-803 cells and mainly caused cells arrest in the G2/M phase in a concentration-dependent manner. Additionally, FS-7 inhibited the colony formation and cell migration in a concentration-dependent manner. Notably, FS-7 noticeably down-regulated glycolysis-related protein HIF-1α, HK-II and PFKP expression in a concentration-dependent manner, possibly causing glycolysis inhibition. Importantly, compared with 5-Fu, FS-7 showed better anticancer activity in the MGC-803 xenograft murine tumor models. Collectively, the present study provided a promising anticancer drug candidate for gastric cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
31. A pH-sensitive prodrug strategy to co-deliver DOX and TOS in TPGS nanomicelles for tumor therapy.
- Author
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Xiong, Shujuan, Wang, Zhe, Liu, Juan, Deng, Xiangping, Xiong, Runde, Cao, Xuan, Xie, Zhizhong, Lei, Xiaoyong, Chen, Yanming, and Tang, Guotao
- Subjects
- *
PH effect , *PRODRUGS , *TUMOR treatment , *DOXORUBICIN , *CARDIOTOXICITY - Abstract
Graphical abstract Highlights • Coupling of doxorubicin and vitamin E succinate via pH-sensitive hydrazone bond. • The pH-sensitive prodrug micelle exhibited pH-triggered drug release profiles. • pH-sensitive prodrug micelles exhibited good antitumor activity in vitro and in vivo. • Co-delivery vitamin E succinate can reduce cardiotoxicity caused by doxorubicin. Abstract This work has presented a novel strategy for designing pH-sensitive TOS-H-DOX prodrug-loaded TPGS nanomicelles for co-delivery TOS and DOX to enhance tumor therapy and reduce the toxic side effects. DOX was covalently conjugated to the vitamin E succinate through hydrazone bond to produce an pH-sensitive prodrug TOS-H-DOX (amido bond as a control, TOS-A-DOX), which was responsive to the acidic environment in tumor cells, and the prodrugs were subsequently encapsulated in the core of TPGS nanomicelles via hydrophobic effects with a significant drug loading capacity. The pH-sensitive prodrug nanomicelles TOS-H-DOX/TPGS exhibited potent release of DOX in acidic media relative to the pH-insensitive prodrug nanomicelles TOS-A-DOX/TPGS, and further studies of their intracellular uptake and intracellular localization demonstrated that TOS-H-DOX/TPGS nanomicelles can be effectively taken up by cells and drugs can be released. In vitro results confirmed that TOS-H-DOX/TPGS nanomicelles exhibited significant antitumor cell proliferation activity compared to TOS-A-DOX/TPGS and free DOX, TPGS. Furthermore, in vivo studies further confirmed an excellent synergistic antitumor efficacy in MCF-7 tumor-bearing nude mice model. More importantly, the H&E staining of the heart, liver, kidney tissue sections of experimental nude mice showed that TOS-H-DOX/TPGS nanomicelles can reduce damage to them. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
32. MiR-33b-5p sensitizes gastric cancer cells to chemotherapy drugs via inhibiting HMGA2 expression.
- Author
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Yang, Xiaoyan, Zhao, Qian, Yin, Huali, Lei, Xiaoyong, and Gan, Runliang
- Subjects
- *
STOMACH cancer treatment , *CANCER chemotherapy , *CANCER cell proliferation , *GENE expression , *MICRORNA - Abstract
MicroRNAs (miRNAs) are internal, non-coding, and ∼22 nt small RNAs that display cell- and tissue-specific expression. They play important regulatory roles in cell proliferation and chemo-sensitivity. This study focused on tumor-suppressive miR-33b-5p expression as well as its role in gastric cancer. MiR-33b-5p was found low expression in gastric cancer cell lines. Functionally, western blots and the luciferase reporter assay were used to confirm that HMGA2 was the potential target of miR-33b-5p. Next, we used CCK-8 kits to analyze the effect of miR-33b-5p combined chemotherapy drugs on cell inhibition rate, and flow cytometry to analyze cells apoptosis. Colony formation ability was determined by plating at 500 cells per well into six-well plates and culturing for 15 d. The results showed that upregulation of miR-33b-5p decreased expression of HMGA2 and inhibited gastric cancer cell growth as well as sensitized gastric cancer cells to chemotherapy drugs. MiR-33b-5p overexpression hindered luciferase activity of HMGA2,3′-untranslated region-based reporter construct in 293 T cells. These data demonstrate that miR-33b-5p may be a potential therapeutic target for gastric cancer and function as tumor-suppressive miRNA through targeting HMGA2 in gastric cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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- View/download PDF
33. The mechanism of action of FXR1P-related miR-19b-3p in SH-SY5Y.
- Author
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Ma, Yun, Tian, Shuai, He, Shuya, Chen, Qiong, Wang, Zongbao, Xiao, Xiao, Fu, Liang, and Lei, Xiaoyong
- Subjects
- *
FRAGILE X syndrome , *MICRORNA , *CELL proliferation , *CELL differentiation , *NEUROBLASTOMA , *APOPTOSIS , *GENE expression , *GENETICS - Abstract
The biological effects of microRNAs (miRNAs) in the Fragile X Syndrome (FXS) have been widely studied. Dysregulation of miRNAs plays a critical role in the progression of nervous system diseases and in cell proliferation and differentiation. Our previous study validated that miR-19b-3p was associated with FXR1 (Fragile X related gene 1), one of homologous genes of FMR1 (Fragile X mental retardation 1). The purpose of this study was to investigate the relationship of FXR1 and miR-19b-3p, and the crucial role of miR-19b-3p in FXS and to validate whether miR-19b-3p could regulate the growth of SH-SY5Y cells. We determined that miR-19b-3p could regulate the expression of not only USP32 , RAB18 and Dusp6 but also FXR1 , and FXR1 could in turn regulate the expression of miR-19b-3p. What's more, the overexpression of miR-19b-3p significantly inhibited the proliferation, contributed the apoptosis and slowed down the cycle of SH-SY5Y cells. Taken together, our results indicate that miR-19b-3p plays a significant role in the molecular pathology of FXS by interacting with FXR1 and influencing the growth of SH-SY5Y cells. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
34. Applications of "linkers" in fragment-based drug design.
- Author
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Wu, Xin, Zhang, Yuan, Liu, Songbin, Liu, Chang, Tang, Guotao, Cao, Xuan, Lei, Xiaoyong, and Peng, Junmei
- Subjects
- *
DRUG design , *PHARMACEUTICAL biotechnology , *BINDING energy , *DRUG discovery , *LEAD compounds - Abstract
[Display omitted] Fragment-based drug discovery, as a complementary method to traditional screening, has a broad momentum of development in academia, as well as large pharmaceutical companies and biotechnology laboratories. It is used to select favorable combinations of fragments or extend new drug molecules to obtain highly active drug candidates. The strategies used to develop active molecules from fragments are usually three approaches: growth, ligation and incorporation, where the ligation approach provides a theoretical opportunity for rapid access to binding energy. Here, we highlight linkers with different types and classifications that have been published in the past ten years, and explain how these linkers are designed and introduced into lead compounds to obtain potential candidate compounds. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
35. Tumor-derived or non-tumor-derived exosomal noncodingRNAs and signaling pathways in tumor microenvironment.
- Author
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Wu, Yiwen, Niu, Dun, Deng, Sijun, Lei, Xiaoyong, Xie, Zhizhong, and Yang, Xiaoyan
- Subjects
- *
CELLULAR signal transduction , *TUMOR microenvironment , *PI3K/AKT pathway , *CATENINS , *NON-coding RNA , *WNT signal transduction , *EXOSOMES , *CARCINOGENESIS - Abstract
• The tumor microenvironment participates in multiple pathological processes of tumors. • Exosomes mediate the modulation of both tumor cells and nontumor cells in the TME. • Tumor cell- and nontumor cell-derived exosomal ncRNAs influence signaling pathways. The tumor microenvironment (TME) involved in multiple pathological processes of tumors is highly complex. Exosomes, as organelles, can be produced by some cells in the TME and have been verified as a special carriers and a key factor for communication between tumor and TME-associated cells. Noncoding RNAs (ncRNAs) involved in tumorigenesis and development have been demonstrated to be released into the TME by exosomes. However, the detailed regulatory functions of exosomal ncRNAs through signaling pathways in the TME are still unclear. In this review, we systematically summarized the detailed molecular mechanisms by which exosomal ncRNAs mediate the modulation of both tumor cells and nontumor cells. Exosomal ncRNAs in the TME exhibited the potential ability to influence cancer development through signaling pathways, including PTEN signaling, NF-κB signaling, Wnt/β-catenin signaling, PI3K/AKT signaling, etc. Expressly, considering that research on circRNAs has gained much momentum in recent years, we more thoroughly described the implication of exosomal circRNAs in the regulation of signaling. Our review might hopefully inspire a deeper understanding of exosomal ncRNA function in terms of signaling pathways. We speculated that exosomal ncRNAs, as useful biomarkers and therapeutic targets, play an important role in the diagnosis and prognosis of cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
36. Involvement of miR-133a and miR-326 in ADM resistance of HepG2 through modulating expression of ABCC1.
- Author
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Ma, Jin, Wang, Ting, Guo, Rui, Yang, Xiaoyan, Yin, Jie, Yu, Jia, Xiang, Qiong, Pan, Xia, Tang, Huifang, and Lei, Xiaoyong
- Subjects
- *
LIVER cancer , *MULTIDRUG resistance-associated proteins , *DOXORUBICIN , *MICRORNA , *DRUG resistance in cancer cells , *CELL lines , *POLYMERASE chain reaction , *PHYSIOLOGY - Abstract
Recent studies have shown that a class of small, functional RNAs, named microRNAs, may regulate multidrug resistance-associated protein 1 (ABCC1). Since ABCC1 is an important efflux transporter responsible for cellular drug disposition, the discovery of microRNAs (miRNA) brings an idea that there may be some other unknown multidrug resistance (MDR) mechanisms exist. Using computational programs, we predicted that the 3′untranslated region (3′UTR) of ABCC1 contains a potential miRNA binding site for miR-133a and also two other for miR-326. These binding sites were confirmed by luciferase reporter assay. ABCC1 mRNA degradation was accelerated dramatically in cells transfected with miR-133a or miR-326 mimics using qRT-PCR, Furthermore, western blot analysis indicated that ABCC1 protein expression was significantly down-regulated in hepatocellular carcinoma cells line HepG2 after transfection with miR-133a or miR-326 mimics, suggesting the involvement of mRNA degradation and protein expression mechanism. The effects of the two miRNAs on adriamycin (ADM) sensitivity to HepG2 cells were determined by MTT assay. Compared with mock transfection, miR-133a or miR-326 mimics transfection sensitized these cells to ADM. These findings for the first time demonstrated that the involvement of miR-133a and miR-326 in MDR is mediated by ABCC1 in hepatocellular carcinoma cell line HepG2 and suggested that miR-133a and miR-326 may be efficient agents for preventing and reversing ADM resistance in cancer cells. [ABSTRACT FROM PUBLISHER]
- Published
- 2015
- Full Text
- View/download PDF
37. Inhibition of Ca2+-independent phospholipase A2β (iPLA2β) ameliorates islet infiltration and incidence of diabetes in NOD mice.
- Author
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Bone, Robert N, Gai, Ying, Magrioti, Victoria, Kokotou, Maroula G, Ali, Tomader, Lei, Xiaoyong, Tse, Hubert M, Kokotos, George, and Ramanadham, Sasanka
- Abstract
Autoimmune β-cell death leads to type 1 diabetes, and with findings that Ca(2+)-independent phospholipase A2β (iPLA2β) activation contributes to β-cell death, we assessed the effects of iPLA2β inhibition on diabetes development. Administration of FKGK18, a reversible iPLA2β inhibitor, to NOD female mice significantly reduced diabetes incidence in association with 1) reduced insulitis, reflected by reductions in CD4(+) T cells and B cells; 2) improved glucose homeostasis; 3) higher circulating insulin; and 4) β-cell preservation. Furthermore, FKGK18 inhibited production of tumor necrosis factor-α (TNF-α) from CD4(+) T cells and antibodies from B cells, suggesting modulation of immune cell responses by iPLA2β-derived products. Consistent with this, 1) adoptive transfer of diabetes by CD4(+) T cells to immunodeficient and diabetes-resistant NOD.scid mice was mitigated by FKGK18 pretreatment and 2) TNF-α production from CD4(+) T cells was reduced by inhibitors of cyclooxygenase and 12-lipoxygenase, which metabolize arachidonic acid to generate bioactive inflammatory eicosanoids. However, adoptive transfer of diabetes was not prevented when mice were administered FKGK18-pretreated T cells or when FKGK18 administration was initiated with T-cell transfer. The present observations suggest that iPLA2β-derived lipid signals modulate immune cell responses, raising the possibility that early inhibition of iPLA2β may be beneficial in ameliorating autoimmune destruction of β-cells and mitigating type 1 diabetes development. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
38. Dysfunctional mitochondrial bioenergetics and oxidative stress in Akita+/Ins2-derived β-cells.
- Author
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Mitchell, Tanecia, Johnson, Michelle S., Ouyang, Xiaosen, Chacko, Balu K., Mitra, Kasturi, Lei, Xiaoyong, Gai, Ying, Moore, D. Ray, Barnes, Stephen, Zhang, Jianhua, Koizumi, Akio, Ramanadham, Sasanka, and Darley-Usmar, Victor M.
- Subjects
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OXIDATIVE stress , *BIOENERGETICS , *INSULIN , *BLOOD sugar , *HOMEOSTASIS , *ENDOPLASMIC reticulum - Abstract
Insulin release from pancreatic β-cells plays a critical role in blood glucose homeostasis, and β-cell dysfunction leads to the development of diabetes mellitus. In cases of monogenic type 1 diabetes mellitus (T1DM) that involve mutations in the insulin gene, we hypothesized that misfolding of insulin could result in endoplasmic reticulum (ER) stress, oxidant production, and mitochondrial damage. To address this, we used the Akita+/Ins2 T1DM model in which misfolding of the insulin 2 gene leads to ER stress-mediated β-cell death and thapsigargin to induce ER stress in two different β-cell lines and in intact mouse islets. Using transformed pancreatic β-cell lines generated from wild-type Ins2+/+ (WT) and Akita+/Ins2 mice, we evaluated cellular bioenergetics, oxidative stress, mitochondrial protein levels, and autophagic flux to determine whether changes in these processes contribute to β-cell dysfunction. In addition, we induced ER stress pharmacologically using thapsigargin in WT β-cells, INS-1 cells, and intact mouse islets to examine the effects of ER stress on mitochondrial function. Our data reveal that Akita+/Ins2-derived β-cells have increased mitochondrial dysfunction, oxidant production, mtDNA damage, and alterations in mitochondrial protein levels that are not corrected by autophagy. Together, these findings suggest that deterioration in mitochondrial function due to an oxidative environment and ER stress contributes to β-cell dysfunction and could contribute to T1DM in which mutations in insulin occur. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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39. Mechanisms of B-cell Injury: the Role of Cellular Bioenergetics and Thiol Protein Modifications
- Author
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Mitchell, Tanecia, Reily, Colin, Lei, Xiaoyong, Koizumi, Akio, Ramanadham, Sasanka, and Darley-Usmar, Victor
- Published
- 2011
- Full Text
- View/download PDF
40. Design, synthesis and biological evaluation of N-anthraniloyl tryptamine derivatives as pleiotropic molecules for the therapy of malignant glioma.
- Author
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Fan, Xiaohong, Li, Junfang, Long, Lin, Shi, Tao, Liu, Dan, Tan, Wen, Zhang, Honghua, Wu, Xiaoyan, Lei, Xiaoyong, and Wang, Zhen
- Subjects
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BIOSYNTHESIS , *GLIOMAS , *TRYPTAMINE , *SURVIVAL rate , *AMINOBENZOIC acids , *CELL death - Abstract
COX-2 and STAT3 are two key culprits in the glioma microenvironment. Herein, to inhibit COX-2 and block STAT3 signaling, we disclosed 27 N- anthraniloyl tryptamine compounds based on the combination of melatonin derivatives and N -substituted anthranilic acid derivatives. Among them, NP16 showed the best antiproliferative activity and moderate COX-2 inhibition. Of note, NP16 decreased the level of p- JAK2 and p -STAT3, and blocked the nuclear translocation of STAT3 in GBM cell lines. Moreover, NP16 downregulated the MMP-9 expression of BV2 cells in a co-culture system of BV2 and C6 glioma cells, abrogated the proliferative/invasive/migratory abilities of GBM cells, induced apoptosis by ROS and the Bcl-2-regulated apoptotic pathway, and induced obvious G 2 /M arrest in glioma cells in vitro. Furthermore, NP16 displayed favorable pharmacokinetic profiles covering long half-life (11.43 ± 0.43 h) and high blood-brain barrier permeability. Finally, NP16 effectively inhibited tumor growth, promoted the survival rate, increased the expression of E -cadherin and reduced overproduction of PGE 2 , MMP-9, VEGF-A and the level of p -STAT3 in tumor tissue, and improved the anxiety-like behavior in C6 glioma model. All these evidences demonstrated N -anthraniloyl tryptamine derivatives as multifunctional anti-glioma agents with high potency could drain the swamp to beat glioma. [Display omitted] • A series of N-anthraniloyl tryptamine derivatives were synthesized as anti-glioma agents. • NP16 effectively attenuated the migration and invasion capacity of glioma cells. • NP16 obviously inhibited the activation of STAT3 in vitro and in vivo. • NP16 was equipped with favorable BBB penetration. • NP16 displayed a significant efficacy in C6 glioma model. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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41. Anti-chronic myeloid leukemia activity and quantitative structure-activity relationship of novel thiazole aminobenzamide derivatives.
- Author
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Zhang, Yuan, Liu, Juan, Wu, Xin, Yang, Suming, Li, Yao, Liu, Songbin, Zhu, Saifei, Cao, Xuan, Xie, Zhizhong, Lei, Xiaoyong, Huang, Honglin, and Peng, Junmei
- Subjects
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DASATINIB , *MYELOID leukemia , *THIAZOLE derivatives , *THIAZOLES , *COMPARATIVE molecular field analysis , *STRUCTURE-activity relationships , *CHRONIC myeloid leukemia - Abstract
[Display omitted] The anti-chronic myeloid leukemia activity of thiazole aminobenzamide derivatives in vitro was tested by a methanethiosulfonate (MTS)-based viability assay method, and the result showed that some compounds exhibited good inhibitory activities against human chronic myeloid leukemia cell line K562, imatinib-resistant strain K562/R and T135I mutant cell line BaF 3 -ABL-BCR-T315I. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods were used to analyze the relationship between the structure of thiazole aminobenzamide derivatives and the inhibition of K562/R cell activity. In CoMFA, Q2 was 0.899 and R2 was 0.963; in CoMSIA, Q2 and R2 were 0.840 and 0.903, respectively. These data indicated that the selected test set showed suitable external predictive ability. Combined with the contour map results, we further analyzed the three-dimensional quantitative structure (3D-QSAR) model. The results demonstrated that in the backbone of the thiazole aminobenzamide derivative, the substitution of a small group at R1 position, or the introduction of a hydrophilic group at R2 position, or the introduction of a large-volume amino acid at R3 position may be beneficial to improve the anti-CML activity of the compound. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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42. Discovery and development of tumor glycolysis rate-limiting enzyme inhibitors.
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Sun, Xueyan, Peng, Yijiao, Zhao, Jingduo, Xie, Zhizhong, Lei, Xiaoyong, and Tang, Guotao
- Subjects
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GLYCOLYSIS , *ENZYME inhibitors , *STRUCTURE-activity relationships , *ENZYME metabolism , *OXIDATIVE phosphorylation , *CELL growth - Abstract
[Display omitted] • A review of inhibitors of glycolysis rate-limiting enzyme. • The structural activity and anti-tumor mechanism of related inhibitors are described. • This review will help further research and application of glycolysis inhibitors. Tumor cells mainly provide necessary energy and substances for rapid cell growth through aerobic perglycolysis rather than oxidative phosphorylation. This phenomenon is called the "Warburg effect". The mechanism of glycolysis in tumor cells is more complicated, which is caused by the comprehensive regulation of multiple factors. Abnormal enzyme metabolism is one of the main influencing factors and inhibiting the three main rate-limiting enzymes in glycolysis is thought to be important strategy for cancer treatment. Therefore, numerous inhibitors of glycolysis rate-limiting enzyme have been developed in recent years, such as the latest HKII inhibitor and PKM2 inhibitor Pachymic acid (PA) and N-(4-(3-(3-(methylamino)-3-oxopropyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)phenyl)propiolamide. The review focuses on source, structure-activity relationship, bioecological activity and mechanism of the three main rate-limiting enzymes inhibitors, and hopes to guide the future research on the design and synthesis of rate-limiting enzyme inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
43. The Impact of the Ca 2+ -Independent Phospholipase A 2 β (iPLA 2 β) on Immune Cells.
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White, Tayleur D., Almutairi, Abdulaziz, Tusing, Ying Gai, Lei, Xiaoyong, and Ramanadham, Sasanka
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BONE growth , *CELL death , *NEUROLOGICAL disorders , *METABOLIC disorders , *AUTOIMMUNE diseases - Abstract
The Ca2+-independent phospholipase A2β (iPLA2β) is a member of the PLA2 family that has been proposed to have roles in multiple biological processes including membrane remodeling, cell proliferation, bone formation, male fertility, cell death, and signaling. Such involvement has led to the identification of iPLA2β activation in several diseases such as cancer, cardiovascular abnormalities, glaucoma, periodontitis, neurological disorders, diabetes, and other metabolic disorders. More recently, there has been heightened interest in the role that iPLA2β plays in promoting inflammation. Recognizing the potential contribution of iPLA2β in the development of autoimmune diseases, we review this issue in the context of an iPLA2β link with macrophages and T-cells. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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44. Metabolic Effects of Selective Deletion of Group VIA Phospholipase A2 from Macrophages or Pancreatic Islet Beta-Cells.
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Turk, John, Song, Haowei, Wohltmann, Mary, Frankfater, Cheryl, Lei, Xiaoyong, and Ramanadham, Sasanka
- Subjects
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PHOSPHOLIPASE A2 , *ISLANDS of Langerhans , *PANCREATIC beta cells , *PHOSPHOLIPASES , *MACROPHAGES , *HIGH-fat diet , *INSULIN - Abstract
To examine the role of group VIA phospholipase A2 (iPLA2β) in specific cell lineages in insulin secretion and insulin action, we prepared mice with a selective iPLA2β deficiency in cells of myelomonocytic lineage, including macrophages (MØ-iPLA2β-KO), or in insulin-secreting β-cells (β-Cell-iPLA2β-KO), respectively. MØ-iPLA2β-KO mice exhibited normal glucose tolerance when fed standard chow and better glucose tolerance than floxed-iPLA2β control mice after consuming a high-fat diet (HFD). MØ-iPLA2β-KO mice exhibited normal glucose-stimulated insulin secretion (GSIS) in vivo and from isolated islets ex vivo compared to controls. Male MØ-iPLA2β-KO mice exhibited enhanced insulin responsivity vs. controls after a prolonged HFD. In contrast, β-cell-iPLA2β-KO mice exhibited impaired glucose tolerance when fed standard chow, and glucose tolerance deteriorated further when introduced to a HFD. β-Cell-iPLA2β-KO mice exhibited impaired GSIS in vivo and from isolated islets ex vivo vs. controls. β-Cell-iPLA2β-KO mice also exhibited an enhanced insulin responsivity compared to controls. These findings suggest that MØ iPLA2β participates in HFD-induced deterioration in glucose tolerance and that this mainly reflects an effect on insulin responsivity rather than on insulin secretion. In contrast, β-cell iPLA2β plays a role in GSIS and also appears to confer some protection against deterioration in β-cell functions induced by a HFD. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
45. FB-15 inhibits MGC-803 cells growth by regulating energy metabolism.
- Author
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Deng, Xiangping, Pi, Yiyuan, Li, Zhongli, Xiong, Runde, Liu, Juan, Zhao, Jingduo, Xie, Zhizhong, Lei, Xiaoyong, and Tang, Guotao
- Subjects
- *
CELL growth , *ENERGY metabolism , *CELL migration , *MOLECULAR docking , *STOMACH cancer , *TUBULINS - Abstract
In this study, we scrutinized the anticancer effects of FB-15 on human gastric carcinoma MGC-803 cells in vitro and vivo , and its preliminary effect on tubulin and HIF-1α. We confirmed that FB-15 not only inhibited the proliferation of a large number of cells in a concentration and time-dependent manner but also inhibited proliferation of a single cell to form clones. FB-15 manifested little cytotoxicity for normal stomach cells GES-1. The flow cytometry analysis displayed that FB-15 induced apoptosis MGC-803 cells and mainly arrested cells in the S phase in a concentration-dependent manner. The results of the wound healing assay indicated that FB-15 suppressed cell migration. Furthermore, the western blotting showed that FB-15 down-regulated the expression of β3-tubulin and HIF-1α, consistent with Immunohistochemical assay. The binding modes of FB-15 with tubulin were clarified by molecular docking. FB-15 significantly suppressed the growth of MGC-803 gastric cancer tumors. The inhibitory effect of FB-15 on tumor growth was superior to 5-Fu. Taken together, these results provided evidence for FB-15 to be used as an effective anticancer drug candidate for gastric cancer. • FB-15 is a flavonoid benzimidazole derivative. • FB-15 down-regulates tubulin and glycolysis-related protein. • FB-15 shows potent anticancer activity against MGC-803 cells in vitro / vivo. • The binding mode of FB-15 with tubulin is clarified by molecular docking. • FB-15 might regulate energy metabolism. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
46. Synthesis and biological evaluation of novel 5,6,7-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents.
- Author
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Liu, Renbo, Deng, Xiangping, Peng, Yijiao, Feng, Wanshi, Xiong, Runde, Zou, Yang, Lei, Xiaoyong, Zheng, Xing, Xie, Zhizhong, and Tang, Guotao
- Subjects
- *
SALICYLATES , *BIOSYNTHESIS , *WESTERN immunoblotting , *PROTEIN expression , *TUMOR proteins , *TUBULINS , *CELL migration - Abstract
• Novel 5,6,7-trimethoxy flavonoid salicylate derivatives were synthesized and characterized. • Compound 7f exhibited potent anti-tumor activity in vitro. • Compound 7f was effective in reducing the stability of microtubule cytoskeleton. • Docking studies mimicked the possible binding mechanisms of compound 7f to tubulin. • 7f down-regulated lactate production and glycolysis-related proteins expression. • Compound 7f decreased HIF-1α expression under hypoxic conditions. 5,6,7-Trimethoxy flavonoid salicylate derivatives were designed by the joining of three important pharmacophores (TMP, flavonoid, and SA) according to the combination principle. A series of novel trimethoxy flavonoid salicylate derivatives were synthesized and their in vitro anti-tumor activities were evaluated. Among these derivatives, compound 7f exhibited excellent antiproliferative activity against HGC-27 cells and MGC-803 cells with IC 50 values of 10.26 ± 6.94 μM and 17.17 ± 3.03 μM, respectively. Subsequently, the effects on cell colony formation (clonogenic survival assay), cell migration (wound healing assay), cell cycle distribution (PI staining assay), cell apoptosis (Hoechst 33258 staining assay and annexin V-FITC/PI dual staining assay), lactate level (lactate measurement), microtubules disarrangement (immunofluorescence staining analysis) and docking posture (molecular docking simulation) were determined. Further western blot analysis confirmed that compound 7f could effectively down-regulate the expression of glycolysis-related proteins HIF-1α, PFKM and PKM2 and tumor angiogenesis-related proteins VEGF. Overall, these studies suggested that compound 7f , as the representative compound of those, might be a promising candidate for the treatment of gastric cancer and deserved the further studies. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
47. Corrigendum to ‘The mechanism of action of FXR1P-related miR-19b-3p in SH-SY5Y’ [Gene. 2016 Apr. 29. pii: S0378-1119(16)303079].
- Author
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Ma, Yun, Tian, Shuai, He, Shuya, Chen, Qiong, Wang, Zongbao, Xiao, Xiao, Fu, Liang, and Lei, Xiaoyong
- Subjects
- *
MICRORNA , *MOLECULAR genetics , *BIOCHEMICAL mechanism of action - Published
- 2017
- Full Text
- View/download PDF
48. The Voltage-Dependant Anion Channel (VDAC) is SGlutathionylated in Ins2Akita Derived Β-Cells.
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Johnson, Michelle S., Mitchell, Tanecia, Ray Moore, D., Lei, Xiaoyong, Barnes, Stephen, Zhang, Jianhua, Koizumi, Akio, Ramanadham, Sasanka, and Darley-Usmar, Victor M.
- Published
- 2013
- Full Text
- View/download PDF
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