The Experts below are selected from a list of 1119 Experts worldwide ranked by ideXlab platform
Xian-cheng Jiang - One of the best experts on this subject based on the ideXlab platform.
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Sphingomyelin Synthase 2 promotes an aggressive breast cancer phenotype by disrupting the homoeostasis of ceramide and Sphingomyelin.
Cell death & disease, 2019Co-Authors: Kehong Zheng, Xian-cheng Jiang, Zetao Chen, Haizhan Feng, Ying Chen, Cheng Zhang, Yunfeng Luo, Liang Zhao, Fujun ShiAbstract:Breast cancer is the most common type of carcinoma in women worldwide, but the mechanisms underlying tumour development and progression remain unclear. Sphingomyelin Synthase 2 (SGMS2) is a crucial regulator involved in ceramide (Cer) and Sphingomyelin (SM) homoeostasis that is mostly studied for its role in lipid metabolism. Our primary study indicated that high SGMS2 expression is associated with breast cancer metastasis. Gain- and loss-of-function assays in vitro and in vivo revealed that SGMS2 promotes cancer cell proliferation by suppressing apoptosis through a Cer-associated pathway and promotes cancer cell invasiveness by enhancing epithelial-to-mesenchymal transition (EMT) initiation through the TGF-β/Smad signalling pathway. Further study determined that SGMS2 activated the TGF-β/Smad signalling pathway primarily by increasing TGF-β1 secretion, which was likely associated with aberrant expression of SM. Thus, our findings indicate that SGMS2-mediated activation of the TGF-β/Smad signalling pathway is important in breast cancer progression, which provides new insight into the mechanisms underlying breast cancer metastasis and suggests a possible anticancer therapy for breast cancer.
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Discovery of 4-Benzyloxybenzo[ d]isoxazole-3-amine Derivatives as Highly Selective and Orally Efficacious Human Sphingomyelin Synthase 2 Inhibitors that Reduce Chronic Inflammation in db/ db Mice.
Journal of medicinal chemistry, 2018Co-Authors: Jintong Yang, Xian-cheng Jiang, Qi Xiangyu, Yu Cao, Fei Jinyu, Yang Chen, Yong Chu, Lu ZhouAbstract:Sphingomyelin Synthase 2 (SMS2) is a promising therapeutic target for several chronic inflammation-associated diseases, including atherosclerosis, fatty liver, and insulin resistance. Herein, we report the identification of 4-benzyloxybenzo[d]isoxazole-3-amine derivatives as potent and highly selective SMS2 inhibitors through a conformational restriction strategy. After systematic structural modifications, several compounds with high selectivity and good potency in vitro were selected for further evaluation. Compound 15w demonstrated good pharmacokinetics (oral bioavailability, F = 56%) in vivo and has an inhibitory potency against Sphingomyelin Synthase activity when Institute of Cancer Research mice are provided with an oral dose of this compound. In addition, compound 15w attenuated chronic inflammation significantly in db/db mice after oral dosing for 6 weeks.
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Discovery of 4‑Benzyloxybenzo[d]isoxazole-3-amine Derivatives as Highly Selective and Orally Efficacious Human Sphingomyelin Synthase 2 Inhibitors that Reduce Chronic Inflammation in db/db Mice
2018Co-Authors: Jintong Yang, Xian-cheng Jiang, Yu Cao, Yang Chen, Yong Chu, Jinyu Fei, Lu ZhouAbstract:Sphingomyelin Synthase 2 (SMS2) is a promising therapeutic target for several chronic inflammation-associated diseases, including atherosclerosis, fatty liver, and insulin resistance. Herein, we report the identification of 4-benzyloxybenzo[d]isoxazole-3-amine derivatives as potent and highly selective SMS2 inhibitors through a conformational restriction strategy. After systematic structural modifications, several compounds with high selectivity and good potency in vitro were selected for further evaluation. Compound 15w demonstrated good pharmacokinetics (oral bioavailability, F = 56%) in vivo and has an inhibitory potency against Sphingomyelin Synthase activity when Institute of Cancer Research mice are provided with an oral dose of this compound. In addition, compound 15w attenuated chronic inflammation significantly in db/db mice after oral dosing for 6 weeks
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discovery synthesis and biological evaluation of 2 4 n phenethylsulfamoyl phenoxy acetamides sapas as novel Sphingomyelin Synthase 1 inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Hui Jiang, Xiaodong Deng, Renxiao Wang, Xian-cheng Jiang, Lu Zhou, Tingbo Ding, Yong Chu, Yanping Dong, Peng MenAbstract:Sphingomyelin Synthase (SMS) has been proved to be a potential drug target for the treatment of atherosclerosis. However, few SMS inhibitors have been reported. In this paper, structure-based virtual screening was performed on hSMS1. SAPA 1a was discovered as a novel SMS1 inhibitor with an IC50 value of 5.2 μM in enzymatic assay. A series of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) were synthesized and their biological activities toward SMS1 were evaluated. Among them, SAPA 1j was found to be the most potent SMS1 inhibitor with an IC50 value of 2.1 μM in in vitro assay. The molecular docking studies suggested the interaction modes of SMS1 inhibitors and PC with the active site of SMS1. Site-directed mutagenesis validated the involvement of residues Arg342 and Tyr338 in enzymatic Sphingomyelin production. The discovery of SAPA derivatives as a novel class of SMS1 inhibitors would advance the development of more effective SMS1 inhibitors.
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Pharmacologic inhibition of Sphingomyelin Synthase (SMS) activity reduces apolipoprotein-B secretion from hepatocytes and attenuates endotoxin-mediated macrophage inflammation.
PloS one, 2014Co-Authors: Bin Lou, Xiaodong Deng, Jibin Dong, Tingbo Ding, Li Yali, Xian-cheng JiangAbstract:Sphingomyelin Synthase (SMS) plays an important role in plasma atherogenic lipoprotein metabolism, inflammation, and the development of atherosclerosis. To understand whether the impaired apoB secretion and inflammation response is a direct result from lack of SMS activity, in this study, we prepared a series of compounds that inhibit SMS activity. Further, we characterized Dy105, the most potent inhibitor. We found that Dy105 treatment significantly reduces SM levels in SM-rich microdomain on cell membranes. Moreover, we found that SMS inhibition reduces apoB secretion in a human hepatoma cell line and reduces the activation of NFκB and p38, a MAP kinase, in bone marrow derived macrophages. These studies provided further evidence that SMS activity regulates atherogenic lipoprotein metabolism and inflammatory responses. Pharmacologic inhibition of SMS may be a new therapy for atherosclerosis by reducing apoB secretion, and reducing inflammation.
Toshiro Okazaki - One of the best experts on this subject based on the ideXlab platform.
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Deficiency of Sphingomyelin Synthase 1 but Not Sphingomyelin Synthase 2 Reduces Bone Formation Due to Impaired Osteoblast Differentiation
Molecular medicine (Cambridge Mass.), 2019Co-Authors: Goichi Matsumoto, Makoto Taniguchi, Chieko Hashizume, Ken Watanabe, Toshiro OkazakiAbstract:There are two isoforms of Sphingomyelin Synthase (SMS): SMS1 and SMS2. SMS1 is located in the Golgi apparatus only while SMS2 is located in both the plasma membrane and the Golgi apparatus. SMS1 and SMS2 act similarly to generate Sphingomyelin (SM). We have undertaken the experiments reported here on SMS and osteoblast differentiation in order to better understand the role SMS plays in skeletal development. We analyzed the phenotype of a conditional knockout mouse, which was generated by mating a Sp7 promoter-driven Cre-expressing mouse with an SMS1-floxed SMS2-deficient mouse (Sp7-Cre;SMS1f/f;SMS2−/− mouse). When we compared Sp7-Cre;SMS1f/f;SMS2−/− mice with C57BL/6, SMS2-deficient mice (SMS1f/f;SMS2−/−) and SP7-Cre positive control mice (Sp7-Cre, Sp7-Cre;SMS1+/+;SMS2+/− and Sp7-Cre;SMS1+/+;SMS2−/−), we found that although cartilage formation is normal, Sp7-Cre;SMS1f/f;SMS2−/− mice showed reduced trabecular and cortical bone mass, had lower bone mineral density, and had a slower mineral apposition rate than control mice. Next, we have used a tamoxifen-inducible knockout system in vitro to show that SMS1 plays an important role in osteoblast differentiation. We cultured osteoblasts derived from ERT2-Cre;SMS1f/f SMS2−/− mice. We observed impaired differentiation of these cells in response to Smad1/5/8 and p38 that were induced by bone morphogenic protein 2 (BMP2). However, Erk1/2 phosphorylation was unaffected by inactivation of SMS1. These findings provide the first genetic evidence that SMS1 plays a role in bone development by regulating osteoblast development in cooperation with BMP2 signaling. Thus, SMS1 acts as an endogenous signaling component necessary for bone formation.
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Knockdown of Sphingomyelin Synthase 2 inhibits osteoclastogenesis by decreasing RANKL expression in mouse primary osteoblasts.
Biomedical research (Tokyo Japan), 2019Co-Authors: Yoshihiro Yoshikawa, Toshiro Okazaki, Tatsuya Yoshizawa, Eisuke Domae, Yuya Hirai, Aiko Kamada, Takashi IkeoAbstract:Sphingomyelin is a major lipid of the plasma membrane and is enriched in microdomains of the plasma membrane that are critical for signal transduction. However, the function of Sphingomyelin in the cell membrane of osteoblasts has not been clarified. Therefore, we examined how Sphingomyelin Synthase 2 (SMS2) affects osteoclast differentiation by osteoblasts. We knocked down the expression of SMS2 with siRNA targeting the Sgms2 gene in mouse primary osteoblasts. The effects of SMS2 knockdown in osteoblasts were examined using polymerase chain reaction and western blotting. The knockdown of SMS2 suppressed the formation of TRAP-positive multinucleated cells by co-culture of osteoblasts and bone marrow cells compared to the control. We found that receptor activator of nuclear factor κB ligand (RANKL) mRNA expression was significantly reduced by 1,25(OH)2D3 stimulation in SMS2 siRNA osteoblasts. The knockdown of SMS2 repressed the expression of retinoid-X-receptor-α (RXRα) regardless of 1,25(OH)2D3 stimulation. TRAP-positive multinucleated cell formation was significantly reduced by RXRα siRNA in osteoblasts in a co-culture system. These results suggest that SMS2 regulates osteoclast differentiation by inducing RANKL expression via RXRα.
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Epidermal permeability barrier function and sphingolipid content in the skin of Sphingomyelin Synthase 2 deficient mice.
Experimental dermatology, 2018Co-Authors: Koji Nomoto, Toshiro Okazaki, Ken Watanabe, Yurina Itaya, Tadashi Yamashita, Yoshihiro TokudomeAbstract:Sphingomyelin Synthase (SMS) is an enzyme that generates Sphingomyelin (SM) from ceramide (CER) and phosphatidylcholine. SM in the epidermis is a precursor of CER, an important lipid for epidermal permeability barrier function. However, the physiological role of SMS in skin is unclear. To uncover the function of SMS in skin, we investigated sphingolipid metabolism enzyme activity in skin, SM content in the epidermis, CER content in the stratum corneum (SC) and transepidermal water loss (TEWL) as an indicator of barrier function in SMS2-knockout (KO) mice. The activities of sphingolipid metabolism enzymes in skin homogenates were measured using a fluorescently labelled substrate. Enzymatic reaction products were detected by high-performance liquid chromatography (HPLC). Lipids in the epidermis or SC were extracted and quantified by high-performance thin layer chromatography (HPTLC). TEWL was measured using a Tewameter TM300. In SMS2-KO mice, SMS activity in skin homogenates, epidermal SM content and SC CER content were significantly decreased relative to wild-type (WT) mice. The TEWL of SMS2-KO mice was significantly increased compared to WT mice. Our data indicate that SMS2 generates SM in the epidermis and contributes to epidermal permeability barrier function and will support understanding of SM-related metabolic disorders.
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Sphingomyelin Synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2017Co-Authors: Toshio Ohnishi, Makoto Taniguchi, Chieko Hashizume, Hidehiro Furumoto, Jia Han, Rongfen Gao, Shinichi Kinami, Takeo Kosaka, Toshiro OkazakiAbstract:Sphingomyelin Synthase 2 (SMS2) is the synthetic enzyme of Sphingomyelin (SM), which regulates membrane fluidity and microdomain structure. SMS2 plays a role in LPS-induced lung injury and inflammation; however, its role in inflammation-mediated tumorigenesis is unclear. We investigated the effect of SMS2 deficiency on dextran sodium sulfate (DSS)-induced murine colitis and found inhibition of DSS-induced inflammation in SMS2-deficient (SMS2-/-) mice. DSS treatment induced a significant increase in ceramide levels, with a decrease of SM levels in SMS2-/- colon tissue, and demonstrated attenuation of the elevation of both inflammation-related gene expression and proinflammatory cytokines and chemokines, leukocyte infiltration, and MAPK and signal transducer and activator of transcription 3 activation. After undergoing transplantation of wild-type bone marrow, SMS2-/- mice also exhibited inhibition of DSS-induced inflammation in the colon, which suggested that SMS2 deficiency in bone marrow-derived immune cells was not involved in the inhibition of colitis. Finally, in an azoxymethane/DSS-induced cancer model, SMS2 deficiency significantly decreased tumor incidence in the colon. Our results demonstrate that SMS2 deficiency inhibits DSS-induced colitis and subsequent colitis-associated colon cancer via inhibition of colon epithelial cell-mediated inflammation; therefore, inhibition of SMS2 may be a potential therapeutic target for human colitis and colorectal cancer.-Ohnishi, T., Hashizume, C., Taniguchi, M., Furumoto, H., Han, J., Gao, R., Kinami, S., Kosaka, T., Okazaki, T. Sphingomyelin Synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer.
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regulation of membrane kcnq1 kcne1 channel density by Sphingomyelin Synthase 1
American Journal of Physiology-cell Physiology, 2016Co-Authors: Makoto Takemoto, Makoto Taniguchi, Toru Takumi, Toshiro Okazaki, Wen Jie SongAbstract:Sphingomyelin Synthase (SMS) catalyzes the conversion of phosphatidylcholine and ceramide to Sphingomyelin and diacylglycerol. We previously showed that SMS1 deficiency leads to a reduction in expr...
Lyudmila V. Dergunova - One of the best experts on this subject based on the ideXlab platform.
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Developmental stage-specific expression of genes for Sphingomyelin Synthase in rat brain
Cell and Tissue Research, 2018Co-Authors: Ivan B. Filippenkov, Timur A. Kolomin, Svetlana A. Limborska, Lyudmila V. DergunovaAbstract:Sphingomyelin Synthase genes ( Sgms1 and Sgms2 ) encode the vital enzymes that participate in the processes of membrane transport, cell proliferation and apoptosis. We previously determined the exon–intron structure of Sgms1 and some features of its expression in human and rodent tissues. The circular RNAs (circRNAs) emerging from exons of the 5′-untranslated region (5′-UTR) of Sgms1 were determined. These circRNAs are represented at a high level in the adult brain. Here, we demonstrate that, in contrast to Sgms1 , Sgms2 does not contain the multi-exon 5′-UTR but encodes circRNAs, which are composed of the coding region of the gene and are expressed at a low level. We present a study of the expression of Sphingomyelin Synthase genes in rat brain at embryonic days 7, 9, 13, 17 and 21 and in adult rat brain. In contrast to Sgms1 , Sgms2 is expressed at a significantly low level in adult brain. In embryonic rat brain, the mRNA expression of Sphingomyelin Synthase genes is varied in a developmental stage-specific manner. The level of Sgms1 mRNAs, differing by 5′-UTR—in the formation of which alternative promoters can participate—changes significantly during the process of embryonic development. The expression of circRNAs of Sgms1 was significantly raised during rat embryonic brain development. We assume that the circRNAs are involved in the regulation of Sphingomyelin Synthase activity in rat brain in different developmental stages.
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Multi-step splicing of Sphingomyelin Synthase linear and circular RNAs.
Gene, 2018Co-Authors: Ivan B. Filippenkov, Svetlana A. Limborska, Olga Yu. Sudarkina, Lyudmila V. DergunovaAbstract:Abstract The SGMS1 gene encodes the enzyme Sphingomyelin Synthase 1 (SMS1), which is involved in the regulation of lipid metabolism, apoptosis, intracellular vesicular transport and other significant processes. The SGMS1 gene is located on chromosome 10 and has a size of 320 kb. Previously, we showed that dozens of alternative transcripts of the SGMS1 gene are present in various human tissues. In addition to mRNAs that provide synthesis of the SMS1 protein, this gene participates in the synthesis of non-coding transcripts, including circular RNAs (circRNAs), which include exons of the 5′-untranslated region (5′-UTR) and are highly represented in the brain. In this study, using the high-throughput technology RNA-CaptureSeq, many new SGMS1 transcripts were identified, including both intronic unspliced RNAs (premature RNAs) and RNAs formed via alternative splicing. Recursive exons (RS-exons) that can participate in the multi-step splicing of long introns of the gene were also identified. These exons participate in the formation of circRNAs. Thus, multi-step splicing may provide a variety of linear and circular RNAs of eukaryotic genes in tissues.
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Circular RNA of the human Sphingomyelin Synthase 1 gene: Multiple splice variants, evolutionary conservatism and expression in different tissues.
RNA biology, 2015Co-Authors: Ivan B. Filippenkov, Svetlana A. Limborska, Olga Yu. Sudarkina, Lyudmila V. DergunovaAbstract:The human Sphingomyelin Synthase 1 gene (SGMS1) encodes an essential enzyme that is involved in the synthesis of Sphingomyelin and diacylglycerol from phosphatidylcholine and ceramide. Among the products of SGMS1, we found new transcripts, circular RNAs (circRNAs), that contain sequences of the gene's 5' untranslated region (5'UTR). Some of them include the gene's coding region and fragments of introns. An analysis of the abundance of circRNAs in human tissues showed that the largest transcripts were predominantly found in different parts of the brain. circRNAs of rat and mouse Sphingomyelin Synthase 1 orthologous genes were detected and are highly similar to the human SGMS1 gene transcripts. A quantitative analysis of the abundance of such transcripts also revealed their elevated amount in the brain. A computational analysis of sequences of human circRNAs showed their high potential of binding microRNAs (miRNAs), including the miRNAs that form complexes with Ago proteins and the mRNA of SGMS1. We assume that the circRNAs identified here participate in the regulation of the function of the SGMS1 gene in the brain.
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Comparative analysis of Sphingomyelin Synthase 1 gene expression at the transcriptional and translational levels in human tissues.
Molecular and cellular biochemistry, 2015Co-Authors: Olga Yu. Sudarkina, Ivan B. Filippenkov, Svetlana A. Limborska, Ilya B Brodsky, Lyudmila V. DergunovaAbstract:Sphingomyelin Synthase 1 (SMS1) catalyses the biosynthesis of Sphingomyelin in eukaryotic cells. We have previously determined the structure of the SGMS1 gene encoding this enzyme and a number of its alternative transcripts. Here, we describe a study of the expression of the full-length SMS1 protein and the sum of the alternative transcripts encoding this protein in human tissues. The SMS1 protein and mRNA levels in tissues differed significantly and were not correlated, implying the active post-transcriptional regulation of SMS1 protein expression. The putative truncated isoforms of the SMS1 protein, which are encoded by a number of alternative transcripts, were not detected by immunoblotting and thus may be absent or present in only small amounts.
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Human Sphingomyelin Synthase 1 gene (SMS1): organization, multiple mRNA splice variants and expression in adult tissues.
Gene, 2011Co-Authors: A. V. Rozhkova, Svetlana A. Limborska, Olga Yu. Sudarkina, Veronika G. Dmitrieva, Olga N. Zhapparova, Elena S. Nadezhdina, Lyudmila V. DergunovaAbstract:Abstract We have previously characterized the structure of the human MOB gene ( TMEM23 ), which encodes a hypothetical transmembrane protein (Vladychenskaya et al., 2002, 2004). The primary structure of the peptide that we predicted coincided completely with the amino acid sequence of the later identified Sphingomyelin Synthase 1 protein (SMS1), which catalyses the transfer of a phosphorylcholine moiety from phosphatidylcholine to ceramide, producing Sphingomyelin and diacylglycerol (Huitema et al., 2004; Yamaoka et al., 2004). The gene we found was the SMS1 gene. The combination of in silico and RT-PCR data helped us identify and characterize numerous new transcripts of the human SMS1 gene. We identified mRNA isoforms that vary in the 5′-untranslated region (UTR) and encode the full-length protein, and transcripts resulting from alternative combinations of the exons in the coding region of the gene and the 3′-UTR. Comparison of the discovered transcripts' structures with the sequence of human chromosome 10 showed that the human SMS1 gene comprises at least 24 exons. RT-PCR and real-time PCR data showed that the expression patterns of the alternative SMS1 transcripts are tissue specific. Our results indicate that the regulation of SMS1 expression is complex and occurs at the transcriptional, post-transcriptional and translational levels.
Ken Watanabe - One of the best experts on this subject based on the ideXlab platform.
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deficiency of Sphingomyelin Synthase 2 prolongs survival by the inhibition of lymphoma infiltration through icam 1 reduction
The FASEB Journal, 2020Co-Authors: Makoto Taniguchi, Chieko Hashizume, Yoshibumi Ueda, Michiko Matsushita, Shingo Nagaya, Kenta Arai, Kazuya Kabayama, Koichi Fukase, Ken WatanabeAbstract:The tumor microenvironment (TME) formation involving host cells and cancer cells through cell adhesion molecules (CAMs) is essential for the multiple steps of cancer metastasis and growth. Sphingomyelin Synthase 2 (SMS2) is involved in inflammatory diseases such as obesity and diabetes mellitus by regulation of the SM/ceramide balance. However, the involvement of SMS2 in TME formation and metastasis is largely unknown. Here, we report that SMS2-deficient (SMS2-KO) mice show suppressed the EL4 cell infiltration to liver and prolonged survival time. ICAM-1 was identified as a candidate for the inhibition of TME formation in immortalized mouse embryonic fibroblasts (tMEFs) from mRNA array analysis for CAMs. Reduced SM/ceramide balance in SMS2-KO tMEFs suppressed the attachment of EL4 cells through transcriptional reduction of ICAM-1 by the inhibition of NF-κB activation. TNF-α-induced NF-κB activation and subsequent induction of ICAM-1 were suppressed in SMS2-KO tMEFs but restored by SMS2 re-introduction. In the EL4 cell infiltration mouse model, EL4 injection increased ICAM-1 expression in WT liver but not in SMS2-KO mouse liver. Therefore, inhibition of SMS2 may be a therapeutic target to suppress the infiltration of malignant lymphoma.
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Deficiency of Sphingomyelin Synthase 2 prolongs survival by the inhibition of lymphoma infiltration through ICAM‐1 reduction
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2020Co-Authors: Makoto Taniguchi, Chieko Hashizume, Ken Watanabe, Yoshibumi Ueda, Michiko Matsushita, Shingo Nagaya, Kenta Arai, Kazuya Kabayama, Koichi Fukase, Lusi Oka WardhaniAbstract:The tumor microenvironment (TME) formation involving host cells and cancer cells through cell adhesion molecules (CAMs) is essential for the multiple steps of cancer metastasis and growth. Sphingomyelin Synthase 2 (SMS2) is involved in inflammatory diseases such as obesity and diabetes mellitus by regulation of the SM/ceramide balance. However, the involvement of SMS2 in TME formation and metastasis is largely unknown. Here, we report that SMS2-deficient (SMS2-KO) mice show suppressed the EL4 cell infiltration to liver and prolonged survival time. ICAM-1 was identified as a candidate for the inhibition of TME formation in immortalized mouse embryonic fibroblasts (tMEFs) from mRNA array analysis for CAMs. Reduced SM/ceramide balance in SMS2-KO tMEFs suppressed the attachment of EL4 cells through transcriptional reduction of ICAM-1 by the inhibition of NF-κB activation. TNF-α-induced NF-κB activation and subsequent induction of ICAM-1 were suppressed in SMS2-KO tMEFs but restored by SMS2 re-introduction. In the EL4 cell infiltration mouse model, EL4 injection increased ICAM-1 expression in WT liver but not in SMS2-KO mouse liver. Therefore, inhibition of SMS2 may be a therapeutic target to suppress the infiltration of malignant lymphoma.
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Deficiency of Sphingomyelin Synthase 1 but Not Sphingomyelin Synthase 2 Reduces Bone Formation Due to Impaired Osteoblast Differentiation
Molecular medicine (Cambridge Mass.), 2019Co-Authors: Goichi Matsumoto, Makoto Taniguchi, Chieko Hashizume, Ken Watanabe, Toshiro OkazakiAbstract:There are two isoforms of Sphingomyelin Synthase (SMS): SMS1 and SMS2. SMS1 is located in the Golgi apparatus only while SMS2 is located in both the plasma membrane and the Golgi apparatus. SMS1 and SMS2 act similarly to generate Sphingomyelin (SM). We have undertaken the experiments reported here on SMS and osteoblast differentiation in order to better understand the role SMS plays in skeletal development. We analyzed the phenotype of a conditional knockout mouse, which was generated by mating a Sp7 promoter-driven Cre-expressing mouse with an SMS1-floxed SMS2-deficient mouse (Sp7-Cre;SMS1f/f;SMS2−/− mouse). When we compared Sp7-Cre;SMS1f/f;SMS2−/− mice with C57BL/6, SMS2-deficient mice (SMS1f/f;SMS2−/−) and SP7-Cre positive control mice (Sp7-Cre, Sp7-Cre;SMS1+/+;SMS2+/− and Sp7-Cre;SMS1+/+;SMS2−/−), we found that although cartilage formation is normal, Sp7-Cre;SMS1f/f;SMS2−/− mice showed reduced trabecular and cortical bone mass, had lower bone mineral density, and had a slower mineral apposition rate than control mice. Next, we have used a tamoxifen-inducible knockout system in vitro to show that SMS1 plays an important role in osteoblast differentiation. We cultured osteoblasts derived from ERT2-Cre;SMS1f/f SMS2−/− mice. We observed impaired differentiation of these cells in response to Smad1/5/8 and p38 that were induced by bone morphogenic protein 2 (BMP2). However, Erk1/2 phosphorylation was unaffected by inactivation of SMS1. These findings provide the first genetic evidence that SMS1 plays a role in bone development by regulating osteoblast development in cooperation with BMP2 signaling. Thus, SMS1 acts as an endogenous signaling component necessary for bone formation.
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Epidermal permeability barrier function and sphingolipid content in the skin of Sphingomyelin Synthase 2 deficient mice.
Experimental dermatology, 2018Co-Authors: Koji Nomoto, Toshiro Okazaki, Ken Watanabe, Yurina Itaya, Tadashi Yamashita, Yoshihiro TokudomeAbstract:Sphingomyelin Synthase (SMS) is an enzyme that generates Sphingomyelin (SM) from ceramide (CER) and phosphatidylcholine. SM in the epidermis is a precursor of CER, an important lipid for epidermal permeability barrier function. However, the physiological role of SMS in skin is unclear. To uncover the function of SMS in skin, we investigated sphingolipid metabolism enzyme activity in skin, SM content in the epidermis, CER content in the stratum corneum (SC) and transepidermal water loss (TEWL) as an indicator of barrier function in SMS2-knockout (KO) mice. The activities of sphingolipid metabolism enzymes in skin homogenates were measured using a fluorescently labelled substrate. Enzymatic reaction products were detected by high-performance liquid chromatography (HPLC). Lipids in the epidermis or SC were extracted and quantified by high-performance thin layer chromatography (HPTLC). TEWL was measured using a Tewameter TM300. In SMS2-KO mice, SMS activity in skin homogenates, epidermal SM content and SC CER content were significantly decreased relative to wild-type (WT) mice. The TEWL of SMS2-KO mice was significantly increased compared to WT mice. Our data indicate that SMS2 generates SM in the epidermis and contributes to epidermal permeability barrier function and will support understanding of SM-related metabolic disorders.
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Increased Oxidative Stress Impairs Adipose Tissue Function in Sphingomyelin Synthase 1 Null Mice
2016Co-Authors: Masato Yano, Tadashi Yamamoto, Naotaka Nishimura, Tomomi Gotoh, Ken WatanabeAbstract:Sphingomyelin Synthase 1 (SMS1) catalyzes the conversion of ceramide to Sphingomyelin. Here, we found that SMS1 null mice showed lipodystrophic phenotype. Mutant mice showed up-regulation of plasma triglyceride concentrations accompanied by reduction of white adipose tissue (WAT) as they aged. Lipoprotein lipase (LPL) activity was severely reduced in mutant mice. In vivo analysis indicated that fatty acid uptake in WAT but not in liver decreased in SMS1 null compared to wild-type mice. In vitro analysis using cultured cell revealed that SMS1 depletion reduced fatty acid uptake. Proteins extracted from WAT of mutant mice were severely modified by oxidative stress, and up-regulation of mRNAs related to apoptosis, redox adjustment, mitochondrial stress response and mitochondrial biogenesis was observed. ATP content of WAT was reduced in SMS1 null mice. Blue native gel analysis indicated that accumulation of mitochondrial respiratory chain complexes was reduced. These results suggest that WAT of SMS1 null mice is severely damaged by oxidative stress and barely functional. Indeed, mutant mice treated with the anti-oxidant N-acetyl cysteine (NAC) showed partial recovery of lipodystrophic phenotypes together with normalized plasma triglyceride concentrations. Altogether, ou
Tingbo Ding - One of the best experts on this subject based on the ideXlab platform.
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Discovery, synthesis and anti-atherosclerotic activities of a novel selective Sphingomyelin Synthase 2 inhibitor.
European journal of medicinal chemistry, 2018Co-Authors: Li Yali, Bin Lou, Tingbo Ding, Qi Xiangyu, Taomin Huang, Chen Yan, Yang CaoAbstract:Abstract The Sphingomyelin Synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 μM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.
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discovery synthesis and biological evaluation of 2 4 n phenethylsulfamoyl phenoxy acetamides sapas as novel Sphingomyelin Synthase 1 inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Hui Jiang, Xiaodong Deng, Renxiao Wang, Xian-cheng Jiang, Lu Zhou, Tingbo Ding, Yong Chu, Yanping Dong, Peng MenAbstract:Sphingomyelin Synthase (SMS) has been proved to be a potential drug target for the treatment of atherosclerosis. However, few SMS inhibitors have been reported. In this paper, structure-based virtual screening was performed on hSMS1. SAPA 1a was discovered as a novel SMS1 inhibitor with an IC50 value of 5.2 μM in enzymatic assay. A series of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) were synthesized and their biological activities toward SMS1 were evaluated. Among them, SAPA 1j was found to be the most potent SMS1 inhibitor with an IC50 value of 2.1 μM in in vitro assay. The molecular docking studies suggested the interaction modes of SMS1 inhibitors and PC with the active site of SMS1. Site-directed mutagenesis validated the involvement of residues Arg342 and Tyr338 in enzymatic Sphingomyelin production. The discovery of SAPA derivatives as a novel class of SMS1 inhibitors would advance the development of more effective SMS1 inhibitors.
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All members in the Sphingomyelin Synthase gene family have ceramide phosphoethanolamine Synthase activity
Journal of lipid research, 2015Co-Authors: Tingbo Ding, Tae-sik Park, Jibin Dong, Inamul Kabir, Caixia Lou, Amirfarbod Yazdanyar, Hongwen Zhou, Mohamed BoutjdirAbstract:Sphingomyelin Synthase-related protein (SMSr) synthesizes the Sphingomyelin analog ceramide phosphoethanolamine (CPE) in cells. Previous cell studies indicated that SMSr is involved in ceramide homeostasis and is crucial for cell function. To further examine SMSr function in vivo, we generated Smsr KO mice that were fertile and had no obvious phenotypic alterations. Quantitative MS analyses of plasma, liver, and macrophages from the KO mice revealed only marginal changes in CPE and ceramide as well as other sphingolipid levels. Because SMS2 also has CPE Synthase activity, we prepared Smsr/Sms2 double KO mice. We found that CPE levels were not significantly changed in macrophages, suggesting that CPE levels are not exclusively dependent on SMSr and SMS2 activities. We then measured CPE levels in Sms1 KO mice and found that Sms1 deficiency also reduced plasma CPE levels. Importantly, we found that expression of Sms1 or Sms2 in SF9 insect cells significantly increased not only SM but also CPE formation, indicating that SMS1 also has CPE Synthase activity. Moreover, we measured CPE Synthase Km and Vmax for SMS1, SMS2, and SMSr using different NBD ceramides. Our study reveals that all mouse SMS family members (SMSr, SMS1, and SMS2) have CPE Synthase activity. However, neither CPE nor SMSr appears to be a critical regulator of ceramide levels in vivo.
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Pharmacologic inhibition of Sphingomyelin Synthase (SMS) activity reduces apolipoprotein-B secretion from hepatocytes and attenuates endotoxin-mediated macrophage inflammation.
PloS one, 2014Co-Authors: Bin Lou, Xiaodong Deng, Jibin Dong, Tingbo Ding, Li Yali, Xian-cheng JiangAbstract:Sphingomyelin Synthase (SMS) plays an important role in plasma atherogenic lipoprotein metabolism, inflammation, and the development of atherosclerosis. To understand whether the impaired apoB secretion and inflammation response is a direct result from lack of SMS activity, in this study, we prepared a series of compounds that inhibit SMS activity. Further, we characterized Dy105, the most potent inhibitor. We found that Dy105 treatment significantly reduces SM levels in SM-rich microdomain on cell membranes. Moreover, we found that SMS inhibition reduces apoB secretion in a human hepatoma cell line and reduces the activation of NFκB and p38, a MAP kinase, in bone marrow derived macrophages. These studies provided further evidence that SMS activity regulates atherogenic lipoprotein metabolism and inflammatory responses. Pharmacologic inhibition of SMS may be a new therapy for atherosclerosis by reducing apoB secretion, and reducing inflammation.
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Identification of small molecule Sphingomyelin Synthase inhibitors.
European journal of medicinal chemistry, 2013Co-Authors: Xiaodong Deng, Ya Zhang, Fu Lin, Lu Zhou, Bin Lou, Jibin Dong, Tingbo Ding, Xian-cheng JiangAbstract:Sphingomyelin Synthase (SMS), which catalyzes ceramide as one of the substrates to produce Sphingomyelin, is a critical factor in the sphingolipid biosynthesis pathway. Recent studies indicated that SMS could serve as a novel potential drug target for the treatment of various metabolic diseases such as insulin resistance and atherosclerosis. However, very few small-molecule inhibitors of SMS are known. In this study, we performed structure-based virtual screening in combination with chemical synthesis and bioassay and discovered a class of small-molecule SMS inhibitors. The most potent compound exhibited an IC50 value lower than 20 mu M in an in vitro enzymatic assay. To the best of our knowledge, this is the first time that small-molecule SMS inhibitors with potency close to the micromolar range are publicly revealed. The structure-activity relationship demonstrated by this class of compounds provides insights into the structural features that are essential for effective SMS inhibition. (C) 2013 Elsevier Masson SAS. All rights reserved.