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Keywords = phosphorylated dihydroceramides

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17 pages, 2767 KB  
Article
Hepatic-Metabolic Activity of α-Lipoic Acid—Its Influence on Sphingolipid Metabolism and PI3K/Akt/mTOR Pathway in a Rat Model of Metabolic Dysfunction-Associated Steatotic Liver Disease
by Klaudia Sztolsztener and Adrian Chabowski
Nutrients 2024, 16(10), 1501; https://doi.org/10.3390/nu16101501 - 16 May 2024
Cited by 2 | Viewed by 2427
Abstract
Excessive lipid deposition affects hepatic homeostasis and contributes to the development of insulin resistance as a crucial factor for the deterioration of simple steatosis to steatohepatitis. So, it is essential to search for an effective agent for a new therapy for hepatic steatosis [...] Read more.
Excessive lipid deposition affects hepatic homeostasis and contributes to the development of insulin resistance as a crucial factor for the deterioration of simple steatosis to steatohepatitis. So, it is essential to search for an effective agent for a new therapy for hepatic steatosis development before it progresses to the more advanced stages. Our study aimed to evaluate the potential protective effect of α-lipoic acid (α-LA) administration on the intrahepatic metabolism of sphingolipid and insulin signaling transduction in rats with metabolic dysfunction-associated steatotic liver disease (MASLD). The experiment was conducted on male Wistar rats subjected to a standard diet or a high-fat diet (HFD) and an intragastrically α-LA administration for eight weeks. High-performance liquid chromatography (HPLC) was used to determine sphingolipid content. Immunoblotting was used to measure the expression of selected proteins from sphingolipid and insulin signaling pathways. Multiplex assay kit was used to assess the level of the phosphorylated form of proteins from PI3K/Akt/mTOR transduction. The results revealed that α-LA decreased sphinganine, dihydroceramide, and sphingosine levels and increased ceramide level. We also observed an increased the concentration of phosphorylated forms of sphingosine and sphinganine. Changes in the expression of proteins from sphingolipid metabolism were consistent with changes in sphingolipid pools. Treatment with α-LA activated the PI3K/Akt/mTOR pathway, which enhanced the hepatic phosphorylation of Akt and mTOR. Based on these data, we concluded that α-lipoic acid may alleviate glucose intolerance and may have a protective influence on the sphingolipid metabolism under HFD; thus, this antioxidant appears to protect from MASLD development and steatosis deterioration. Full article
(This article belongs to the Special Issue Dietary Strategies in Metabolic Disorders)
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31 pages, 16879 KB  
Article
In Situ Raman Study of Neurodegenerated Human Neuroblastoma Cells Exposed to Outer-Membrane Vesicles Isolated from Porphyromonas gingivalis
by Giuseppe Pezzotti, Tetsuya Adachi, Hayata Imamura, Davide Redolfi Bristol, Keiji Adachi, Toshiro Yamamoto, Narisato Kanamura, Elia Marin, Wenliang Zhu, Toshihisa Kawai, Osam Mazda, Toru Kariu, Tomonori Waku, Frank C. Nichols, Pietro Riello, Flavio Rizzolio, Tania Limongi and Kazu Okuma
Int. J. Mol. Sci. 2023, 24(17), 13351; https://doi.org/10.3390/ijms241713351 - 28 Aug 2023
Cited by 9 | Viewed by 3441
Abstract
The aim of this study was to elucidate the chemistry of cellular degeneration in human neuroblastoma cells upon exposure to outer-membrane vesicles (OMVs) produced by Porphyromonas gingivalis (Pg) oral bacteria by monitoring their metabolomic evolution using in situ Raman spectroscopy. Pg [...] Read more.
The aim of this study was to elucidate the chemistry of cellular degeneration in human neuroblastoma cells upon exposure to outer-membrane vesicles (OMVs) produced by Porphyromonas gingivalis (Pg) oral bacteria by monitoring their metabolomic evolution using in situ Raman spectroscopy. Pg-OMVs are a key factor in Alzheimer’s disease (AD) pathogenesis, as they act as efficient vectors for the delivery of toxins promoting neuronal damage. However, the chemical mechanisms underlying the direct impact of Pg-OMVs on cell metabolites at the molecular scale still remain conspicuously unclear. A widely used in vitro model employing neuroblastoma SH-SY5Y cells (a sub-line of the SK-N-SH cell line) was spectroscopically analyzed in situ before and 6 h after Pg-OMV contamination. Concurrently, Raman characterizations were also performed on isolated Pg-OMVs, which included phosphorylated dihydroceramide (PDHC) lipids and lipopolysaccharide (LPS), the latter in turn being contaminated with a highly pathogenic class of cysteine proteases, a key factor in neuronal cell degradation. Raman characterizations located lipopolysaccharide fingerprints in the vesicle structure and unveiled so far unproved aspects of the chemistry behind protein degradation induced by Pg-OMV contamination of SH-SY5Y cells. The observed alterations of cells’ Raman profiles were then discussed in view of key factors including the formation of amyloid β (Aβ) plaques and hyperphosphorylated Tau neurofibrillary tangles, and the formation of cholesterol agglomerates that exacerbate AD pathologies. Full article
(This article belongs to the Special Issue Application of Biotechnology to Dental Treatment)
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16 pages, 2722 KB  
Article
A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes
by Sun-Hye Shin, Hee-Yeon Kim, Hee-Soo Yoon, Woo-Jae Park, David R. Adams, Nigel J. Pyne, Susan Pyne and Joo-Won Park
Int. J. Mol. Sci. 2020, 21(21), 8371; https://doi.org/10.3390/ijms21218371 - 8 Nov 2020
Cited by 16 | Viewed by 3059
Abstract
Sphingosine kinases (SK) catalyze the phosphorylation of sphingosine to generate sphingosine-1-phosphate. Two isoforms of SK (SK1 and SK2) exist in mammals. Previously, we showed the beneficial effects of SK2 inhibition, using ABC294640, in a psoriasis mouse model. However, ABC294640 also induces the degradation [...] Read more.
Sphingosine kinases (SK) catalyze the phosphorylation of sphingosine to generate sphingosine-1-phosphate. Two isoforms of SK (SK1 and SK2) exist in mammals. Previously, we showed the beneficial effects of SK2 inhibition, using ABC294640, in a psoriasis mouse model. However, ABC294640 also induces the degradation of SK1 and dihydroceramide desaturase 1 (DES1). Considering these additional effects of ABC294640, we re-examined the efficacy of SK2 inhibition in an IMQ-induced psoriasis mouse model using a novel SK2 inhibitor, HWG-35D, which exhibits nM potency and 100-fold selectivity for SK2 over SK1. Topical application of HWG-35D ameliorated IMQ-induced skin lesions and normalized the serum interleukin-17A levels elevated by IMQ. Application of HWG-35D also decreased skin mRNA levels of interleukin-17A, K6 and K16 genes induced by IMQ. Consistent with the previous data using ABC294640, HWG-35D also blocked T helper type 17 differentiation of naïve CD4+ T cells with concomitant reduction of SOCS1. Importantly, HWG-35D did not affect SK1 or DES1 expression levels. These results reaffirm an important role of SK2 in the T helper type 17 response and suggest that highly selective and potent SK2 inhibitors such as HWG-35D might be of therapeutic use for the treatment of psoriasis. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases)
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