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1
Kutkowska-Kaźmierczak, Anna, Małgorzata Rydzanicz, Aleksander Chlebowski, et al. "Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features." Journal of Medical Genetics 55, no. 6 (2018): 408–14. http://dx.doi.org/10.1136/jmedgenet-2017-105172.
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BackgroundIchthyosis and neurological involvement occur in relatively few known Mendelian disorders caused by mutations in genes relevant both for epidermis and neural function.ObjectivesTo identify the cause of a similar phenotype of ichthyotic keratoderma, spasticity, mild hypomyelination (on MRI) and dysmorphic features (IKSHD) observed in two unrelated paediatric probands without family history of disease.MethodsWhole exome sequencing was performed in both patients. The functional effect of prioritised variant in ELOVL1 (very-long-chain fatty acids (VLCFAs) elongase) was analysed by VLCFA profiling by gas chromatography–mass spectrometry in stably transfected HEK2932 cells and in cultured patient’s fibroblasts.ResultsProbands shared novel heterozygous ELOVL1 p.Ser165Phe mutation (de novo in one family, while in the other family, father could not be tested). In transfected cells p.Ser165Phe: (1) reduced levels of FAs C24:0-C28:0 and C26:1 with the most pronounced effect for C26:0 (P=7.8×10−6 vs HEK293 cells with wild type (wt) construct, no difference vs naïve HEK293) and (2) increased levels of C20:0 and C22:0 (P=6.3×10−7, P=1.2×10−5, for C20:0 and C22:0, respectively, comparison vs HEK293 cells with wt construct; P=2.2×10−7, P=1.9×10−4, respectively, comparison vs naïve HEK293). In skin fibroblasts, there was decrease of C26:1 (P=0.014), C28:0 (P=0.001) and increase of C20:0 (P=0.033) in the patient versus controls. There was a strong correlation (r=0.92, P=0.008) between the FAs profile of patient’s fibroblasts and that of p.Ser165Phe transfected HEK293 cells. Serum levels of C20:0–C26:0 FAs were normal, but the C24:0/C22:0 ratio was decreased.ConclusionThe ELOVL1 p.Ser165Phe mutation is a likely cause of IKSHD.
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Schutgens, R. B., I. W. Bouman, A. A. Nijenhuis, R. J. Wanders, and M. E. Frumau. "Profiles of very-long-chain fatty acids in plasma, fibroblasts, and blood cells in Zellweger syndrome, X-linked adrenoleukodystrophy, and rhizomelic chondrodysplasia punctata." Clinical Chemistry 39, no. 8 (1993): 1632–37. http://dx.doi.org/10.1093/clinchem/39.8.1632.
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Abstract Profiles of saturated very-long-chain (> C22) fatty acids were studied in plasma, fibroblasts, erythrocytes, platelets, and leukocytes of patients affected by peroxisomal disorders such as Zellweger syndrome, X-linked adrenoleukodystrophy (X-ALD), and classic rhizomelic chondrodysplasia punctata (RCDP) and in controls. In Zellweger patients, the concentration of hexacosanoic acid (C26:0) and the C26:0/C22:0 ratio are greatly increased in plasma and fibroblasts. However, the plasma concentration of docosanoic acid (C22:0) is greatly decreased. Also in platelets, leukocytes, and to a lesser extent erythrocytes, the C26:0 concentrations and both the C26:0/C22:0 and C24:0/C22:0 ratios are greatly increased. The C24:0/C22:0 ratio is significantly increased in plasma, platelets, and leukocytes, but not in erythrocytes. In X-ALD, the C26:0 concentration and the C26:0/C22:0 and C24:0/C22:0 ratios are significantly increased in plasma, fibroblasts, platelets, and leukocytes, but the erythrocytes show substantial overlap in the 5-90% ranges between controls and patients. In RCDP, slightly increased C26:0 and C26:0/C22:0 ratios are found in erythrocytes, platelets, and leukocytes, but not in plasma and fibroblasts. We conclude that plasma and fibroblasts are the specimens of choice for biochemical diagnosis of Zellweger syndrome and X-ALD, respectively. The slight increase in C26:0 in blood cells of RCDP patients suggests a decreased flux of very-long-chain fatty acids through the peroxisomal beta-oxidation pathway in liver in this genetic disorder.
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Yamaguchi, A., T. Katagiri, T. Ikeda, et al. "Recombinant human bone morphogenetic protein-2 stimulates osteoblastic maturation and inhibits myogenic differentiation in vitro." Journal of Cell Biology 113, no. 3 (1991): 681–87. http://dx.doi.org/10.1083/jcb.113.3.681.
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The in vitro effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on osteogenic and myogenic differentiation was examined in two clonal cell lines of rat osteoblast-like cells at different differentiation stages, ROB-C26 (C26) and ROB-C20 (C20). The C26 is a potential osteoblast precursor cell line that is also capable of differentiating into muscle cells and adipocytes; the C20 is a more differentiated osteoblastic cell line. Proliferation was stimulated by rhBMP-2 in C26 cells, but inhibited in C20 cells. rhBMP-2 greatly increased alkaline phosphate (ALP) activity in C26 cells, but not in C20 cells. The steady-state level of ALP mRNA was also increased by rhBMP-2 in C26 cells, but not in C20 cells. Production of 3',5'-cAMP in response to parathyroid hormone (PTH) was dose-dependently enhanced by adding rhBMP-2 in both C26 and C20 cells, though the stimulatory effect was much greater in the former. There was neither basal expression of osteocalcin mRNA nor its protein synthesis in C26 cells, but they were strikingly induced by rhBMP-2 in the presence of 1 alpha,25-dihydroxyvitamin D3. rhBMP-2 induced no appreciable changes in procollagen mRNA levels of type I and type III in the two cell lines. Differentiation of C26 cells into myotubes was greatly inhibited by adding rhBMP-2. The inhibitory effect of rhBMP-2 on myogenic differentiation was also observed in clonal rat skeletal myoblasts (L6). Like BMP-2, TGF-beta 1 inhibited myogenic differentiation. However, unlike BMP-2, TGF-beta 1 decreased ALP activity in both C26 and C20 cells. TGF-beta 1 induced neither PTH responsiveness nor osteocalcin production in C26 cells, but it increased PTH responsiveness in C20 cells. These results clearly indicate that rhBMP-2 is involved, at least in vitro, not only in inducing differentiation of osteoblast precursor cells into more mature osteoblast-like cells, but also in inhibiting myogenic differentiation.
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Zarrouk, Amira, Anne Vejux, Thomas Nury, et al. "Induction of Mitochondrial Changes Associated with Oxidative Stress on Very Long Chain Fatty Acids (C22:0, C24:0, or C26:0)-Treated Human Neuronal Cells (SK-NB-E)." Oxidative Medicine and Cellular Longevity 2012 (2012): 1–15. http://dx.doi.org/10.1155/2012/623257.
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In Alzheimer's disease, lipid alterations point towards peroxisomal dysfunctions. Indeed, a cortical accumulation of saturated very long chain fatty acids (VLCFAs: C22:0, C24:0, C26:0), substrates for peroxisomalβ-oxidation, has been found in Alzheimer patients. This study was realized to investigate the effects of VLCFAs at the mitochondrial level since mitochondrial dysfunctions play crucial roles in neurodegeneration. On human neuronal SK-NB-E cells treated with C22:0, C24:0, or C26:0 (0.1–20 μM; 48 h), an inhibition of cell growth and mitochondrial dysfunctions were observed by cell counting with trypan blue, MTT assay, and measurement of mitochondrial transmembrane potential (Δψm) with DiOC6(3). A stimulation of oxidative stress was observed with DHE and MitoSOX used to quantify superoxide anion production on whole cells and at the mitochondrial level, respectively. With C24:0 and C26:0, by Western blotting, lower levels of mitochondrial complexes III and IV were detected. After staining with MitoTracker and by transmission electron microscopy used to study mitochondrial topography, mass and morphology, major changes were detected in VLCFAs treated-cells: modification of the cytoplasmic distribution of mitochondria, presence of large mitochondria, enhancement of the mitochondrial mass. Thus, VLCFAs can be potential risk factors contributing to neurodegeneration by inducing neuronal damages via mitochondrial dysfunctions.
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Santalova, Elena A., Alexandra S. Kuzmich, Ekaterina A. Chingizova, Ekaterina S. Menchinskaya, Evgeny A. Pislyagin, and Pavel S. Dmitrenok. "Phytoceramides from the Marine Sponge Monanchora clathrata: Structural Analysis and Cytoprotective Effects." Biomolecules 13, no. 4 (2023): 677. http://dx.doi.org/10.3390/biom13040677.
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In our research on sphingolipids from marine invertebrates, a mixture of phytoceramides was isolated from the sponge Monanchora clathrata (Western Australia). Total ceramide, ceramide molecular species (obtained by RP-HPLC, high-performance liquid chromatography on reversed-phase column) and their sphingoid/fatty acid components were analyzed by NMR (nuclear magnetic resonance) spectroscopy and mass spectrometry. Sixteen new (1b, 3a, 3c, 3d, 3f, 3g, 5c, 5d, 5f, 5g, 6b–g) and twelve known (2b, 2e, 2f, 3b, 3e, 4a–c, 4e, 4f, 5b, 5e) compounds were shown to contain phytosphingosine-type backbones i-t17:0 (1), n-t17:0 (2), i-t18:0 (3), n-t18:0 (4), i-t19:0 (5), or ai-t19:0 (6), N-acylated with saturated (2R)-2-hydroxy C21 (a), C22 (b), C23 (c), i-C23 (d), C24 (e), C25 (f), or C26 (g) acids. The used combination of the instrumental and chemical methods permitted the more detailed investigation of the sponge ceramides than previously reported. It was found that the cytotoxic effect of crambescidin 359 (alkaloid from M. clathrata) and cisplatin decreased after pre-incubation of MDA-MB-231 and HL-60 cells with the investigated phytoceramides. In an in vitro paraquat model of Parkinson’s disease, the phytoceramides decreased the neurodegenerative effect and ROS (reactive oxygen species) formation induced by paraquat in neuroblastoma cells. In general, the preliminary treatment (for 24 or 48 h) of the cells with the phytoceramides of M. clathrata was necessary for their cytoprotective functions, otherwise the additive damaging effect of these sphingolipids and cytotoxic compounds (crambescidin 359, cisplatin or paraquat) was observed.
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Yamada, T., N. Kubushiro, K. Shigemasa, T. Ikeda та M. Takagi. "Effects of Transforming Growth Factor-β1 on Decorin Expression by Undifferentiated Osteoblastic Cells". Microscopy and Microanalysis 3, S2 (1997): 187–88. http://dx.doi.org/10.1017/s1431927600007820.
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Decorin is the predominant proteoglycan isolated from bone of several animal species. Bone matrix decorin appears to bind transforming growth factor β (TGF-β) and enhances its bioactivity. TGF-β is stored in bone matrix in abundant amounts and modulates the synthesis of bone matrix proteins by osteoblasts. Thus it appears to play a role in regulation of bone formation during the bone remodeling process. The effect of TGF-β on decorin expression in bone cells has been evaluated in murine osteoblastic cells, but the results are divergent depending on the experimental conditions and cell types used. The present study investigated the effect of TGF-βl on the expression of decorin mRNA in two clonal rat osteoblastic cell lines with different stages of differentiation, ROS-C26 (C26) and ROS-C20 (C20); C26 is a potential osteoblast precursor cell line that is also capable of differentiating into muscle cells and adipocytes; C20 is a more differentiated osteoblastic cell line.
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Eisenkolb, Marlis, Christoph Zenzmaier, Erich Leitner, and Roger Schneiter. "A Specific Structural Requirement for Ergosterol in Long-chain Fatty Acid Synthesis Mutants Important for Maintaining Raft Domains in Yeast." Molecular Biology of the Cell 13, no. 12 (2002): 4414–28. http://dx.doi.org/10.1091/mbc.e02-02-0116.
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Fungal sphingolipids contain ceramide with a very-long-chain fatty acid (C26). To investigate the physiological significance of the C26-substitution on this lipid, we performed a screen for mutants that are synthetically lethal with ELO3. Elo3p is a component of the ER-associated fatty acid elongase and is required for the final elongation cycle to produce C26 from C22/C24 fatty acids.elo3Δ mutant cells thus contain C22/C24- instead of the natural C26-substituted ceramide. We now report that under these conditions, an otherwise nonessential, but also fungal-specific, structural modification of the major sterol of yeast, ergosterol, becomes essential, because mutations in ELO3 are synthetically lethal with mutations in ERG6. Erg6p catalyzes the methylation of carbon atom 24 in the aliphatic side chain of sterol. The lethality of an elo3Δ erg6Δ double mutant is rescued by supplementation with ergosterol but not with cholesterol, indicating a vital structural requirement for the ergosterol-specific methyl group. To characterize this structural requirement in more detail, we generated a strain that is temperature sensitive for the function of Erg6p in an elo3Δ mutant background. Examination of raft association of the GPI-anchored Gas1p and plasma membrane ATPase, Pma1p, in the conditional elo3Δ erg6 ts double mutant, revealed a specific defect of the mutant to maintain raft association of preexisting Pma1p. Interestingly, in an elo3Δ mutant at 37°C, newly synthesized Pma1p failed to enter raft domains early in the biosynthetic pathway, and upon arrival at the plasma membrane was rerouted to the vacuole for degradation. These observations indicate that the C26 fatty acid substitution on lipids is important for establishing raft association of Pma1p and stabilizing the protein at the cell surface. Analysis of raft lipids in the conditional mutant strain revealed a selective enrichment of ergosterol in detergent-resistant membrane domains, indicating that specific structural determinants on both sterols and sphingolipids are required for their association into raft domains.
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SCHNEITER, Roger, Britta BRÜGGER, Clare M. AMANN, et al. "Identification and biophysical characterization of a very-long-chain-fatty-acid-substituted phosphatidylinositol in yeast subcellular membranes." Biochemical Journal 381, no. 3 (2004): 941–49. http://dx.doi.org/10.1042/bj20040320.
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Morphological analysis of a conditional yeast mutant in acetyl-CoA carboxylase acc1ts/mtr7, the rate-limiting enzyme of fatty acid synthesis, suggested that the synthesis of C26 VLCFAs (very-long-chain fatty acids) is important for maintaining the structure and function of the nuclear membrane. To characterize this C26-dependent pathway in more detail, we have now examined cells that are blocked in pathways that require C26. In yeast, ceramide synthesis and remodelling of GPI (glycosylphosphatidylinositol)-anchors are two pathways that incorporate C26 into lipids. Conditional mutants blocked in either ceramide synthesis or the synthesis of GPI anchors do not display the characteristic alterations of the nuclear envelope observed in acc1ts, indicating that the synthesis of another C26-containing lipid may be affected in acc1ts mutant cells. Lipid analysis of isolated nuclear membranes revealed the presence of a novel C26-substituted PI (phosphatidylinositol). This C26-PI accounts for approx. 1% of all the PI species, and is present in both the nuclear and the plasma membrane. Remarkably, this C26-PI is the only C26-containing glycerophospholipid that is detectable in wild-type yeast, and the C26-substitution is highly specific for the sn-1 position of the glycerol backbone. To characterize the biophysical properties of this lipid, it was chemically synthesized. In contrast to PIs with normal long-chain fatty acids (C16 or C18), the C26-PI greatly reduced the bilayer to hexagonal phase transition of liposomes composed of 1,2-dielaidoyl-sn-glycero-3-phosphoethanolamine (DEPE). The biophysical properties of this lipid are thus consistent with a possible role in stabilizing highly curved membrane domains.
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Rodolfo, M., C. Zilocchi, C. Melani, et al. "Immunotherapy of experimental metastases by vaccination with interleukin gene-transduced adenocarcinoma cells sharing tumor-associated antigens. Comparison between IL-12 and IL-2 gene-transduced tumor cell vaccines." Journal of Immunology 157, no. 12 (1996): 5536–42. http://dx.doi.org/10.4049/jimmunol.157.12.5536.
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Abstract We have compared the therapeutic activity and characterized the antitumor response induced by IL-12 and IL-2 gene-transduced tumor cell vaccines. Mice bearing lung metastases of the BALB/c colon carcinoma C51 were treated with syngenic, histologically related, and antigenically cross-reacting irradiated IL-12 (C26/IL12) or IL-2 (C26/IL2) gene-transduced C26 tumor cells given s.c. Vaccination with C26/IL12 cells cured 40% of mice, while vaccination with C26/IL2 cells reduced the number of metastatic nodules without affecting survival. Despite this difference, similar antitumor CTL activation was shown in mice treated with C26/IL12 or C26/IL2 cells. The lytic pattern of CTL was shown to be directed to tumor-associated Ags (TAA) shared between the colon carcinomas C51, C26, and CC36 as well as with other syngenic tumors. Both treatments induced anti-TAA Abs, but only sera from mice treated with C26/IL12 contained Ab that lysed tumor cells in a C-dependent cytotoxicity assay. Early infiltration of activated T cells was found in the lungs of mice vaccinated with C26/IL12. CD4+ lymphocytes purified from the lymph nodes draining the vaccination site or from the spleen showed a higher production of IFN-gamma in response to anti-CD3 mAb in C26/IL12 vaccinated mice, while a higher production of IL-4 was shown in mice vaccinated with C26/IL2 cells. These results indicate that the better therapeutic efficacy of vaccination with C26/IL12 is associated with the production of C-binding Ab, an early infiltration of the metastatic lungs by activated T lymphocytes and a predominant systemic activation of Th1 more than Th2 cells.
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Smakman, Niels, Diana J. M. van den Wollenberg, Inne H. M. Borel Rinkes, Rob C. Hoeben, and Onno Kranenburg. "Sensitization to Apoptosis Underlies KrasD12-Dependent Oncolysis of Murine C26 Colorectal Carcinoma Cells by Reovirus T3D." Journal of Virology 79, no. 23 (2005): 14981–85. http://dx.doi.org/10.1128/jvi.79.23.14981-14985.2005.
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ABSTRACT Reovirus T3D is an oncolytic agent that preferentially targets tumor cells expressing an activated Ras oncogene. Ras signaling interferes with the cellular stress response that inhibits translation of reovirus RNAs. Murine C26 colorectal carcinoma cells express a mutant KrasD12 gene. Reovirus T3D efficiently kills C26 cells, but not C26 cells in which the KrasD12 mRNA is stably repressed by expression of KrasD12-directed short-hairpin RNAs. Surprisingly, neither reovirus T3D protein synthesis nor T3D virus yields were suppressed by deletion of KrasD12. Rather, reovirus-induced tumor cell apoptosis was completely abrogated as a result of Kras knockdown. We conclude that sensitization of C26 tumor cells to reovirus-induced apoptosis underlies the Ras dependency of reovirus T3D oncolysis.
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Vilchèze, Catherine, Hector R. Morbidoni, Torin R. Weisbrod, et al. "Inactivation of the inhA-Encoded Fatty Acid Synthase II (FASII) Enoyl-Acyl Carrier Protein Reductase Induces Accumulation of the FASI End Products and Cell Lysis of Mycobacterium smegmatis." Journal of Bacteriology 182, no. 14 (2000): 4059–67. http://dx.doi.org/10.1128/jb.182.14.4059-4067.2000.
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ABSTRACT The mechanism of action of isoniazid (INH), a first-line antituberculosis drug, is complex, as mutations in at least five different genes (katG, inhA, ahpC,kasA, and ndh) have been found to correlate with isoniazid resistance. Despite this complexity, a preponderance of evidence implicates inhA, which codes for an enoyl-acyl carrier protein reductase of the fatty acid synthase II (FASII), as the primary target of INH. However, INH treatment of Mycobacterium tuberculosis causes the accumulation of hexacosanoic acid (C26:0), a result unexpected for the blocking of an enoyl-reductase. To test whether inactivation of InhA is identical to INH treatment of mycobacteria, we isolated a temperature-sensitive mutation in the inhA gene of Mycobacterium smegmatis that rendered InhA inactive at 42°C. Thermal inactivation of InhA in M. smegmatis resulted in the inhibition of mycolic acid biosynthesis, a decrease in hexadecanoic acid (C16:0) and a concomitant increase of tetracosanoic acid (C24:0) in a manner equivalent to that seen in INH-treated cells. Similarly, INH treatment of Mycobacterium bovis BCG caused an inhibition of mycolic acid biosynthesis, a decrease in C16:0, and a concomitant accumulation of C26:0. Moreover, the InhA-inactivated cells, like INH-treated cells, underwent a drastic morphological change, leading to cell lysis. These data show that InhA inactivation, alone, is sufficient to induce the accumulation of saturated fatty acids, cell wall alterations, and cell lysis and are consistent with InhA being a primary target of INH.
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Pekkala, Satu, Anniina Keskitalo, Emilia Kettunen, et al. "Blocking Activin Receptor Ligands Is Not Sufficient to Rescue Cancer-Associated Gut Microbiota—A Role for Gut Microbial Flagellin in Colorectal Cancer and Cachexia?" Cancers 11, no. 11 (2019): 1799. http://dx.doi.org/10.3390/cancers11111799.
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Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. Further, we examined the possible relationship between the microbial surface molecule flagellin and CRC. CRC cells (C26) were inoculated into mice. Activin receptor (ACVR) ligands were blocked, either before tumor formation or before and after, to increase muscle mass and prevent muscle loss. The effects of flagellin on C26-cells were studied in vitro. The occurrence of similar phenomena were studied in murine and human tumors. Cancer modulated the gut microbiota without consistent effects of blocking the ACVR ligands. However, continued treatment for muscle loss modified the association between microbiota and weight loss. Several abundant microbial taxa in cancer were flagellated. Exposure of C26-cells to flagellin increased IL6 and CCL2/MCP-1 mRNA and IL6 excretion. Murine C26 tumors expressed more IL6 and CCL2/MCP-1 mRNA than C26-cells, and human CRC tumors expressed more CCL2/MCP-1 than healthy colon sites. Additionally, flagellin decreased caspase-1 activity and the production of reactive oxygen species, and increased cytotoxicity in C26-cells. Conditioned media from flagellin-treated C26-cells deteriorated C2C12-myotubes and decreased their number. In conclusion, cancer increased flagellated microbes that may promote CRC survival and cachexia by inducing inflammatory proteins such as MCP-1. Cancer-associated gut microbiota could not be rescued by blocking ACVR ligands.
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Zhou, Jie, Marcia R. Terluk, Paul J. Orchard, James C. Cloyd, and Reena V. Kartha. "N-Acetylcysteine Reverses the Mitochondrial Dysfunction Induced by Very Long-Chain Fatty Acids in Murine Oligodendrocyte Model of Adrenoleukodystrophy." Biomedicines 9, no. 12 (2021): 1826. http://dx.doi.org/10.3390/biomedicines9121826.
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The accumulation of saturated very long-chain fatty acids (VLCFA, ≥C22:0) due to peroxisomal impairment leads to oxidative stress and neurodegeneration in X-linked adrenoleukodystrophy (ALD). Among the neural supporting cells, myelin-producing oligodendrocytes are the most sensitive to the detrimental effect of VLCFA. Here, we characterized the mitochondrial dysfunction and cell death induced by VLFCA, and examined whether N-acetylcysteine (NAC), an antioxidant, prevents the cytotoxicity. We exposed murine oligodendrocytes (158 N) to hexacosanoic acid (C26:0, 1–100 µM) for 24 h and measured reactive oxygen species (ROS) and cell death. Low concentrations of C26:0 (≤25 µM) induced a mild effect on cell survival with no alterations in ROS or total glutathione (GSH) concentrations. However, analysis of the mitochondrial status of cells treated with C26:0 (25 µM) revealed depletion in mitochondrial GSH (mtGSH) and a decrease in the inner membrane potential. These results indicate that VLCFA disturbs the mitochondrial membrane potential causing ROS accumulation, oxidative stress, and cell death. We further tested whether NAC (500 µM) can prevent the mitochondria-specific effects of VLCFA in C26:0-treated oligodendrocytes. Our results demonstrate that NAC improves mtGSH levels and mitochondrial function in oligodendrocytes, indicating that it has potential use in the treatment of ALD and related disorders.
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Zilocchi, Chiara, Antonella Stoppacciaro, Claudia Chiodoni, Mariella Parenza, Nadia Terrazzini та Mario P. Colombo. "Interferon γ–independent Rejection of Interleukin 12–transduced Carcinoma Cells Requires CD4+ T Cells and Granulocyte/Macrophage Colony–stimulating Factor". Journal of Experimental Medicine 188, № 1 (1998): 133–43. http://dx.doi.org/10.1084/jem.188.1.133.
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We analyzed the ability of interferon (IFN)-γ knockout mice (GKO) to reject a colon carcinoma transduced with interleukin (IL)-12 genes (C26/IL-12). Although the absence of IFN-γ impaired the early response and reduced the time to tumor onset in GKO mice, the overall tumor take rate was similar to that of BALB/c mice. In GKO mice, C26/IL-12 tumors had a reduced number of infiltrating leukocytes, especially CD8 and natural killer cells. Analysis of the tumor site, draining nodes, and spleens of GKO mice revealed reduced expression of IFN- inducible protein 10 and monokine induced by γ-IFN. Despite these defects, GKO mice that rejected C26/IL-12 tumor, and mice that were primed in vivo with irradiated C26/IL-12 cells, showed the same cytotoxic T lymphocyte activity but higher production of granulocyte/macrophage colony–stimulating factor (GM-CSF) as compared with control BALB/c mice. Treatment with monoclonal antibodies against GM-CSF abrogated tumor regression in GKO but not in BALB/c mice. CD4 T lymphocytes, which proved unnecessary or suppressive during rejection of C26/IL-12 cells in BALB/c mice, were required for tumor rejection in GKO mice. CD4 T cell depletion was coupled with a decline in GM-CSF expression by lymphocytes infiltrating the tumors or in the draining nodes, and with the reduction and disappearance of granulocytes and CD8 T cells, respectively, in tumor nodules. These results suggest that GM-CSF can substitute for IFN-γ in maintaining the CD8–polymorphonuclear leukocyte cross-talk that is a hallmark of tumor rejection.
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Rojas-Tapias, Daniel, Oriana Ortega Sierra, Diego Rivera Botía, and Ruth Bonilla. "Preservation of Azotobacter chroococcum vegetative cells in dry polymers." Universitas Scientiarum 20, no. 2 (2014): 201. http://dx.doi.org/10.11144/javeriana.sc20-2.pacv.
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We studied the preservation of Azotobacter chroococcum C26 using three dry polymers: carrageenin, sodium alginate, and HPMC, using a method of accelerated degradation. Bacterial viability, as response variable, was measured at three temperatures in four different times, which was followed by calculation of bacterial degradation rates. Results showed that temperature, time of storage, and protective agent influenced both viability and degradation rates (P;lt;0.05). We observed, using the Arrhenius thermodynamic model, that the use of polymers increased the activation energy of bacterial degradation compared to control. We obtained thermodynamic models for each polymer, based on the Arrhenius equation, which predicted the required time for thermal degradation of the cells at different temperatures. Analysis of the models showed that carrageenin was the best polymer to preserve A. chroococcum C26 since ~ 900 days are required at 4 ºC to reduce its viability in two log units. We conclude, therefore, that long-term preservation of A. chroococcum C26 using dry polymers is suitable under adequate preservation and storage conditions.
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Cerantola, Vanessa, Christine Vionnet, Olivier F. Aebischer, Titus Jenny, Jens Knudsen, and Andreas Conzelmann. "Yeast sphingolipids do not need to contain very long chain fatty acids." Biochemical Journal 401, no. 1 (2006): 205–16. http://dx.doi.org/10.1042/bj20061128.
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Synthesis of VLCFAs (very long chain fatty acids) and biosynthesis of DHS (dihydrosphingosine) both are of vital importance for Saccharomyces cerevisiae. The bulk of VLCFAs and DHS are used for ceramide synthesis by the Lag1p (longevity-assurance gene 1)/Lac1p (longevity-assurance gene cognate 1)/Lip1p (Lag1p/Lac1p interacting protein) ceramide synthase. LAG1 and LAC1 are redundant but LIP1 is essential. Here we show that 4Δ (lag1Δlac1Δypc1Δydc1Δ) cells devoid of all known endogenous ceramide synthesis pathways are unviable but can be rescued by the expression of Lass5, a mouse LAG1 homologue. Ceramide synthase activity of 4Δ.Lass5 cells only utilizes C16 and C18 fatty acids and does not require the help of Lip1p, an essential cofactor of Lag1p/Lac1p. HPLC-electrospray ionization-MS/MS analysis demonstrated that in IPCs (inositolphosphorylceramides) of 4Δ.Lass5, the very long chain fatty acids (C26 and C24) account for <1% instead of the normal >97%. Notwithstanding, IPCs incorporated into glycosylphosphatidylinositol anchors of 4Δ.Lass5 show normal mobility on TLC and the ceramide- and raft-dependent traffic of Gas1p (glycophospholipid-anchored surface protein) from endoplasmic reticulum to Golgi remains almost normal. Moreover, the biosynthesis of C24:0 fatty acids remains essential. Thus, C24:0 and dihydrosphingosine are both necessary for survival of yeast cells even if they utilize C16 and C18 fatty acids for sphingolipid biosynthesis.
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Bosson, Régine, and Andreas Conzelmann. "Multiple functions of inositolphosphorylceramides in the formation and intracellular transport of glycosylphosphatidylinositol-anchored proteins in yeast." Biochemical Society Symposia 74 (January 12, 2007): 199–209. http://dx.doi.org/10.1042/bss2007c17.
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The mature sphingolipids of yeast consist of IPCs (inositolphosphorylceramides) and glycosylated derivatives thereof. Beyond being an abundant membrane constituent in the organelles of the secretory pathway, IPCs are also used to constitute the lipid moiety of the majority of GPI (glycosylphosphatidylinositol) proteins, while a minority of GPI proteins contain PI (phosphatidylinositol). Thus all GPI anchor lipids (as well as free IPCs) typically contain C26 fatty acids. However, the primary GPI lipid that isadded to newly synthesized proteins in the endoplasmic reticulum consists of a PI with conventional C16 and C18 fatty acids. A new class of enzymes is required to replace the fatty acid in sn-2 by a C26 fatty acid. Cells lacking this activity make normal amounts of GPI proteins but accumulate GPI anchors containing lyso-PI. As a consequence, the endoplasmic reticulum to Golgi transport of the GPI protein Gas1p is slow, and mature Gas1p is lost from the plasma membrane into the medium. The GPI anchor containing C26 in sn-2 can further be remodelled by the exchange of diacylglycerol for ceramide. This process is also dependent on the presence of specific phosphorylethanolamine side-chains on the GPI anchor.
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Aquila, Giorgio, Andrea David Re Cecconi, Mara Forti, et al. "Trabectedin and Lurbinectedin Extend Survival of Mice Bearing C26 Colon Adenocarcinoma, without Affecting Tumor Growth or Cachexia." Cancers 12, no. 8 (2020): 2312. http://dx.doi.org/10.3390/cancers12082312.
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Trabectedin (ET743) and lurbinectedin (PM01183) limit the production of inflammatory cytokines that are elevated during cancer cachexia. Mice carrying C26 colon adenocarcinoma display cachexia (i.e., premature death and body wasting with muscle, fat and cardiac tissue depletion), high levels of inflammatory cytokines and subsequent splenomegaly. We tested whether such drugs protected these mice from cachexia. Ten-week-old mice were inoculated with C26 cells and three days later randomized to receive intravenously vehicle or 0.05 mg/kg ET743 or 0.07 mg/kg PM01183, three times a week for three weeks. ET743 or PM01183 extended the lifespan of C26-mice by 30% or 85%, respectively, without affecting tumor growth or food intake. Within 13 days from C26 implant, both drugs did not protect fat, muscle and heart from cachexia. Since PM01183 extended the animal survival more than ET743, we analyzed PM01183 further. In tibialis anterior of C26-mice, but not in atrophying myotubes, PM01183 restrained the NF-κB/PAX7/myogenin axis, possibly reducing the pro-inflammatory milieu, and failed to limit the C/EBPβ/atrogin-1 axis. Inflammation-mediated splenomegaly of C26-mice was inhibited by PM01183 for as long as the treatment lasted, without reducing IL-6, M-CSF or IL-1β in plasma. ET743 and PM01183 extend the survival of C26-bearing mice unchanging tumor growth or cachexia but possibly restrain muscle-related inflammation and C26-induced splenomegaly.
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ZĂHAN, Marius, Ana Maria MUŢOIU, Liliana OLENIC, Ileana MICLEA, Adriana CRISTE, and Vasile MICLEA. "Cytotoxic Effect of Chitosan-Gold Nanoparticles on Two Cell Lines in Culture." Bulletin of University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca. Animal Science and Biotechnologies 74, no. 2 (2017): 139. http://dx.doi.org/10.15835/buasvmcn-asb:0017.
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Among metallic nanoparticles gold possess several unique properties. It has been argued that AuNPs have significant toxicity both in vitro and in vivo but that coating may partially prevent harmful effects. Chitosan is a natural polysaccharide derivative of chitin known to have immunoenhancing effects, antitumor, antifungal and antimicrobial activities. The aim of this study was to investigate the cytotoxic effect of chitosan-AuNPs on C26 (murine colon carcinoma) and HeLa (human cervix carcinoma) cell lines. C26 and HeLa cells were exposed to 10 and 60 nm sized chitosan-AuNPs at five different concentrations (5, 10, 25, 50 and 100 μg/ml). After 24 h of incubation, cytotoxicity was assessed by the MTT colorimetric method and IC50 values were calculated. In C26 cells 60 nm particles were more toxic than 10 nm particles. On the other hand in HeLa cells the situation was reversed and 10 nm particles had the most harmful effect at a concentration 2.5 times smaller than that of 60 nm particles. Our results could suggest that chitosan-AuNPs have an antiproliferative effect on C26 and HeLa cell lines but that this depends on cell type and is influenced by particle size and concentration.
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Lokireddy, Sudarsanareddy, Isuru Wijerupage Wijesoma, Sabeera Bonala, et al. "Myostatin is a novel tumoral factor that induces cancer cachexia." Biochemical Journal 446, no. 1 (2012): 23–36. http://dx.doi.org/10.1042/bj20112024.
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Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin–proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy–lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice.
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Bosson, Régine, Malika Jaquenoud, and Andreas Conzelmann. "GUP1 of Saccharomyces cerevisiae Encodes an O-Acyltransferase Involved in Remodeling of the GPI Anchor." Molecular Biology of the Cell 17, no. 6 (2006): 2636–45. http://dx.doi.org/10.1091/mbc.e06-02-0104.
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The anchors of mature glycosylphosphatidylinositol (GPI)-anchored proteins of Saccharomyces cerevisiae contain either ceramide or diacylglycerol with a C26:0 fatty acid in the sn2 position. The primary GPI lipid added to newly synthesized proteins in the ER consists of diacylglycerol with conventional C16 and C18 fatty acids. Here we show that GUP1 is essential for the synthesis of the C26:0-containing diacylglycerol anchors. Gup1p is an ER membrane protein with multiple membrane-spanning domains harboring a motif that is characteristic of membrane-bound O-acyl-transferases (MBOAT). Gup1Δ cells make normal amounts of GPI proteins but most mature GPI anchors contain lyso-phosphatidylinositol, and others possess phosphatidylinositol with conventional C16 and C18 fatty acids. The incorporation of the normal ceramides into the anchors is also disturbed. As a consequence, the ER-to-Golgi transport of the GPI protein Gas1p is slow, and mature Gas1p is lost from the plasma membrane into the medium. Gup1Δ cells have fragile cell walls and a defect in bipolar bud site selection. GUP1 function depends on the active site histidine of the MBOAT motif. GUP1 is highly conserved among fungi and protozoa and the gup1Δ phenotype is partially corrected by GUP1 homologues of Aspergillus fumigatus and Trypanosoma cruzi.
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Plas, Rogier L. C., Mieke Poland, Joyce Faber, et al. "A Diet Rich in Fish Oil and Leucine Ameliorates Hypercalcemia in Tumour-Induced Cachectic Mice." International Journal of Molecular Sciences 20, no. 20 (2019): 4978. http://dx.doi.org/10.3390/ijms20204978.
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Background: Dietary supplementation with leucine and fish oil rich in omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) has previously been shown to reduce cachexia-related outcomes in C26 tumour-bearing mice. To further explore associated processes and mechanisms we investigated changes in plasma Ca2+ levels, the involvement of parathyroid hormone related protein (PTHrP), and its possible interactions with cyclooxygenase 2 (COX-2). Methods: CD2F1 mice were subcutaneously inoculated with C26 adenocarcinoma cells or sham treated and divided in: (1) controls, (2) tumour-bearing controls, and (3) tumour-bearing receiving experimental diets. After 20 days, body and organ masses and total plasma Ca2+ levels were determined. Furthermore, effects of DHA, EPA and leucine on production of PTHrP were studied in cultured C26 cells. Results: The combination of leucine and fish oil reduced tumour-associated hypercalcemia. Plasma Ca2+ levels negatively correlated with carcass mass and multiple organ masses. DHA was able to reduce PTHrP production by C26 cells in vitro. Results indicate that this effect occurred independently of COX-2 inhibition. Conclusion: Our results suggest that cancer-related hypercalcemia may be ameliorated by a nutritional intervention rich in leucine and fish oil. The effect of fish oil possibly relates to a DHA-induced reduction of PTHrP excretion by the tumour.
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Fujita, Morihisa, Mariko Umemura, Takehiko Yoko-o, and Yoshifumi Jigami. "PER1 Is Required for GPI-Phospholipase A2 Activity and Involved in Lipid Remodeling of GPI-anchored Proteins." Molecular Biology of the Cell 17, no. 12 (2006): 5253–64. http://dx.doi.org/10.1091/mbc.e06-08-0715.
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Glycosylphoshatidylinositol (GPI) anchors are remodeled during their transport to the cell surface. Newly synthesized proteins are transferred to a GPI anchor, consisting of diacylglycerol with conventional C16 and C18 fatty acids, whereas the lipid moiety in mature GPI-anchored proteins is exchanged to either diacylglycerol containing a C26:0 fatty acid in the sn-2 position or ceramide in Saccharomyces cerevisiae. Here, we report on PER1, a gene encoding a protein that is required for the GPI remodeling pathway. We found that GPI-anchored proteins could not associate with the detergent-resistant membranes in per1Δ cells. In addition, the mutant cells had a defect in the lipid remodeling from normal phosphatidylinositol (PI) to a C26 fatty acid–containing PI in the GPI anchor. In vitro analysis showed that PER1 is required for the production of lyso-GPI, suggesting that Per1p possesses or regulates the GPI-phospholipase A2 activity. We also found that human PERLD1 is a functional homologue of PER1. Our results demonstrate for the first time that PER1 encodes an evolutionary conserved component of the GPI anchor remodeling pathway, highlighting the close connection between the lipid remodeling of GPI and raft association of GPI-anchored proteins.
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Patras, Laura, Marcel H. A. M. Fens, Pieter Vader, et al. "Normoxic Tumour Extracellular Vesicles Modulate the Response of Hypoxic Cancer and Stromal Cells to Doxorubicin In Vitro." International Journal of Molecular Sciences 21, no. 17 (2020): 5951. http://dx.doi.org/10.3390/ijms21175951.
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Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour–stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma–extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance.
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Lautaoja, Juulia H., Maciej Lalowski, Tuuli A. Nissinen, et al. "Muscle and serum metabolomes are dysregulated in colon-26 tumor-bearing mice despite amelioration of cachexia with activin receptor type 2B ligand blockade." American Journal of Physiology-Endocrinology and Metabolism 316, no. 5 (2019): E852—E865. http://dx.doi.org/10.1152/ajpendo.00526.2018.
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Cancer-associated cachexia reduces survival, which has been attenuated by blocking the activin receptor type 2B (ACVR2B) ligands in mice. The purpose of this study was to unravel the underlying physiology and novel cachexia biomarkers by use of the colon-26 (C26) carcinoma model of cancer cachexia. Male BALB/c mice were subcutaneously inoculated with C26 cancer cells or vehicle control. Tumor-bearing mice were treated with vehicle (C26+PBS) or soluble ACVR2B either before (C26+sACVR/b) or before and after (C26+sACVR/c) tumor formation. Skeletal muscle and serum metabolomics analysis was conducted by gas chromatography-mass spectrometry. Cancer altered various biologically functional groups representing 1) amino acids, 2) energy sources, and 3) nucleotide-related intermediates. Muscle metabolomics revealed increased content of free phenylalanine in cancer that strongly correlated with the loss of body mass within the last 2 days of the experiment. This correlation was also detected in serum. Decreased ribosomal RNA content and phosphorylation of a marker of pyrimidine synthesis revealed changes in nucleotide metabolism in cancer. Overall, the effect of the experimental C26 cancer predominated over blocking ACVR2B ligands in both muscle and serum. However, the level of methyl phosphate, which was decreased in muscle in cancer, was restored by sACVR2B-Fc treatment. In conclusion, experimental cancer affected muscle and blood metabolomes mostly independently of blocking ACVR2B ligands. Of the affected metabolites, we have identified free phenylalanine as a promising biomarker of muscle atrophy or cachexia. Finally, the decreased capacity for pyrimidine nucleotide and protein synthesis in tumor-bearing mice opens up new avenues in cachexia research.
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McNamara, M. K., and J. S. Wiley. "Passive permeability of human red blood cells to calcium." American Journal of Physiology-Cell Physiology 250, no. 1 (1986): C26—C31. http://dx.doi.org/10.1152/ajpcell.1986.250.1.c26.
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Ca2+ influx was measured into human erythrocytes in which efflux was blocked by either introduction of an intracellular Ca2+ chelator, introduction of the Ca2+ chelator followed by ATP depletion, or depletion of the Ca2+ pump cofactors ATP and Mg2+. The Ca2+ influx under all three conditions was 14-20 mumol . 1 cells-1 . h-1, which is an order of magnitude higher than the influx previously reported for cells depleted of either ATP or Mg2+ separately. The difference between the two values was explained by the finding of substantial Ca2+ efflux from the Ca2+-loaded ATP-depleted cells, whereas this efflux was insignificant from cells loaded with quin 2 and then ATP depleted. Under these latter conditions Ca2+ influx estimates the unidirectional permeability to this cation. Studies using this technique showed that Ca2+ influx was the same in media of isotonic sodium, potassium, lithium, choline, or magnesium chlorides. Moreover the dependence of Ca2+ influx on external Ca2+ concentration was well described by the sum of saturable and nonsaturable (linear) components.
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Inoue, M., N. Fujishiro, and I. Imanaga. "Retardation of cation channel deactivation by mitochondrial dysfunction in adrenal medullary cells." American Journal of Physiology-Cell Physiology 278, no. 1 (2000): C26—C32. http://dx.doi.org/10.1152/ajpcell.2000.278.1.c26.
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The mechanism for cyanide (CN) activation of a nonselective cation (NS) channel coupled with a muscarinic receptor in a guinea pig chromaffin cell was studied with the perforated-patch method. Bath application of a protein kinase inhibitor resulted in a dose-dependent inhibition of muscarine-induced current ( I M) but had no apparent effect on the CN-induced current ( I CN). On the other hand, production of I CN occluded muscarine activation of NS channels in an amplitude-dependent manner. Deactivation of I M after washout was retarded while I CN was also active, and the extent of the retardation increased with an increase in the relative production of I CN on muscarinic stimulation. Restoration of Na+ pump activity from CN suppression was conspicuously retarded below 19–20°C, and the apparent diminution of I M and I CN after washout was retarded in parallel with a decrease in temperature. The results suggest that CN activation of NS channels is due to suppression of deactivation of the channel.
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Jørgensen, Nanna Koschmieder, Stine Falsig Petersen, and Else Kay Hoffmann. "Thrombin-, bradykinin-, and arachidonic acid-induced Ca2+ signaling in Ehrlich ascites tumor cells." American Journal of Physiology-Cell Physiology 276, no. 1 (1999): C26—C37. http://dx.doi.org/10.1152/ajpcell.1999.276.1.c26.
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Stimulation of single Ehrlich ascites tumor cells with agonists (bradykinin, thrombin) and with arachidonic acid (AA) induces increases in the free intracellular Ca2+ concentration ([Ca2+]i) in the presence and absence of extracellular Ca2+, measured using the Ca2+-sensitive probe fura 2. Sequential stimulation with two agonists elicits sequential increases in [Ca2+]i, unlike addition of the same agonist twice. Bradykinin and thrombin have additive effects on [Ca2+]iin Ca2+-free medium. The phosphoinositidase C inhibitor U-73122 inhibits the agonist-induced increases in [Ca2+]i, whereas ryanodine has no effect. Pretreatment of cells in Ca2+-free medium with thapsigargin abolishes the bradykinin-induced increase in [Ca2+]ibut not the response to thrombin. The AA-induced response is not inhibited by U-73122 and cannot be mimicked by the inactive structural analog trifluoromethylarachidonyl ketone. Pretreatment of the cells with 50 μM AA (but not with 10 μM AA) abolishes the agonist-induced increase in [Ca2+]i. Thus bradykinin, thrombin, and AA induce increases in [Ca2+]iin Ehrlich cells due to Ca2+ entry and release from intracellular stores. Thrombin causes release of Ca2+ from an intracellular store that is insensitive to bradykinin and is not depleted by thapsigargin but is depleted by AA.
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Porfire, Alina, Ioan Tomuta, Dana Muntean, et al. "Optimizing long-circulating liposomes for delivery of simvastatin to C26 colon carcinoma cells." Journal of Liposome Research 25, no. 4 (2014): 261–69. http://dx.doi.org/10.3109/08982104.2014.987787.
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Zare, Fatemeh. "Controlling role of Ly6Chigh Monocytes in breast cancer and C26 colon carcinoma." Journal of Immunology 196, no. 1_Supplement (2016): 211.13. http://dx.doi.org/10.4049/jimmunol.196.supp.211.13.
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Abstract Tumor microenvironment encompasses a wide variety of immune cells, which macrophages comprise the most dominant portion of them and thus are the major players in the connection between inflammation and cancer. These tumor-associated macrophages (TAMs) are derived from blood monocyte precursors and subsequently acquire distinct characteristics as a result of tumor micro-environmental cues. Monocytes are a heterogeneous population in the blood with an enormous plasticity whose fate and functions are dictated by the microenvironment. Therefore, the roles of specific Monocytes subsets in tumor progression and the molecular mechanisms for their impacts need to be elucidated. Ly6Chigh and Ly6Clow are two main different types of murine monocytes subsets that have been defined by distinct phenotypes and immunoregulatory functions. Recent data demonstrates that Ly6Chigh monocytes can recruit to inflammation loci while Ly6Clow monocytes are patrolling cells. We have developed a method to produce large number of Ly6Chigh monocytes in vitro. In our study we observed that, injection of these cells affects tumor progression in breast cancer and C26 colon carcinoma animal models. Activation of Ly6Clow monocytes by pro- or anti-inflammatory cytokines, results in displaying a genetic expression profile, corresponding to pro- or anti-inflammatory genes, respectively. Injection of pre- activated Ly6Clow monocytes toward pro- or anti-inflammatory polarization in C26 colon carcinoma showed that anti-inflammatory activated monocytes are more beneficial in delaying cancer cachexia. Increased knowledge of monocytes improves the chances to find therapies against a broad spectrum of diseases including cancer.
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Angelotti, Austin, Rachel Cole, Amy Webb, Maciej Pietrzak, and Martha Belury. "Diet-Induced Gene Expression Changes of Cachectic Muscle, Adipose, and Liver." Current Developments in Nutrition 6, Supplement_1 (2022): 234. http://dx.doi.org/10.1093/cdn/nzac052.001.
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Abstract Objectives Cancer cachexia is a systemic disease characterized by muscle and adipose loss that cannot be reversed by increasing caloric intake. Our previous research has shown insulin resistance precedes cancer cachexia in the C26 mouse model of cachexia, and a diet high in linoleic acid, the essential omega-6 polyunsaturated fatty acid, attenuates the C26-induced insulin resistance. Therefore, to better understand how dietary linoleic acid is improving insulin sensitivity, we characterized gene expression changes in three major tissues responsible for controlling insulin sensitivity: skeletal muscle, adipose, and liver. Methods Male CD2F1 (Charles River, MA) were randomized to semi-purified diet (24% fat by weight) containing fat prominently from lard, or containing fat prominently from safflower oil (a linoleic acid-rich oil). One week after diet randomization, mice were inoculated with colon-26 (C26) adenocarcinoma cells (1.0E6 cells). 13 days after inoculation mice were euthanized and gastrocnemius skeletal muscle, epididymal white adipose tissue, and liver tissue were collected for total transcriptome analysis using poly-A enriched next generation RNA-sequencing. Differentially expressed genes were selected based on p-values &lt; 0.05. Results There were no detectable differences in body weight or food intake between the two diets in mice with C26 tumors. Between the two diets 12 genes were differentially expressed in the muscle, while 57 genes were differentially expressed in the liver, and 314 genes were differentially expressed in adipose. Conclusions A linoleic acid enriched diet had little effect on the skeletal muscle transcriptome but induced larger transcriptome changes in liver and adipose. This could suggest dietary linoleic acid increases insulin sensitivity through affecting metabolism in adipose and liver, rather than skeletal muscle. Determining these diet-induced transcriptome changes allows us to better target tissue-specific molecular mechanisms of linoleic acid in future research. Funding Sources This work was supported by the Pelotonia Fellowship Program, the Ohio State University Comprehensive Cancer Center, and the National Institutes of Health.
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Serrao, Simone, Cristina Contini, Giulia Guadalupi, et al. "Salivary Cystatin D Interactome in Patients with Systemic Mastocytosis: An Exploratory Study." International Journal of Molecular Sciences 24, no. 19 (2023): 14613. http://dx.doi.org/10.3390/ijms241914613.
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Mastocytosis, a rare blood disorder characterized by the proliferation of clonal abnormal mast cells, has a variegated clinical spectrum and diagnosis is often difficult and delayed. Recently we proposed the cathepsin inhibitor cystatin D-R26 as a salivary candidate biomarker of systemic mastocytosis (SM). Its C26 variant is able to form multiprotein complexes (mPCs) and since protein–protein interactions (PPIs) are crucial for studying disease pathogenesis, potential markers, and therapeutic targets, we aimed to define the protein composition of the salivary cystatin D-C26 interactome associated with SM. An exploratory affinity purification-mass spectrometry method was applied on pooled salivary samples from SM patients, SM patient subgroups with and without cutaneous symptoms (SM+C and SM−C), and healthy controls (Ctrls). Interactors specifically detected in Ctrls were found to be implicated in networks associated with cell and tissue homeostasis, innate system, endopeptidase regulation, and antimicrobial protection. Interactors distinctive of SM−C patients participate to PPI networks related to glucose metabolism, protein S-nitrosylation, antibacterial humoral response, and neutrophil degranulation, while interactors specific to SM+C were mainly associated with epithelial and keratinocyte differentiation, cytoskeleton rearrangement, and immune response pathways. Proteins sensitive to redox changes, as well as proteins with immunomodulatory properties and activating mast cells, were identified in patients; many of them were involved directly in cytoskeleton rearrangement, a process crucial for mast cell activation. Although preliminary, these results demonstrate that PPI alterations of the cystatin D-C26 interactome are associated with SM and provide a basis for future investigations based on quantitative proteomic analysis and immune validation.
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Takayama, Takuma, Taro Shimizu, Amr S. Abu Lila, et al. "Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil®) in C26 Tumor-Bearing Immunocompetent Mice." Pharmaceutics 12, no. 10 (2020): 990. http://dx.doi.org/10.3390/pharmaceutics12100990.
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Doxorubicin (DXR) has been reported to have direct cytotoxicity against cancer cells and indirect immunotoxicity by modulation of host antitumor immunity. Hence, it may prevent cancer progression by a dual mechanism. Doxil®, a formulation of DXR encapsulated in polyethylene glycol modified (PEGylated) liposomes, is the most widely used of the clinically approved liposomal anticancer drugs. However, the effect of Doxil® on host antitumor immunity is not well understood. In this study, Doxil® efficiently suppressed tumor growth in immunocompetent mice bearing C26 murine colorectal carcinomas, but not in T cell-deficient nude mice, indicating a contribution of T cells to the overall antitumor effect of Doxil®. In immunocompetent mice, Doxil® increased major histocompatibility complex (MHC-1) levels in C26 tumors, which may be an indicator of increased immunogenicity of tumor cells, and potentially amplified tumor immunogenicity by decreasing immunosuppressive cells such as regulatory T cells, tumor-associated microphages and myeloid-derived suppressor cells that collectively suppress T cell-mediated antitumor responses. This suggests that encapsulation of DXR into PEGylated liposomes increased the therapeutic efficacy of DXR though effects on host antitumor immunogenicity in addition to direct cytotoxic effects on tumor cells. This report describes the role of host antitumor immunity in the overall therapeutic effects of Doxil®. Manipulating pharmacokinetics and biodistribution of chemotherapeutic agents with immunomodulatory properties may increase their therapeutic efficacies by amplifying host antitumor immunity in addition to direct cytotoxic effects on tumor cells.
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Chitti, Sai V., Akbar L. Marzan, Sanjay Shahi, Taeyoung Kang, Pamali Fonseka, and Suresh Mathivanan. "Repurposing of Antibiotic Sulfisoxazole Inhibits Lipolysis in Pre-Clinical Model of Cancer-Associated Cachexia." Biology 10, no. 8 (2021): 700. http://dx.doi.org/10.3390/biology10080700.
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Clinical management of cancer-associated cachexia, a multi-organ wasting syndrome, has been challenging without effective treatment strategies. An effective treatment that directly targets cancer-induced wasting is desperately needed to improve the quality of life and the survival of cancer patients. Recently, an antibiotic SFX was shown to have anti-tumour and anti-metastatic effects in mouse models of breast cancer. Hence, in this study, we examined the efficacy of SFX in the treatment of cancer-induced cachexia. C26 cachexic mice models were administered with SFX, and the tumour volume and body weight were regularly measured. Blood glucose, skeletal muscles, and adipose tissue were examined at the endpoint. Contrary to a previous study, SFX did not reduce the tumour volume in mice bearing C26 cells. Administration of SFX neither revealed any survival benefit nor rescued C26 cachectic mice from muscle wasting. Interestingly, SFX administration partially rescued (~10%) tumour-induced weight loss by preserving both the subcutaneous and intestinal fat mass. Together, these results suggest that the administration of SFX could partially rescue cancer-induced weight loss by inhibiting lipolysis. As anti-cachexia therapies are scarce, the results could facilitate the design of combinatorial therapies involving SFX, standard-of-care chemotherapeutics, and drugs that inhibit muscle atrophy for the treatment of cancer cachexia.
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Mueller, Noomi, Takayuki Sassa, Susanne Morales-Gonzalez, et al. "De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy." Journal of Medical Genetics 56, no. 3 (2018): 164–75. http://dx.doi.org/10.1136/jmedgenet-2018-105711.
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BackgroundVery long-chain fatty acids (VLCFAs) are essential for functioning of biological membranes. ELOVL fatty acid elongase 1 catalyses elongation of saturated and monounsaturated C22-C26-VLCFAs. We studied two patients with a dominant ELOVL1 mutation. Independently, Kutkowska-Kaźmierczak et al. had investigated the same patients and found the same mutation. We extended our study towards additional biochemical, functional, and therapeutic aspects.MethodsWe did mutation screening by whole exome sequencing. RNA-sequencing was performed in patient and control fibroblasts. Ceramide and sphingomyelin levels were measured by LC-MS/MS. ELOVL1 activity was determined by a stable isotope-labelled [13C]malonyl-CoA elongation assay. ELOVL1 expression patterns were investigated by immunofluorescence, in situ hybridisation and RT-qPCR. As treatment option, we investigated VLCFA loading of fibroblasts.ResultsBoth patients carried an identical heterozygous de novo ELOVL1 mutation (c.494C>T, NM_001256399; p.S165F) not deriving from a founder allele. Patients suffered from epidermal hyperproliferation and increased keratinisation (ichthyosis). Hypomyelination of the central white matter explained spastic paraplegia and central nystagmus, while optic atrophy was causative for reduction of peripheral vision and visual acuity. The mutation abrogated ELOVL1 enzymatic activity and reduced ≥C24 ceramides and sphingomyelins in patient cells. Fibroblast loading with C22:0-VLCFAs increased C24:0-ceramides and sphingomyelins. We found competitive inhibition for ceramide and sphingomyelin synthesis between saturated and monounsaturated VLCFAs. Transcriptome analysis revealed upregulation of modules involved in epidermal development and keratinisation, and downregulation of genes for neurodevelopment, myelination, and synaptogenesis. Many regulated genes carried consensus proliferator-activated receptor (PPAR)α and PPARγ binding motifs in their 5’-regions.ConclusionA dominant ELOVL1 mutation causes a neuro-ichthyotic disorder possibly amenable to treatment with PPAR-modulating drugs.
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Zarrouk, A., T. Nury, J. M. Riedinger, O. Rouaud, M. Hammami, and Gérard Lizard. "Dual effect of docosahexaenoic acid (attenuation or amplification) on C22:0-, C24:0-, and C26:0-Induced mitochondrial dysfunctions and oxidative stress on human neuronal SK-N-BE cells." Journal of nutrition, health & aging 19, no. 2 (2014): 198–205. http://dx.doi.org/10.1007/s12603-014-0518-0.
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Karaman, Maja, Kristina Atlagić, Aleksandra Novaković, et al. "Fatty Acids Predominantly Affect Anti-Hydroxyl Radical Activity and FRAP Value: The Case Study of Two Edible Mushrooms." Antioxidants 8, no. 10 (2019): 480. http://dx.doi.org/10.3390/antiox8100480.
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Compared to plants, nowadays mushrooms attract more attention as functional foods, due to a number of advantages in manipulating them. This study aimed to screen the chemical composition (fatty acids and phenolics) and antioxidant potential (OH•, 2,2-diphenyl-1-picrylhydrazyl (DPPH•) and ferric reducing ability of plasma (FRAP)) of two edible mushrooms, Coprinus comatus and Coprinellus truncorum, collected from nature and submerged cultivation. Partial least square regression analysis has pointed out the importance of some fatty acids—more precisely, unsaturated fatty acids (UFAs) followed by fatty acids possessing both short (C6:0 and C8:0) and long (C23:0 and C24:0) saturated chains—and phenolic compounds (such as protocatechuic acid, daidzein, p-hydroxybenzoic acid, genistein and vanillic acid) for promising anti-OH•, FRAP and anti-DPPH• activities, respectively. However, other fatty acids (C16:0, C18:0 and C18:3n3) along with the flavonol isorhamnetin are actually suspected to negatively affect (by acting pro-oxidative) the aforementioned parameters, respectively. Taken together, design of new food supplements targeting oxidative stress might be predominantly based on the various UFAs combinations (C18:2n6, C20:1, C20:2, C20:4n6, C22:2, C22:1n9, etc.), particularly if OH• is suspected to play an important role.
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Ebisawa, T., K. Tada, I. Kitajima, et al. "Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation." Journal of Cell Science 112, no. 20 (1999): 3519–27. http://dx.doi.org/10.1242/jcs.112.20.3519.
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Bone morphogenetic protein (BMP)-6 is a member of the transforming growth factor (TGF)-(β) superfamily, and is most similar to BMP-5, osteogenic protein (OP)-1/BMP-7, and OP-2/BMP-8. In the present study, we characterized the endogenous BMP-6 signaling pathway during osteoblast differentiation. BMP-6 strongly induced alkaline phosphatase (ALP) activity in cells of osteoblast lineage, including C2C12 cells, MC3T3-E1 cells, and ROB-C26 cells. The profile of binding of BMP-6 to type I and type II receptors was similar to that of OP-1/BMP-7 in C2C12 cells and MC3T3-E1 cells; BMP-6 strongly bound to activin receptor-like kinase (ALK)-2 (also termed ActR-I), together with type II receptors, i.e. BMP type II receptor (BMPR-II) and activin type II receptor (ActR-II). In addition, BMP-6 weakly bound to BMPR-IA (ALK-3), to which BMP-2 also bound. In contrast, binding of BMP-6 to BMPR-IB (ALK-6), and less efficiently to ALK-2 and BMPR-IA, together with BMPR-II was detected in ROB-C26 cells. Intracellular signalling was further studied using C2C12 and MC3T3-E1 cells. Among the receptor-regulated Smads activated by BMP receptors, BMP-6 strongly induced phosphorylation and nuclear accumulation of Smad5, and less efficiently those of Smad1. However, Smad8 was constitutively phosphorylated, and no further phosphorylation or nuclear accumulation of Smad8 by BMP-6 was observed. These findings indicate that in the process of differentiation to osteoblasts, BMP-6 binds to ALK-2 as well as other type I receptors, and transduces signals mainly through Smad5 and possibly through Smad1.
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Bosson, Régine, Isabelle Guillas, Christine Vionnet, Carole Roubaty, and Andreas Conzelmann. "Incorporation of Ceramides into Saccharomyces cerevisiae Glycosylphosphatidylinositol-Anchored Proteins Can Be Monitored In Vitro." Eukaryotic Cell 8, no. 3 (2008): 306–14. http://dx.doi.org/10.1128/ec.00257-08.
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ABSTRACT After glycosylphosphatidylinositols (GPIs) are added to GPI proteins of Saccharomyces cerevisiae, a fatty acid of the diacylglycerol moiety is exchanged for a C26:0 fatty acid through the subsequent actions of Per1 and Gup1. In most GPI anchors this modified diacylglycerol-based anchor is subsequently transformed into a ceramide-containing anchor, a reaction which requires Cwh43. Here we show that the last step of this GPI anchor lipid remodeling can be monitored in microsomes. The assay uses microsomes from cells that have been grown in the presence of myriocin, a compound that blocks the biosynthesis of dihydrosphingosine (DHS) and thus inhibits the biosynthesis of ceramide-based anchors. Such microsomes, when incubated with [3H]DHS, generate radiolabeled, ceramide-containing anchor lipids of the same structure as made by intact cells. Microsomes from cwh43Δ or mcd4Δ mutants, which are unable to make ceramide-based anchors in vivo, do not incorporate [3H]DHS into anchors in vitro. Moreover, gup1Δ microsomes incorporate [3H]DHS into the same abnormal anchor lipids as gup1Δ cells synthesize in vivo. Thus, the in vitro assay of ceramide incorporation into GPI anchors faithfully reproduces the events that occur in mutant cells. Incorporation of [3H]DHS into GPI proteins is observed with microsomes alone, but the reaction is stimulated by cytosol or bovine serum albumin, ATP plus coenzyme A (CoA), or C26:0-CoA, particularly if microsomes are depleted of acyl-CoA. Thus, [3H]DHS cannot be incorporated into proteins in the absence of acyl-CoA.
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Mărgăoan, Rodica, Marius Zăhan, Liviu A. Mărghitaş, Daniel S. Dezmirean, Silvio Erler, and Otilia Bobiş. "Antiproliferative activity and apoptotic effects of Filipendula ulmaria pollen against C26 mice colon tumour cells." Journal of Apicultural Science 60, no. 1 (2016): 135–44. http://dx.doi.org/10.1515/jas-2016-0014.
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Abstract Honeybee collected pollen exhibits high nutritional and pharmaceutical benefits for the human diet and medicine. Pollen’s antioxidant, anti-ageing, anti-inflammatory, anti-atherosclerosis, and cardioprotective activity, depending on the floral origin, are well known. Recent studies proposed that pollen may also be an excellent cancer-fighting candidate, as pollen harbours high amounts of phenolic substances. In our study, Filipendula ulmaria pollen (bee collected) was methanol-water extracted and used to verify its in vitro pharmacological activities on C26 mice cancer tumour cells. Three different concentrations of the extract were tested in antitumour assays. Monitoring was done after 6, 12, 24, and 48 hours. Promising results were obtained for antiproliferative and apoptotic activity of the pollen extracts, with high efficiency for the highest concentration (1 mg/mL). For both activities, time and concentration-dependent effects were observed. Pollen extracts or bee collected pollen has a high potential as an antitumour agent for use in human medicine, because they are both rich in bioactive compounds.
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Naito, Masako, Yoshikazu Mikami, Minoru Takagi, and Tomihisa Takahashi. "Up-regulation of Axin2 by dexamethasone promotes adipocyte differentiation in ROB-C26 mesenchymal progenitor cells." Cell and Tissue Research 354, no. 3 (2013): 761–70. http://dx.doi.org/10.1007/s00441-013-1696-5.
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Potara, Monica, Manisha Bawaskar, Timea Simon, et al. "Biosynthesized silver nanoparticles performing as biogenic SERS-nanotags for investigation of C26 colon carcinoma cells." Colloids and Surfaces B: Biointerfaces 133 (September 2015): 296–303. http://dx.doi.org/10.1016/j.colsurfb.2015.06.024.
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Lee, Wan-Chi, Chih-Hsien Chang, Chung-Li Ho, et al. "Early Detection of Tumor Response by FLT/MicroPET Imaging in a C26 Murine Colon Carcinoma Solid Tumor Animal Model." Journal of Biomedicine and Biotechnology 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/535902.
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Fluorine-18 fluorodeoxyglucose (-FDG) positron emission tomography (PET) imaging demonstrated the change of glucose consumption of tumor cells, but problems with specificity and difficulties in early detection of tumor response to chemotherapy have led to the development of new PET tracers. Fluorine-18-fluorothymidine (-FLT) images cellular proliferation by entering the salvage pathway of DNA synthesis. In this study, we evaluate the early response of colon carcinoma to the chemotherapeutic drug, lipo-Dox, in C26 murine colorectal carcinoma-bearing mice by -FDG and -FLT. The male BALB/c mice were bilaterally inoculated with and C26 tumor cells per flank. Mice were intravenously treated with 10 mg/kg lipo-Dox at day 8 after -FDG and -FLT imaging. The biodistribution of -FDG and -FLT were followed by the microPET imaging at day 9. For the quantitative measurement of microPET imaging at day 9, -FLT was superior to -FDG for early detection of tumor response to Lipo-DOX at various tumor sizes (). The data of biodistribution showed similar results with those from the quantification of SUV (standard uptake value) by microPET imaging. The study indicates that -FLT/microPET is a useful imaging modality for early detection of chemotherapy in the colorectal mouse model.
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Luput, Lavinia, Emilia Licarete, Denise Minerva Drotar, et al. "In Vivo Double Targeting of C26 Colon Carcinoma Cells and Microenvironmental Protumor Processes Using Liposomal Simvastatin." Journal of Cancer 9, no. 2 (2018): 440–49. http://dx.doi.org/10.7150/jca.21560.
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Patras, Laura, Alina Sesarman, Emilia Licarete, et al. "Dual role of macrophages in the response of C26 colon carcinoma cells to 5-fluorouracil administration." Oncology Letters 12, no. 2 (2016): 1183–91. http://dx.doi.org/10.3892/ol.2016.4708.
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Morozova, N. B., E. A. Plotnikova, A. D. Plyutinskaya, et al. "Preclinical trial of Bacteriosens used for the photodynamic therapyof malignant tumors, including prostate cancer." Russian Journal of Biotherapy 17, no. 3 (2018): 55–64. http://dx.doi.org/10.17650/1726-9784-2018-17-3-55-64.
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Introduction.Bacteriochlorins are the most promising photosensitizers absorbing in the near-infrared spectral region. Their use can enhance the efficiency of photodynamic therapy due to the deeper penetration of radiation into the tumor.Objectiveto conduct a preclinical study of the photoinduced antitumor activity and biodistribution of Bacteriosens.Materials and methods.Bacteriosens is a preparation based on meso-tetra(3-pyridyl)bacteriochlorin absorbing at 747 nm. Photoinduced cytotoxicity was investigated in vitro using human tumor cells: A549, Hep 2, BT-474, MCF-7, SK-BR-3, PC3, and EJ and murine tumor cells: S37, C26, and LLC. In vivo studies were performed in mice with large and small tumors (S37, LLC, and C26).Results.In vitro investigation show that bacteriosens during optical irradiation led to the effective suppression of tumor cell growth in culture (the IC50 value varied from 0,08μМ to 1,21 μМ) and had no toxicity without exposure to light. The effective photodynamic therapy regimen using Bacteriosens in mice with inoculated small and large tumors of different genesis resulted in regression of a primary tumor node on 90–100 % of the animals in the absence of tumor recurrence within 90 days after treatment.Conclusion.Bacteriosens is a promising agent for the photodynamic therapy of small and large tumors; it can be successfully used as an alternative, organ-sparing minimally invasive treatment for malignant tumors, including prostate cancer.
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Kobayashi, Scott D., and Marek M. Nagiec. "Ceramide/Long-Chain Base Phosphate Rheostat in Saccharomyces cerevisiae: Regulation of Ceramide Synthesis by Elo3p and Cka2p." Eukaryotic Cell 2, no. 2 (2003): 284–94. http://dx.doi.org/10.1128/ec.2.2.284-294.2003.
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ABSTRACT Sphingolipid precursors, namely, ceramide and long-chain base phosphates (LCBPs), are important growth regulators with often opposite effects on mammalian cells. A set of enzymes that regulate the levels of these precursors, referred to as a ceramide/LCBP rheostat, is conserved in all eukaryotes. In order to gain further insight into the function of the rheostat in Saccharomyces cerevisiae, we searched for mutants that are synthetically lethal with a deletion of the LCB3 gene encoding LCBP phosphatase. In addition to acquiring expected mutants lacking the LCBP lyase, the screen revealed elo3 (sur4) mutants that were defective in fatty acid elongation and cka2 mutants lacking the α′ subunit of the protein kinase CK2 (casein kinase). Both mutations affected the in vivo activity of the acyl coenzyme A (acyl-CoA)-dependent and fumonisin B1-sensitive ceramide synthase (CS). The Elo3 protein is necessary for synthesis of C26-CoA, which in wild-type yeast is a source of C26 fatty acyls found in the ceramide moieties of all sphingolipids. In the in vitro assay, CS had a strong preference for acyl-CoAs containing longer acyl chains. This finding suggests that a block in the formation of C26-CoA in yeast may cause a reduction in the conversion of LCBs into ceramides and lead to an overaccumulation of LCBPs that is lethal in strains lacking the Lcb3 phosphatase. In fact, elo3 mutants were found to accumulate high levels of LCBs and LCBPs. The cka2 mutants, on the other hand, exhibited only 25 to 30% of the in vitro CS activity found in wild-type membranes, indicating that the α′ subunit of CK2 kinase is necessary for full activation of CS. The cka2 mutants also accumulated high levels of LCBs and had elevated levels of LCBPs. In addition, both the elo3 and cka2 mutants showed increased sensitivity to the CS inhibitors australifungin and fumonisin B1. Together, our data demonstrate that the levels of LCBPs in yeast are regulated by the rate of ceramide synthesis, which depends on CK2 kinase activity and is also strongly affected by the supply of C26-CoA. This is the first evidence indicating the involvement of protein kinase in the regulation of de novo sphingolipid synthesis in any organism.
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Massart, Isabelle S., Geneviève Paulissen, Audrey Loumaye, et al. "Marked Increased Production of Acute Phase Reactants by Skeletal Muscle during Cancer Cachexia." Cancers 12, no. 11 (2020): 3221. http://dx.doi.org/10.3390/cancers12113221.
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Loss of skeletal muscle mass in cancer cachexia is recognized as a predictor of mortality. This study aimed to characterize the changes in the muscle secretome associated with cancer cachexia to gain a better understanding of the mechanisms involved and to identify secreted proteins which may reflect this wasting process. The changes in the muscle proteome of the C26 model were investigated by label-free proteomic analysis followed by a bioinformatic analysis in order to identify potentially secreted proteins. Multiple reaction monitoring and Western blotting were used to verify the presence of candidate proteins in the circulation. Our results revealed a marked increased muscular production of several acute phase reactants (APR: Haptoglobin, Serine protease inhibitor A3N, Complement C3, Serum amyloid A-1 protein) which are released in the circulation during C26 cancer cachexia. This was confirmed in other models of cancer cachexia as well as in cancer patients. Glucocorticoids and proinflammatory cytokines are responsible for an increased production of APR by muscle cells. Finally, their muscular expressions are strongly positively correlated with body weight loss as well as the muscular induction of atrogens. Our study demonstrates therefore a marked increased production of APR by the muscle in cancer cachexia.
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Pierron, Alix, Laurence Guzylack-Piriou, Didier Tardieu, Gilles Foucras, and Philippe Guerre. "Zymosan-Induced Murine Peritonitis Is Associated with an Increased Sphingolipid Synthesis without Changing the Long to Very Long Chain Ceramide Ratio." International Journal of Molecular Sciences 24, no. 3 (2023): 2773. http://dx.doi.org/10.3390/ijms24032773.
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Sphingolipids are key molecules in inflammation and defense against pathogens. Their role in dectin-1/TLR2-mediated responses is, however, poorly understood. This study investigated the sphingolipidome in the peritoneal fluid, peritoneal cells, plasma, and spleens of mice after intraperitoneal injection of 0.1 mg zymosan/mouse or PBS as a control. Samples were collected at 2, 4, 8, and 16 h post-injection, using a total of 36 mice. Flow cytometry analysis of peritoneal cells and measurement of IL-6, IL-1β, and TNF-α levels in the peritoneal lavages confirmed zymosan-induced peritonitis. The concentrations of sphingoid bases, dihydroceramides, ceramides, dihydrosphingomyelins, sphingomyelins, monohexosylceramides, and lactosylceramides were increased after zymosan administration, and the effects varied with the time and the matrix measured. The greatest changes occurred in peritoneal cells, followed by peritoneal fluid, at 8 h and 4 h post-injection, respectively. Analysis of the sphingolipidome suggests that zymosan increased the de novo synthesis of sphingolipids without change in the C14–C18:C20–C26 ceramide ratio. At 16 h post-injection, glycosylceramides remained higher in treated than in control mice. A minor effect of zymosan was observed in plasma, whereas sphinganine, dihydrosphingomyelins, and monohexosylceramides were significantly increased in the spleen 16 h post-injection. The consequences of the observed changes in the sphingolipidome remain to be established.
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Naito, Masako, Kazuki Omoteyama, Yoshikazu Mikami, Tomihisa Takahashi та Minoru Takagi. "Inhibition of Wnt/β-catenin signaling by dexamethasone promotes adipocyte differentiation in mesenchymal progenitor cells, ROB-C26". Histochemistry and Cell Biology 138, № 6 (2012): 833–45. http://dx.doi.org/10.1007/s00418-012-1007-3.
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