scholarly journals A spontaneously immortalized Schwann cell line from aldose reductase-deficient mice as a useful tool for studying polyol pathway and aldehyde metabolism

2018 ◽  
Vol 144 (6) ◽  
pp. 710-722 ◽  
Author(s):  
Naoko Niimi ◽  
Hideji Yako ◽  
Shizuka Takaku ◽  
Hiroshi Kato ◽  
Takafumi Matsumoto ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Cell Line ◽  
Aldose Reductase ◽  
Polyol Pathway ◽  
Deficient Mice

scholarly journals Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems

2021 ◽  
Vol 22 (3) ◽  
pp. 1031
Author(s):  
Naoko Niimi ◽  
Hideji Yako ◽  
Shizuka Takaku ◽  
Sookja K. Chung ◽  
Kazunori Sango
Keyword(s):  
Schwann Cells ◽  
Aldose Reductase ◽  
Critical Role ◽  
Polyol Pathway ◽  
Glucose Flux ◽  
Rate Limiting ◽  
Deficient Mice ◽  
Excess Glucose ◽  
Shed Light ◽  
Immortalized Schwann Cells

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.

Gedunin, A Neem Limonoid in Combination with Epalrestat Inhibits Cancer Hallmarks by Attenuating Aldose Reductase-Driven Oncogenic Signaling in SCC131 Oral Cancer Cells

2019 ◽  
Vol 18 (14) ◽  
pp. 2042-2052 ◽  
Author(s):  
Kranthi K.K. Tanagala ◽  
Abdul B. Baba ◽  
Jaganathan Kowshik ◽  
Geereddy B. Reddy ◽  
Siddavaram Nagini
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Oral Cancer ◽  
Cell Line ◽  
Aldose Reductase ◽  
Cancer Cell Line ◽  
Polyol Pathway ◽  
Ros Generation ◽  
Subcellular Localisation ◽  
Oncogenic Signaling

Background and Objectives: Aldose Reductase (AR), a polyol pathway enzyme that mediates diabetic complications is implicated in tumour development and progression. This study was undertaken to determine whether gedunin, a neem limonoid prevents the hallmarks of cancer by inhibiting AR and the associated downstream PI3K/Akt/mTOR/ERK/NF-κB signalling axis in the SCC131 oral cancer cell line. Methods: The expression of AR and key molecules involved in cell proliferation, apoptosis, autophagy, invasion and angiogenesis was analysed by qRT-PCR, and immunoblotting. ROS generation and cell cycle were analysed by FACS. Alamar blue assay and scratch assay were used to evaluate cell proliferation and migration in the endothelial cell line Eahy926. Results: Gedunin and the AR inhibitor epalrestat inhibited AR expression and ROS generation. Cell cycle arrest at G1/S was associated with cell death by autophagy with subsequent switch over to apoptosis. Furthermore, hypoxia-induced cell migration was inhibited in Eahy926 cells with downregulation of pro-invasive and proangiogenic proteins in SCC131 as well as Eahy926 cells. Co-inactivation of Akt and ERK was coupled with abrogation of IKK/NF-κB signaling. However, the combination of gedunin and epalrestat was more effective than single agents. Conclusion: Inhibition of AR-mediated ROS signalling may be a key mechanism by which gedunin and epalrestat exert their anticancer effects. Our results provide compelling evidence that the combination of gedunin and epalrestat modulates expression of key oncogenic signalling kinases and transcription factors primarily by influencing phosphorylation and subcellular localisation. AR inhibitors such as gedunin and epalrestat are novel candidate agents for cancer prevention and therapy.

Polyol pathway and osmoregulation in JS1 Schwann cells grown in hyperglycemic and hyperosmotic conditions

1996 ◽  
Vol 270 (1) ◽  
pp. F90-F97
Author(s):  
A. P. Mizisin ◽  
L. Li ◽  
M. Perello ◽  
J. D. Freshwater ◽  
M. W. Kalichman ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Osmotic Stress ◽  
Schwann Cells ◽  
Aldose Reductase ◽  
Polyol Pathway ◽  
Cell Number ◽  
Excess Glucose ◽  
Cells Cultured

To test the osmoregulatory rules of Schwann cell aldose reductase (AR) and myo-inositol, JS1 Schwann cells were grown under control and hyperosmotic conditions with and without excess glucose or galactose. JS1 cells cultured in control conditions possessed AR protein and activity that were not altered by the inclusion of 25 mM glucose or galactose. Following culture with 100 mM NaCl, there was a decline in cell number accompanied by an increase in AR activity, both of which were attenuated by the addition of 25 mM glucose or galactose. Sorbitol was not detected in JS1 Schwann cells following culture in control, glucose-supplemented, or hyperosmotic medium, and dulcitol accumulated only following culture with galactose. However, both polyols were dramatically increased in JS1 cells cultured in hyperosmotic medium supplemented with 25 mM glucose or galactose. In contrast, myo-inositol levels were elevated only during hyperosmotic exposure but decreased when glucose or galactose was also present. These data are consistent with the use of polyol formation by JS1 Schwann cells as a means of responding to osmotic stress.

scholarly journals Transposon Mutagenesis-Guided CRISPR/Cas9 Screening Strongly Implicates Dysregulation of Hippo/YAP Signaling in Malignant Peripheral Nerve Sheath Tumor Development

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1584
Author(s):  
Germán L. Vélez-Reyes ◽  
Nicholas Koes ◽  
Ji Hae Ryu ◽  
Gabriel Kaufmann ◽  
Mariah Berner ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Schwann Cell ◽  
Peripheral Nerve ◽  
Cell Line ◽  
Schwann Cells ◽  
Tumor Suppressor Genes ◽  
Tumor Formation ◽  
Loss Of Function ◽  
Suppressor Genes ◽  
Nerve Sheath

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive, genomically complex, have soft tissue sarcomas, and are derived from the Schwann cell lineage. Patients with neurofibromatosis type 1 syndrome (NF1), an autosomal dominant tumor predisposition syndrome, are at a high risk for MPNSTs, which usually develop from pre-existing benign Schwann cell tumors called plexiform neurofibromas. NF1 is characterized by loss-of-function mutations in the NF1 gene, which encode neurofibromin, a Ras GTPase activating protein (GAP) and negative regulator of RasGTP-dependent signaling. In addition to bi-allelic loss of NF1, other known tumor suppressor genes include TP53, CDKN2A, SUZ12, and EED, all of which are often inactivated in the process of MPNST growth. A sleeping beauty (SB) transposon-based genetic screen for high-grade Schwann cell tumors in mice, and comparative genomics, implicated Wnt/β-catenin, PI3K-AKT-mTOR, and other pathways in MPNST development and progression. We endeavored to more systematically test genes and pathways implicated by our SB screen in mice, i.e., in a human immortalized Schwann cell-based model and a human MPNST cell line, using CRISPR/Cas9 technology. We individually induced loss-of-function mutations in 103 tumor suppressor genes (TSG) and oncogene candidates. We assessed anchorage-independent growth, transwell migration, and for a subset of genes, tumor formation in vivo. When tested in a loss-of-function fashion, about 60% of all TSG candidates resulted in the transformation of immortalized human Schwann cells, whereas 30% of oncogene candidates resulted in growth arrest in a MPNST cell line. Individual loss-of-function mutations in the TAOK1, GDI2, NF1, and APC genes resulted in transformation of immortalized human Schwann cells and tumor formation in a xenograft model. Moreover, the loss of all four of these genes resulted in activation of Hippo/Yes Activated Protein (YAP) signaling. By combining SB transposon mutagenesis and CRISPR/Cas9 screening, we established a useful pipeline for the validation of MPNST pathways and genes. Our results suggest that the functional genetic landscape of human MPNST is complex and implicate the Hippo/YAP pathway in the transformation of neurofibromas. It is thus imperative to functionally validate individual cancer genes and pathways using human cell-based models, to determinate their role in different stages of MPNST development, growth, and/or metastasis.

Dexamethasone Inhibits the Growth of a Uterine Cell Line Derived from p53-Deficient Mice

1998 ◽  
Vol 15 (2) ◽  
pp. 277-281 ◽  
Author(s):  
Makoto Hanazono ◽  
Kengo Moro ◽  
Yasuhiro Tomooka
Keyword(s):  
Cell Line ◽  
Deficient Mice

scholarly journals Protective Pleiotropic Effect of Flavonoids on NAD+Levels in Endothelial Cells Exposed to High Glucose

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Daniëlle M. P. H. J. Boesten ◽  
Saskia N. I. von Ungern-Sternberg ◽  
Gertjan J. M. den Hartog ◽  
Aalt Bast
Keyword(s):  
Endothelial Cells ◽  
Enzyme Activity ◽  
Aldose Reductase ◽  
High Glucose ◽  
Umbilical Vein ◽  
Polyol Pathway ◽  
Pleiotropic Effect ◽  
Protective Role ◽  
Parp Activation

NAD+is important for oxidative metabolism by serving as an electron transporter. Hyperglycemia decreases NAD+levels by activation of the polyol pathway and by overactivation of poly(ADP-ribose)-polymerase (PARP). We examined the protective role of three structurally related flavonoids (rutin, quercetin, and flavone) during high glucose conditions in anin vitromodel using human umbilical vein endothelial cells (HUVECs). Additionally we assessed the ability of these flavonoids to inhibit aldose reductase enzyme activity. We have previously shown that flavonoids can inhibit PARP activation. Extending these studies, we here provide evidence that flavonoids are also able to protect endothelial cells against a high glucose induced decrease in NAD+. In addition, we established that flavonoids are able to inhibit aldose reductase, the key enzyme in the polyol pathway. We conclude that this protective effect of flavonoids on NAD+levels is a combination of the flavonoids ability to inhibit both PARP activation and aldose reductase enzyme activity. This study shows that flavonoids, by a combination of effects, maintain the redox state of the cell during hyperglycemia. This mode of action enables flavonoids to ameliorate diabetic complications.

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