scholarly journals Peripheral Neuropathy in the Twitcher Mouse Involves the Activation of Axonal Caspase 3

ASN NEURO ◽  
2011 ◽  
Vol 3 (4) ◽  
pp. AN20110019 ◽  
Author(s):  
Benjamin Smith ◽  
Francesca Galbiati ◽  
Ludovico Cantuti Castelvetri ◽  
Maria I Givogri ◽  
Aurora Lopez-Rosas ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Caspase 3 ◽  
Twitcher Mouse

Design, Synthesis and In Vitro Anti-Cancer Evaluation of Novel Derivatives of 2-(2-Methyl-1,5-diaryl-1H-pyrrol-3-yl)-2-oxo-N-(pyridin-3- yl)acetamide

2020 ◽  
Vol 16 (3) ◽  
pp. 340-349
Author(s):  
Ebrahim S. Moghadam ◽  
Farhad Saravani ◽  
Ernest Hamel ◽  
Zahra Shahsavari ◽  
Mohsen Alipour ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Peripheral Neuropathy ◽  
Cell Line ◽  
Normal Cell ◽  
Caspase 3 ◽  
Annexin V ◽  
Normal Cell Line ◽  
Anti Cancer ◽  
Mcf 7

Objective: Several anti-tubulin agents were introduced for the cancer treatment so far. Despite successes in the treatment of cancer, these agents cause toxic side effects, including peripheral neuropathy. Comparing anti-tubulin agents, indibulin seemed to cause minimal peripheral neuropathy, but its poor aqueous solubility and other potential clinical problems have led to its remaining in a preclinical stage. Methods: Herein, indibulin analogues were synthesized and evaluated for their in vitro anti-cancer activity using MTT assay (on the MCF-7, T47-D, MDA-MB231 and NIH-3T3 cell lines), annexin V/PI staining assay, cell cycle analysis, anti-tubulin assay and caspase 3/7 activation assay. Results: One of the compounds, 4a, showed good anti-proliferative activity against MCF-7 cells (IC50: 7.5 μM) and low toxicity on a normal cell line (IC50 > 100 μM). All of the tested compounds showed lower cytotoxicity on normal cell line in comparison to reference compound, indibulin. In the annexin V/PI staining assay, induction of apoptosis in the MCF-7 cell line was observed. Cell cycle analysis illustrated an increasing proportion of cells in the sub-G-1 phase, consistent with an increasing proportion of apoptotic cells. No increase in G2/M cells was observed, consistent with the absence of anti-tubulin activity. A caspase 3/7 assay protocol showed that apoptosis induction by more potent compounds was due to activation of caspase 3. Conclusion: Newly synthesized compounds exerted acceptable anticancer activity and further investigation of current scaffold would be beneficial.

Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels

2008 ◽  
Vol 115 (5) ◽  
pp. 577-587 ◽  
Author(s):  
Kuriko Kagitani-Shimono ◽  
Ikuko Mohri ◽  
Takashi Yagi ◽  
Masako Taniike ◽  
Kinuko Suzuki
Keyword(s):  
Extracellular Matrix ◽  
Peripheral Neuropathy ◽  
Ion Channels ◽  
Twitcher Mouse ◽  
Aberrant Expression

scholarly journals Glutathione Ameliorates Bortezomib (Velcade) -Induced Neuronal Toxicity in N2a and SHSY5Y Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5863-5863
Author(s):  
Jinny Park ◽  
Lalita Subedi ◽  
Su Jung Park ◽  
Oh kyung Lim ◽  
ChanJong Yoo ◽  
...  
Keyword(s):  
Cell Death ◽  
Peripheral Neuropathy ◽  
Cell Survival ◽  
Caspase 3 ◽  
Conflicts Of Interest ◽  
Neuronal Cells ◽  
Lactate Dehydrogenase Activity ◽  
Bortezomib Treatment ◽  
Neuronal Toxicity ◽  
Apoptotic Proteins

Abstract Bortezomib (Velcade, Millennium Pharmaceuticals, Inc.), a potent proteasome inhibitor, is a boronic acid dipeptide that induce cancer cell death. It is an effective drug for both newly diagnosed or relapsed multiple myeloma (MM) patients and is widely used in the treatment of various kinds of lymphomas and other diseases. Peripheral nerve damage is one of the most significant nonhematologic toxicities of bortezomib. The reported incidence of bortezomib-induced peripheral neuropathy (BIPN) ranges from 25 to 75 % . When it occurs, the painful sensory neuropathy can interfere with quality of life (QOL) and with performance of activities of daily living, and it may also adversely affect clinical outcomes by forcing dose modification and/or premature treatment discontinuation. Therefore there are many efforts to improve multiple symptoms associated with BIPN. But there are no reports on amelioration of neurotoxicity which occurred in patients with treatment of bortezomib .Therefore control of this toxicity by the concomitant use of other safe candidates can make it a better option for the cancer therapy with bortezomib. Glutathione (GSH) is a substance produced naturally by the liver and it is also found in fruits, vegetables, and meats. GSH is an important antioxidant and capable of preventing damage to important cellular components caused by reactive oxygen species (ROS) such as free radicals, peroxides, lipid peroxides, and heavy metals. Several small randomized trials have addressed the protective effect of GSH against chemotherapy induced peripheral neuropathy (CIPN )with a platinum agent . In this study we observed that treatment of GSH either in the pre-treatment or in the post treatment inhibited the bortezomib -induced neuronal cell death in both mouse neuronal cells (N2a) as well as dopaminergic neuron of human origin (SHSY5Y). Bortezomib treatment at the concentration of 100 and 200 µg/ml significantly increased the cell death with increased lactate dehydrogenase activity (LDH) and increased apoptotic proteins expressions in the 24 h of treatment of both cells. GSH treatment (1 mg/ml) not only inhibited the bortezomib -induced cell death but also inhibited the LDH activity, suggesting that GSH ameliorates bortezomib -induced neuronal toxicity. A clear activation of the autophagy was also observed in the bortezomib treatment that was lowered by the GSH treatment. In addition to this inhibition of the apoptotic proteins specially Cleaved caspase 3 was observed in the neuronal cells and also the increased Bcl2 and NRF2 protein which are responsible for the cell survival was upregulated with GSH treatment suggesting that GSH increase the cell survival against bortezomib -induced neurotoxicity. Inhibition of the cleaved caspase-3, Bax and LC3 protein are prominent in SHSY5Y cells while activation of the BCL2 and NRF2 is more significant in N2a cells. To elucidate the role of GSH in the development and maintenance of bortezomib -induced neurotoxicity, we will additionally assess ROS and antioxidant enzyme activity levels in the cellular system. This research suggests that GSH ameliorates BIPN and thus can improve the QOL and increase the survival rate of patients treated with bortezomib. Disclosures No relevant conflicts of interest to declare.

scholarly journals TXNIP, a novel key factor to cause Schwann cell dysfunction in diabetic peripheral neuropathy, under the regulation of PI3K/Akt pathway inhibition-induced DNMT1 and DNMT3a overexpression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Xiang Zhang ◽  
Song Zhao ◽  
Qingqing Yuan ◽  
Lin Zhu ◽  
Fan Li ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Schwann Cell ◽  
Schwann Cells ◽  
High Glucose ◽  
Diabetic Peripheral Neuropathy ◽  
Caspase 3 ◽  
Akt Pathway ◽  
Diabetic Mice ◽  
Sciatic Nerves ◽  
Pathway Inhibition

AbstractDiabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM) and the dysfunction of Schwann cells plays an important role in the pathogenesis of DPN. Thioredoxin-interacting protein (TXNIP) is known as an inhibitor of thioredoxin and associated with oxidative stress and inflammation. However, whether TXNIP is involved in dysfunction of Schwann cells of DPN and the exact mechanism is still not known. In this study, we first reported that TXNIP expression was significantly increased in the sciatic nerves of diabetic mice, accompanied by abnormal electrophysiological indexes and myelin sheath structure. Similarly, in vitro cultured Schwann cells TXNIP was evidently enhanced by high glucose stimulation. Again, the function experiment found that knockdown of TXNIP in high glucose-treated RSC96 cells led to a 4.12 times increase of LC3-II/LC3-I ratio and a 25.94% decrease of cleaved caspase 3/total caspase 3 ratio. Then, DNA methyltransferase (DNMT) inhibitor 5-Aza has been reported to benefit Schwann cell in DPN, and here 5-Aza treatment reduced TXNIP protein expression, improved autophagy and inhibited apoptosis in high glucose-treated RSC96 cells and the sciatic nerves of diabetic mice. Furthermore, DNMT1 and DNMT3a upregulation were found to be involved in TXNIP overexpression in high glucose-stimulated RSC96 cells. Silencing of DNMT1 and DNMT3a effectively reversed high glucose-enhanced TXNIP. Moreover, high glucose-inhibited PI3K/Akt pathway led to DNMT1, DNMT3a, and TXNIP upregulation in RSC96 cells. Knockdown of DNMT1 and DNMT3a prevented PI3K/Akt pathway inhibition-caused TXNIP upregulation in RSC96 cells. Finally, in vivo knockout of TXNIP improved nerve conduction function, increased autophagosome and LC3 expression, and decreased cleaved Caspase 3 and Bax expression in diabetic mice. Taken together, PI3K/Akt pathway inhibition mediated high glucose-induced DNMT1 and DNMT3a overexpression, leading to cell autophagy inhibition and apoptosis via TXNIP protein upregulation in Schwann cells of DPN.

FT-IR microspectroscopic analysis of diseased white matter brain tissues

1995 ◽  
Vol 53 ◽  
pp. 968-969
Author(s):  
Steven M. Le Vine ◽  
David L. Wetzel
Keyword(s):  
White Matter ◽  
Gray Matter ◽  
Twitcher Mouse ◽  
Grid Pattern ◽  
Marked Contrast ◽  
Spatially Resolved ◽  
Ft Ir ◽  
Ir Microspectroscopy ◽  
Chemical Evidence

In situ FT-IR microspectroscopy has allowed spatially resolved interrogation of different parts of brain tissue. In previous work the spectrrscopic features of normal barin tissue were characterized. The white matter, gray matter and basal ganglia were mapped from appropriate peak area measurements from spectra obtained in a grid pattern. Bands prevalent in white matter were mostly associated with the lipid. These included 2927 and 1469 cm-1 due to CH2 as well as carbonyl at 1740 cm-1. Also 1235 and 1085 cm-1 due to phospholipid and galactocerebroside, respectively (Figs 1and2). Localized chemical changes in the white matter as a result of white matter diseases have been studied. This involved the documentation of localized chemical evidence of demyelination in shiverer mice in which the spectra of white matter lacked the marked contrast between it and gray matter exhibited in the white matter of normal mice (Fig. 3).The twitcher mouse, a model of Krabbe’s desease, was also studied. The purpose in this case was to look for a localized build-up of psychosine in the white matter caused by deficiencies in the enzyme responsible for its breakdown under normal conditions.

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