One of the most common issues caused by antineoplastic agents is chemotherapy-induced peripheral neuropathy (CIPN). In patients, CIPN is a sensory neuropathy accompanied by various motor and autonomic changes. With a high prevalence of cancer patients, CIPN is becoming a major problem for both cancer patients and for their health care providers. Nonetheless, there are lacking effective interventions preventing CIPN and treating the CIPN symptoms. A number of studies have demonstrated the cellular and molecular signaling pathways leading to CIPN using experimental models and the beneficial effects of some interventions on the CIPN symptoms related to those potential mechanisms. This review will summarize results obtained from recent human and animal studies, which include the abnormalities in mechanical and temperature sensory responses following chemotherapy such as representative bortezomib, oxaliplatin and paclitaxel. The underlying mechanisms of CIPN at cellular and molecular levels will be also discussed for additional in-depth studies needed to be better explored. Overall, this paper reviews the basic picture of CIPN and the signaling mechanisms of the most common antineoplastic agents in the peripheral and central nerve systems. A better understanding of the risk factors and fundamental mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.
BACKGROUND AND PURPOSE: Characterization of iron deposition associated with demyelinating lesions of multiple sclerosis and neuromyelitis optica has not been well studied. Our aim was to investigate the potential of ultra-high-field MR imaging to distinguish MS from neuromyelitis optica and to characterize tissue injury associated with iron pathology within lesions. MATERIALS AND METHODS: Twenty-one patients with MS and 21 patients with neuromyelitis optica underwent 7T high-resolution 2D-gradient-echo-T2* and 3D-susceptibility-weighted imaging. An in-house-developed algorithm was used to reconstruct quantitative susceptibility mapping from SWI. Lesions were classified as "iron-laden" if they demonstrated hypointensity on gradient-echo-T2*-weighted images and/or SWI and hyperintensity on quantitative susceptibility mapping. Lesions were considered "non-iron-laden" if they were hyperintense on gradient-echo-T2* and isointense or hyperintense on quantitative susceptibility mapping. RESULTS: Of 21 patients with MS, 19 (90.5%) demonstrated at least 1 quantitative susceptibility mapping-hyperintense lesion, and 11/21 (52.4%) had iron-laden lesions. No quantitative susceptibility mapping-hyperintense or iron-laden lesions were observed in any patients with neuromyelitis optica. Iron-laden and non-iron-laden lesions could each be further characterized into 2 distinct patterns based on lesion signal and morphology on gradient-echo-T2*/SWI and quantitative susceptibility mapping. In MS, most lesions (n = 262, 75.9% of all lesions) were hyperintense on gradient-echo T2* and isointense on quantitative susceptibility mapping (pattern A), while a small minority (n = 26, 7.5% of all lesions) were hyperintense on both gradient-echo-T2* and quantitative susceptibility mapping (pattern B). Iron-laden lesions (n = 57, 16.5% of all lesions) were further classified as nodular (n = 22, 6.4%, pattern C) or ringlike (n = 35, 10.1%, pattern D). CONCLUSIONS: Ultra-high-field MR imaging may be useful in distinguishing MS from neuromyelitis optica. Different patterns related to iron and noniron pathology may provide in vivo insight into the pathophysiology of lesions in MS.
- MeSH
- algoritmy MeSH
- dítě MeSH
- dospělí MeSH
- elektromagnetická pole MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mapování mozku MeSH
- mladiství MeSH
- mladý dospělý MeSH
- neuromyelitis optica diagnostické zobrazování metabolismus MeSH
- novorozenec MeSH
- počítačové zpracování obrazu MeSH
- předškolní dítě MeSH
- roztroušená skleróza diagnostické zobrazování metabolismus MeSH
- železo metabolismus MeSH
- zobrazování trojrozměrné MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
As a novel gasotransmitter, hydrogen sulfide (H(2)S) has vasodilating and antihypertensive effects in cardiovascular system. Thus, we hypothesized that H(2)S might have beneficial effects on thoracic endothelial function in two-kidney one-clip (2K1C) rats, a model of renovascular hypertension. Sodium hydrosulfide (NaHS, 56 micromol/kg/day) was administrated intra-peritoneally from the third day after the 2K1C operation. Along with the development of hypertension, the systolic blood pressure (SBP) was measured before the operation and each week thereafter. The oxidative stress was determined by measurement of malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity and protein expression of oxidative stress-related proteins (AT(1)R, NADPH oxidase subunits). Acetylcholine (ACh)-induced vasorelaxation and angiotensin II (Ang II)-induced vasocontraction were performed on isolated thoracic aorta. The SBP was significantly increased from the first week after operation, and was lowered by NaHS. NaHS supplementation ameliorated endothelial dysfunction. The protein expression of oxidative stress-related proteins were downregulated, while SOD activity upregulated. In conclusion, improvement of endothelial function is involved in the antihypertensive mechanism of H(2)S. The protective effect of H(2)S is attributable to suppression of vascular oxidative stress that involves inhibition of Ang II-AT(1)R action, downregulation of oxidases, as well as upregulation of antioxidant enzyme.
- MeSH
- cévní endotel metabolismus patofyziologie MeSH
- krysa rodu rattus MeSH
- oxidační stres účinky léků fyziologie MeSH
- potkani Sprague-Dawley MeSH
- renovaskulární hypertenze krev farmakoterapie patofyziologie MeSH
- sulfan krev MeSH
- sulfidy farmakologie terapeutické užití MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
TopBP1 and Claspin are adaptor proteins that facilitate phosphorylation of Chk1 by the ATR kinase in response to genotoxic stress. Despite their established requirement for Chk1 activation, the exact way in which TopBP1 and Claspin control Chk1 phosphorylation remains unclear. We show that TopBP1 tightly colocalizes with ATR in distinct nuclear subcompartments generated by DNA damage. Although depletion of TopBP1 by RNA interference (RNAi) strongly impaired phosphorylation of multiple ATR targets, including Chk1, Nbs1, Smc1, and H2AX, it did not interfere with ATR assembly at the sites of DNA damage. These findings challenge the current concept of ATR activation by recruitment to damaged DNA. In contrast, Claspin, like Chk1, remained distributed throughout the nucleus both before and after DNA damage. Consistently, the RNAi-mediated ablation of Claspin selectively abrogated ATR's ability to phosphorylate Chk1 but not other ATR targets. In addition, downregulation of Claspin mimicked Chk1 inactivation by inducing spontaneous DNA damage. Finally, we show that TopBP1 is required for the DNA damage-induced interaction between Claspin and Chk1. Together, these results suggest that while TopBP1 is a general regulator of ATR, Claspin operates downstream of TopBP1 to selectively regulate the Chk1-controlled branch of the genotoxic stress response.
- MeSH
- adaptorové proteiny signální transdukční * metabolismus MeSH
- aktivace enzymů MeSH
- ATM protein MeSH
- DNA vazebné proteiny MeSH
- down regulace genetika MeSH
- fenotyp MeSH
- fosforylace MeSH
- jaderné proteiny MeSH
- lidé MeSH
- modely genetické MeSH
- nádorové buňky kultivované MeSH
- poškození DNA genetika MeSH
- protein-serin-threoninkinasy * metabolismus MeSH
- proteinkinasy * metabolismus MeSH
- proteiny buněčného cyklu * metabolismus MeSH
- replikace DNA genetika MeSH
- RNA interference MeSH
- signální transdukce * MeSH
- transportní proteiny * metabolismus MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
