Krü ppel-like factor 4 (KLF4) is an evolutionarily conserved zinc finger-containing transcription factor with diverse regulatory functions in cell growth, proliferation, differentiation, and embryogenesis. However, little is known about the response of KLF4 to heat stress. In this study, Western blot and reverse transcriptase-polymerase chain reaction were performed to determine the changes in KLF4 expression in response to heat stress. The results showed that heat stress up-regulated KLF4 messenger RNA and protein levels in a time-dependent manner in vivo and in 4 cell lines. Moreover, a study with heat shock transcription factor 1 (Hsf1) gene knockout mice indicated that the induction of KLF4 in response to heat stress was mediated by Hsf1. This process occurred rapidly, indicating that KLF4 is an immediate early response gene of heat stress. Next, the roles of KLF4 under heat stress conditions were analyzed for cells overexpressing or deficient in KLF4. The results showed overexpression of KLF4 increased the death rate of C 2 C 12 cells, whereas KLF4 deficiency decreased the injury of C 2 C 12 cells from heat stress conditions, suggesting that KLF4 might play an important role in cell injury induced by heat stress. KLF4 might be an immediate early response gene and could play an important role in cell injury induced by heat stress.
Aquaporin-3 (AQP3), a water/glycerol-transporting protein that facilitates water, urea, and glycerol transport, can inhibit arsenite-induced apoptosis by up-regulating Bcl-2. However, whether it has a protective role in ultraviolet A (UVA)-induced apoptosis in normal human skin fibroblasts is not known. In this study, we demonstrate that mild UVA treatment fails to induce oxidative cell stress and apoptosis in normal human skin fibroblasts (NHSFs) overexpressing AQP3. After severe UVA irradiation, there was an increase in oxidative cell stress and apoptosis when AQP3 levels decreased. We also found that silencing AQP3 sensitized NHSFs to low-dose UVA. Overexpressing AQP3 was protective against high-dose UVA-induced oxidative stress and apoptosis. Besides, we observed that Bcl-2 may be involved in UVA-induced apoptosis. Our findings suggested that the water/glycerol-transporting protein AQP3 plays a role in resistance to UVA-induced apoptosis.
The growing concerns about human pollution has motivated practitioners and researchers to focus on the environmental and social impacts of logistics and supply chains. In this paper, we consider the environmental impact of carbon dioxide emission on a vehicle routing problem with multiple depots. We present a hybrid evolutionary algorithm (HEA) to tackle it by combining a variable neighborhood search and an evolutionary algorithm. The proposed hybrid evolutionary algorithm includes several distinct features such as multiple neighborhood operators, a route-based crossover operator, and a distance- and quality-based population updating strategy. The results from our numerical experiments confirm the effectiveness and superiority of the proposed HEA in comparison with the best-performing methods in the literature and the public exact optimization solver CPLEX. Furthermore, an important aspect of the HEA is studied to assess its effect on the performance of the HEA.
It has been reported that nucleolar fragmentation is a part of the overall apoptotic morphology, however, it is currently obscure whether and how nucleolar fragmentation can be induced by hydrogen peroxide (H 2 O 2 ) and heat shock protein 70 (Hsp70) can prevent nucleolar fragmentation. To dissect these two questions, C 2 C 12 myogenic cells and immortalized mouse embryonic fibroblasts (MEFs) with heat shock transcriptional factor 1 (HSF1) null mutation were treated with heat shock response (HS) (42.5±0.5°C for 1 h and recovery at 37°C for 24 h) and then were insulted with 0.5 mmol/L H 2 O 2 . Morphological changes of nucleoli were observed under contrast microscope or electronic microscope. It was found that (1) stimulation with H 2 O 2 -induced nucleolar fragmentation by mediating cleavage and down-regulation of nucleolar protein, nucleolin in C 2 C 12 myocytes and MEFs; (2) HS suppressed nucleolar fragmentation by inducing the expression of Hsp70 in an HSF1-dependent manner as indicated by assays of transfection with Hsp70 antisense oligonucleotides (AS-ONs) or recombinant plasmids of full-length Hsp70 cDNA; (3) protection of Hsp70 against nucleolar fragmentation was related to its accumulation in nucleolus mediated by nuclear localization sequence and its inhibition against cleavage and down-regulation of nucleolin. These results suggested that H 2 O 2 -induced nucleolar fragmentation and HS or Hsp70 inhibit H 2 O 2 -induced nucleolar fragmentation through the translocation of Hsp70 into nucleolar and its protection against impairment of nucleolin.
In this study, we report the role of DNA methyltransferase 1 (DNMT1) in ultraviolet A (UVA)-induced senescence in human dermal fibroblasts (HDFs). We show that DNMT1 expression was significantly reduced during UVA-induced senescence, and this senescence could be alleviated or aggravated by the up- or down-regulation of DNMT1, respectively. Expression of the transcription factor zinc finger E-box binding homeobox 1(ZEB1) also decreased after UVA irradiation, following a UVA-induced increase of intracellular reactive oxygen species (ROS). We show that ZEB1 binds to the DMNT1 promoter and regulates its transcription, which, in turn, affects cellular senescence. These changes in DMNT1 and ZEB1 expression following UVA exposure were confirmed in matched skin specimens that had or had not been sun-exposed. On analyzing the promoter methylation of 24 senescence associated genes in these matched skin specimens, we discovered that p53 promoter methylation was significantly reduced in sun-exposed skin. In vitro experiments confirmed that UVA irradiation reduced p53 promoter methylation, and DNMT1 up-regulation could reverse this effect. Collectively, down-regulation of ZEB1 caused by UVA induced ROS could transcriptionally inhibit DNMT1, leading to low methylation level of senescence related proteins p53 and increase its expression, eventually result in cellar senescence.
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