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Enhanced DNA double-strand break repair of microbeam targeted A549 lung carcinoma cells by adjacent WI38 normal lung fibroblast cells via bi-directional signaling

Kobayashi A, Tengku Ahmad TAF, Autsavapromporn N, Oikawa M, Homma-Takeda S, Furusawa Y, et al.

Mutat Res, 2017 10;803-805:1-8.
PMID: 28689138 DOI: 10.1016/j.mrfmmm.2017.06.006

Understanding the mechanisms underlying the radiation-induced bystander effect (RIBE) and bi-directional signaling between irradiated carcinoma cells and their surrounding non-irradiated normal cells is relevant to cancer radiotherapy. The present study investigated propagation of RIBE signals between human lung carcinoma A549 cells and normal lung fibroblast WI38 cells in bystander cells, either directly or indirectly contacting irradiated A549 cells. We prepared A549-GFP/WI38 co-cultures and A549-GFP/A549 co-cultures, in which A549-GFP cells stably expressing H2BGFP were co-cultured with either A549 cells or WI38 cells, respectively. Using the SPICE-NIRS microbeam, only the A549-GFP cells were irradiated with 500 protons per cell. The level of γ-H2AX, a marker for DNA double-strand breaks (DSB), was subsequently measured for up to 24h post-irradiation in three categories of cells: (1) "targeted"/irradiated A549-GFP cells; (2) "neighboring"/non-irradiated cells directly contacting the "targeted" cells; and (3) "distant"/non-irradiated cells, which were not in direct contact with the "targeted" cells. We found that DSB repair in targeted A549-GFP cells was enhanced by co-cultured WI38 cells. The bystander response in A549-GFP/A549 cell co-cultures, as marked by γ-H2AX levels at 8h post-irradiation, showed a decrease to non-irradiated control level when approaching 24h, while the neighboring/distant bystander WI38 cells in A549-GFP/WI38 co-cultures was maintained at a similar level until 24h post-irradiation. Surprisingly, distant A549-GFP cells in A549-GFP/WI38 co-cultures showed time dependency similar to bystander WI38 cells, but not to distant cells in A549-GFP/A549 co-cultures. These observations indicate that γ-H2AX was induced in WI38 cells as a result of RIBE. WI38 cells were not only involved in rescue of targeted A549, but also in the modification of RIBE against distant A549-GFP cells. The present results demonstrate that radiation-induced bi-directional signaling had extended a profound influence on cellular sensitivity to radiation as well as the sensitivity to RIBE.

Matched MeSH terms: Fibroblasts/radiation effects*
Evaluation of human embryonic stem cells and their differentiated fibroblastic progenies as cellular models for in vitro genotoxicity screening

Vinoth KJ, Manikandan J, Sethu S, Balakrishnan L, Heng A, Lu K, et al.

J Biotechnol, 2014 Aug 20;184:154-68.
PMID: 24862194 DOI: 10.1016/j.jbiotec.2014.05.009

This study evaluated human embryonic stem cells (hESC) and their differentiated fibroblastic progenies as cellular models for genotoxicity screening. The DNA damage response of hESCs and their differentiated fibroblastic progenies were compared to a fibroblastic cell line (HEPM, CRL1486) and primary cultures of peripheral blood lymphocytes (PBL), upon exposure to Mitomycin C, gamma irradiation and H2O2. It was demonstrated that hESC-derived fibroblastic progenies (H1F) displayed significantly higher chromosomal aberrations, micronuclei formation and double strand break (DSB) formation, as compared to undifferentiated hESC upon exposure to genotoxic stress. Nevertheless, H1F cell types displayed comparable sensitivities to genotoxic challenge as HEPM and PBL, both of which are representative of somatic cell types commonly used for genotoxicity screening. Subsequently, transcriptomic and pathways analysis identified differential expression of critical genes involved in cell death and DNA damage response upon exposure to gamma irradiation. The results thus demonstrate that hESC-derived fibroblastic progenies are as sensitive as commonly-used somatic cell types for genotoxicity screening. Moreover, hESCs have additional advantages, such as their genetic normality compared to immortalized cell lines, as well as their amenability to scale-up for producing large, standardized quantities of cells for genotoxicity screening on an industrial scale, something which can never be achieved with primary cell cultures.

Matched MeSH terms: Fibroblasts/radiation effects
Fulltext Nanolayered composite with enhanced ultraviolet ray absorption properties from simultaneous intercalation of sunscreen molecules

Megat Nabil Mohsin S, Hussein MZ, Sarijo SH, Fakurazi S, Arulselvan P, Taufiq-Yap YH

Int J Nanomedicine, 2018;13:6359-6374.
PMID: 30349255 DOI: 10.2147/IJN.S171390

Introduction: The potential of layered double hydroxide (LDH) as a host of multiple ultraviolet-ray absorbers was investigated by simultaneous intercalation of benzophenone 4 (B4) and Eusolex® 232 (EUS) in Zn/Al LDH.
Methods: The nanocomposites were prepared via coprecipitation method at various molar ratios of B4 and EUS.
Results: At equal molar ratios, the obtained nanocomposite showed an intercalation selectivity that is preferential to EUS. However, the selectivity ratio of intercalated anions was shown to be capable of being altered by adjusting the molar ratio of intended guests during synthesis. Dual-guest nanocomposite synthesized with B4:EUS molar ratio 3:1 (ZEB [3:1]) showed an intercalation selectivity ratio of B4:EUS =53:47. Properties of ZEB (3:1) were monitored using powder X-ray diffractometer to show a basal spacing of 21.8 Å. Direct-injection mass spectra, Fourier transform infrared spectra, and ultraviolet-visible spectra confirmed the dual intercalation of both anions into the interlayer regions of dual-guest nanocomposite. The cytotoxicity study of dual-guest nanocomposite ZEB (3:1) on human dermal fibroblast cells showed no significant toxicity until 25 μg/mL.
Conclusion: Overall, the findings demonstrate successful customization of ultraviolet-ray absorbers composition in LDH host.

Matched MeSH terms: Fibroblasts/radiation effects
Fulltext Gelam honey protects against gamma-irradiation damage to antioxidant enzymes in human diploid fibroblasts

Ahmad TA, Jubri Z, Rajab NF, Rahim KA, Yusof YA, Makpol S

Molecules, 2013 Feb 11;18(2):2200-11.
PMID: 23434870 DOI: 10.3390/molecules18022200

The present study was designed to determine the radioprotective effects of Malaysian Gelam honey on gene expression and enzyme activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) of human diploid fibroblasts (HDFs) subjected to gamma-irradiation. Six groups of HDFs were studied: untreated control, irradiated HDFs, Gelam honey-treated HDFs and HDF treated with Gelam honey pre-, during- and post-irradiation. HDFs were treated with 6 mg/mL of sterilized Gelam honey (w/v) for 24 h and exposed to 1 Gray (Gy) of gamma rays at the dose rate of 0.25 Gy/min. Gamma-irradiation was shown to down-regulate SOD1, SOD2, CAT and GPx1 gene expressions (p < 0.05). Conversely, HDFs treated with Gelam honey alone showed up-regulation of all genes studied. Similarly, SOD, CAT and GPx enzyme activities in HDFs decreased with gamma-irradiation and increased when cells were treated with Gelam honey (p < 0.05). Furthermore, of the three different stages of study treatment, pre-treatment with Gelam honey caused up-regulation of SOD1, SOD2 and CAT genes expression and increased the activity of SOD and CAT. As a conclusion, Gelam honey modulates the expression of antioxidant enzymes at gene and protein levels in irradiated HDFs indicating its potential as a radioprotectant agent.

Matched MeSH terms: Fibroblasts/radiation effects
BYSTANDER WI-38 CELLS MODULATE DNA DOUBLE-STRAND BREAK REPAIR IN MICROBEAM-TARGETED A549 CELLS THROUGH GAP JUNCTION INTERCELLULAR COMMUNICATION

Kobayashi A, Autsavapromporn N, Ahmad TAFT, Oikawa M, Homma-Takeda S, Furusawa Y, et al.

Radiat Prot Dosimetry, 2019 May 01;183(1-2):142-146.
PMID: 30535060 DOI: 10.1093/rpd/ncy249

Bi-directional signaling involved in radiation-induced bystander effect (RIBE) between irradiated carcinoma cells and their surrounding non-irradiated normal cells is relevant to radiation cancer therapy. Using the SPICE-NIRS microbeam, we delivered 500 protons to A549-GFP lung carcinoma cells, stably expressing H2B-GFP, which were co-cultured with normal WI-38 cells. The level of γ-H2AX, a marker for DNA double-strand breaks (DSB), was subsequently measured up to 24-h post-irradiation in both targeted and bystander cells. As a result, inhibition of gap junction intercellular communication (GJIC) attenuated DSB repair in targeted A549-GFP cells, and suppressed RIBE in bystander WI-38 cells but not in distant A549-GFP cells. This suggests that GJIC plays a two-way role through propagating DNA damage effect between carcinoma to normal cells and reversing the bystander signaling, also called 'rescue effect' from bystander cells to irradiated cells, to enhance the DSB repair in targeted cells.

Matched MeSH terms: Fibroblasts/radiation effects
Fulltext RNA-Seq analysis revealed genes associated with UV-induced cell necrosis through MAPK/TNF-α pathways in human dermal fibroblast cells as an inducer of premature photoaging

Alafiatayo AA, Lai KS, Ahmad S, Mahmood M, Shaharuddin NA

Genomics, 2020 01;112(1):484-493.
PMID: 30946891 DOI: 10.1016/j.ygeno.2019.03.011

Exposing the skin to solar UV radiation induces cascades of signaling pathways and biological alterations such as redox imbalance, suppression of antioxidant genes and programmed cell death. Therefore, the aim of this study was to use RNA-Seq to unravel the effects of UV radiation on Normal Human Adult Fibroblast cells (NHDF). Cells were exposed to UV (20 mJ/cm2 for 3 mins) and incubated for 24 h. Total mRNA from the cells generated libraries of 72,080,648 and 40,750,939 raw reads from UV-treated and control cells respectively. Of the differentially expressed genes (DEGs) produced 2,007 were up-regulated and 2,791 were down-regulated (fold change ≥2, p 

Matched MeSH terms: Fibroblasts/radiation effects*
Fulltext Protective effect of curcumin against ultraviolet A irradiation‑induced photoaging in human dermal fibroblasts

Liu X, Zhang R, Shi H, Li X, Li Y, Taha A, et al.

Mol Med Rep, 2018 05;17(5):7227-7237.
PMID: 29568864 DOI: 10.3892/mmr.2018.8791

Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in skin, resulting in photoaging. Natural botanicals have gained considerable attention due to their beneficial protection against the harmful effects of UV irradiation. The present study aimed to evaluate the ability of curcumin (Cur) to protect human dermal fibroblasts (HDFs) against ultraviolet A (UVA)‑induced photoaging. HDFs were treated with 0‑10 µM Cur for 2 h and subsequently exposed to various intensities of UVA irradiation. The cell viability and apoptotic rate of HDFs were investigated by MTT and flow cytometry assays, respectively. The effect of UVA and Cur on the formation of reactive oxygen species (ROS), malondialdehyde levels, which are an indicator of ROS, and the levels/activity of antioxidative defense proteins, including glutathione, superoxide dismutase and catalase, were evaluated using 2',7'-dichlorofluorescin diacetate and commercial assay kits. Furthermore, western blotting was performed to determine the levels of proteins associated with endoplasmic reticulum (ER) stress, the apoptotic pathway, inflammation and the collagen synthesis pathway. The results demonstrated that Cur reduced the accumulation of ROS and restored the activity of antioxidant defense enzymes, indicating that Cur minimized the damage induced by UVA irradiation in HDFs. Furthermore, western blot analysis demonstrated that Cur may attenuate UVA‑induced ER stress, inflammation and apoptotic signaling by downregulating the protein expression of glucose‑regulated protein 78, C/EBP‑homologous protein, nuclear factor‑κB and cleaved caspase‑3, while upregulating the expression of Bcl‑2. Additionally, it was demonstrated that Cur may regulate collagen metabolism by decreasing the protein expression of matrix metalloproteinase (MMP)‑1 and MMP‑3, and may promote the repair of cells damaged as a result of UVA irradiation through increasing the protein expression of transforming growth factor‑β (TGF‑β) and Smad2/3, and decreasing the expression of the TGF‑β inhibitor, Smad7. In conclusion, the results of the present study indicate the potential benefits of Cur for the protection of HDFs against UVA‑induced photoaging and highlight the potential for the application of Cur in skin photoprotection.

Matched MeSH terms: Fibroblasts/radiation effects*
Fulltext Gelam honey attenuated radiation-induced cell death in human diploid fibroblasts by promoting cell cycle progression and inhibiting apoptosis

Tengku Ahmad TA, Jaafar F, Jubri Z, Abdul Rahim K, Rajab NF, Makpol S

BMC Complement Altern Med, 2014;14:108.
PMID: 24655584 DOI: 10.1186/1472-6882-14-108

The interaction between ionizing radiation and substances in cells will induce the production of free radicals. These free radicals inflict damage to important biomolecules such as chromosomes, proteins and lipids which consequently trigger the expression of genes which are involved in protecting the cells or repair the oxidative damages. Honey has been known for its antioxidant properties and was used in medical and cosmetic products. Currently, research on honey is ongoing and diversifying. The aim of this study was to elucidate the role of Gelam honey as a radioprotector in human diploid fibroblast (HDFs) which were exposed to gamma-rays by determining the expression of genes and proteins involved in cell cycle regulation and cell death.

Matched MeSH terms: Fibroblasts/radiation effects