• Journal of Ginseng Research
• /
• v.48 no.3
• /
• pp.323-332
• /
• 2024

Background: Studies have reported that the combination of two or more therapeutic compounds at certain ratios has more noticeable pharmaceutical properties than single compounds and requires reduced dosage of each agent. Red ginseng and velvet antler have been extensively used in boosting immunity and physical strength and preventing diseases. Thus, this study was conducted to elucidate the skin-protective potentials of red ginseng extract (RGE) and velvet antler extract (VAE) alone or in combination on ultraviolet (UVB)-irradiated human keratinocytes and SKH-1 hairless mice. Methods: HaCaT cells were preincubated with RGE/VAE alone or in combination for 2 h before UVB (30 mJ/cm²) irradiation. SKH-1 mice were orally given RGE/VAE alone or in combination for 15 days before exposure to single dose of UVB (600 mJ/cm²). Treated cells and treated skin tissues were collected and subjected to subsequent experiments. Results: RGE/VAE pretreatment alone or in combination significantly prevented UVB-induced cell death, apoptosis, reactive oxygen species production, and DNA damage in keratinocytes and SKH-1 mouse skins by downregulating mitogen-activated protein kinases/activator protein 1/nuclear factor kappa B and caspase signaling pathways. These extracts also strengthened the antioxidant defense systems and skin barriers in UVB-irradiated HaCaT cells and SKH-1 mouse skins. Furthermore, RGE/VAE co-administration appeared to be more effective in preventing UVB-caused skin injury than these extracts used alone. Conclusion: Overall, these findings suggest that the consumption of RGE/VAE, especially in combination, offers a protective ability against UVB-caused skin injury by preventing inflammation and apoptosis and enhancing antioxidant capacity.

• Journal of Life Science
• /
• v.28 no.11
• /
• pp.1268-1276
• /
• 2018

The cytidine analog decitabine (DEC) acts as a nucleic acid synthesis inhibitor, whereas ammonium pyrrolidine dithiocarbamate (PDTC) is an inhibitor of nuclear factor-${\kappa}B$. The aim of this study was to investigate the possible synergistic inhibitory effect of these two inhibitors on proliferation of human gastric cancer AGS cells. The inhibitory effect of PDTC on AGS cell proliferation was significantly increased by DEC in a concentration-dependent manner, and this inhibition was associated with cell cycle arrest at the G2/M phase and the induction of apoptosis. This induction of apoptosis by the co-treatment with PDTC and DEC was related to the induction of DNA damage, as assessed by H2AX phosphorylation. Further studies demonstrated that co-treatment with PDTC and DEC induced the disruption of mitochondrial membrane potential, increased the generation of intracellular reactive oxygen species (ROS) and the expression of pro-apoptotic Bax, and down-regulated the expression of anti-apoptotic Bcl-2, ultimately resulting in the release of cytochrome c from the mitochondria into the cytoplasm. Co-treatment with PDTC and DEC also activated caspase-8 and caspase-9, which are representative caspases of the extrinsic and intrinsic apoptosis pathways. Co-treatment also activated caspase-3, which was accompanied by proteolytic degradation of poly (ADP-ribose) polymerase. Taken together, these data clearly indicated that co-treatment with PDTC and DEC suppressed the proliferation of AGS cells by increasing DNA damage and activating the ROS-mediated extrinsic and intrinsic apoptosis pathways.

• Molecular & Cellular Toxicology
• /
• v.1 no.2
• /
• pp.78-86
• /
• 2005

Dioxins, especially 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin), are ubiquitous environmental contaminants. TCDD is known that it has toxic effects in animals and humans, including chloracne, immune, reproductive and developmental toxicities, carcinogenicity, wasting syndrome and death. TCDD induces a broad spectrum of biological responses, including disruption of normal hormone signaling pathways, reproductive and developmental defects, immunotoxicity, liver damage, wasting syndrome and cancer. Many researches showed that TCDD induces gene expression of transcriptional factors related cell proliferation, signal transduction, immune system and cell cycle arrest at molecular and cellular levels. These toxic actions of TCDD are usually mediated with AhR (receptor, resulted from cell culture, animal and clinical studies). cDNA microarray can be used as a highly sensitive and informative marker for toxicity. Additionally, microarray analysis of dioxin-toxicity is able to provide an opportunity for the development of candidate bridging biomarkers of dioxin-toxicity. Through microarray technology, it is possible to understand the therapeutic effects of agonists within the context of toxic effects, classify new chemicals as to their complete effects on biological systems, and identify environmental factors that may influence safety.

• IMMUNE NETWORK
• /
• v.23 no.3
• /
• pp.25.1-25.17
• /
• 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces excessive pro-inflammatory cytokine release and cell death, leading to organ damage and mortality. High-mobility group box 1 (HMGB1) is one of the damage-associated molecular patterns that can be secreted by pro-inflammatory stimuli, including viral infections, and its excessive secretion levels are related to a variety of inflammatory diseases. Here, the aim of the study was to show that SARS-CoV-2 infection induced HMGB1 secretion via active and passive release. Active HMGB1 secretion was mediated by post-translational modifications, such as acetylation, phosphorylation, and oxidation in HEK293E/ACE2-C-GFP and Calu-3 cells during SARS-CoV-2 infection. Passive release of HMGB1 has been linked to various types of cell death; however, we demonstrated for the first time that PANoptosis, which integrates other cell death pathways, including pyroptosis, apoptosis, and necroptosis, is related to passive HMGB1 release during SARS-CoV-2 infection. In addition, cytoplasmic translocation and extracellular secretion or release of HMGB1 were confirmed via immunohistochemistry and immunofluorescence in the lung tissues of humans and angiotensin-converting enzyme 2-overexpressing mice infected with SARS-CoV-2.

• The Korean Journal of Physiology and Pharmacology
• /
• v.7 no.1
• /
• pp.9-14
• /
• 2003

Recent studies indicated that cancer cells become resistant to ionizing radiation (IR) and chemotherapy drugs by enhanced DNA repair of the lesions. Therefore, it is expected to increase the killing of cancer cells and reduce drug resistance by inhibiting DNA repair pathways that tumor cells rely on to escape chemotherapy. There are a number of key human DNA repair pathways which depend on multimeric polypeptide activities. For example, Ku heterodimer regulatory DNA binding subunits (Ku70/Ku80) on binding to double strand DNA breaks (DSBs) are able to interact with 470-kDa DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and are essential for DNA-dependent protein kinase (DNA-PK) activity. It has been known that DNA-PK is an important factor for DNA repair and also is a sensor-transmitting damage signal to downstream targets, leading to cell cycles arrest. Our ultimate goal is to develop a treatment of breast tumors by targeting proteins involved in damage-signaling pathway and/or DNA repair. This would greatly facilitate tumor cell cytotoxic activity and programmed cell death through DNA damaging drug treatment. Therefore, we designed a domain of Ku80 mutants that binds to Ku70 but not DNA end binding activity and used the peptide in co-therapy strategy to see whether the targeted inhibition of DNA-PK activity sensitized breast cancer cells to irradiation or chemotherapy drug. We observed that the synthesized peptide (HNI-38) prevented DNA-PKcs from binding to Ku70/Ku80, thus resulting in inactivation of DNA-PK activity. Consequently, the peptide treated cells exhibited poor to no DNA repair, and became highly sensitive to IR or chemotherapy drugs, and the growth of breast cancer cells was inhibited. Additionally, the results obtained in the present study also support the physiological role of resistance of cancer cells to IR or chemotherapy.

• The Korean Journal of Physiology and Pharmacology
• /
• v.12 no.4
• /
• pp.185-191
• /
• 2008

Activation of c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, is an important cellular response that modulates the outcome of the cells which are exposed to the tumor necrosis factor (TNF) or the genotoxic stress including DNA damaging agents. Although it is known that JNK is activated in response to genotoxic stress, neither the pathways to transduce signals to activate JNK nor the primary sensors of the cells that trigger the stress response have been identified. Here, we report that the receptor interacting protein (RIP), a key adaptor protein of TNF signaling, was required to activate JNK in the cells treated with certain DNA damaging agents such as adriamycin (Adr) and 1-${\beta}$-D-arabinofuranosylcytosine (Ara-C) that cause slow and sustained activation, but it was not required when treated with N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and short wavelength UV, which causes quick and transient activation. Our findings revealed that this sustained JNK activation was not mediated by the TNF (tumor necrosis factor) receptor signaling, but it required a functional ATM (ataxia telangiectasia) activity. In addition, JNK inhibitor SP-600125 significantly blocked the Adr-induced cell death, but it did not affect the cell death induced by MNNG. These findings suggest that the sustained activation of JNK mediated by RIP plays an important role in the DNA damage-induced cell death, and that the duration of JNK activation relays a different stress response to determine the cell fate.

• Tuberculosis and Respiratory Diseases
• /
• v.41 no.2
• /
• pp.73-86
• /
• 1994

In addition to classic cholinergic and adrenergic pathways, the existence of a third division of autonomic control in the human airways has been proved. It is called a nonadrenergic noncholinergic(NANC) nervous system, and difficult to study in the absence of specific blockers. Neuropeptides are certainly suggested to be transmitters of this NANC nervous system. It is very frustrating to understand the pathophysiologic role of these peptides in the absence of any specific antagonists. However, further studies of neuropeptides might eventually lead to novel forms of treatment for bronchial asthma. Another study of the interaction between different components of the autonomic nervous system, either in ganglionic neurotransmission or by presynaptic modulation of neurotransmitters at the end-organ will elute neural control in airway disease, particularly in asthma. Studies of how autonomic control may be disordered in airway disease should lead to improvements in clinical management. Epithelial damage due to airway inflammation in asthma may induce bronchial hyperresponsiveness. Axon reflex mechanism is one of possible mechanisms in bronchial hyperresponsiveness. Epithelial damage may expose sensory nerve terminals and C-fiber nrve endings are stimulated by inflammatory mediators. Bi-directional communication between the nerves and mast cells may have important roles in allergic process. The psychological factors and conditioning of allergic reactions is suggested that mast cell activation might be partly regulated by the central nervous system via the peripheral nerves. Studies in animal models, in huamn airways in vitro and in patients with airway disease will uncover the interaction between allergic disease processes and psychologic factors or neural mechainsms.

• Molecules and Cells
• /
• v.21 no.3
• /
• pp.356-359
• /
• 2006

The transcription factor E2F1 coordinates cell cycle progression and induces apoptosis in response to DNA damage stress. Aside from DNA damage, the role of E2F1 in the endoplasmic reticulum (ER) stress signaling pathways is unclear. We found that $E2F1^{-/-}$ murine embryonic fibroblasts (MEFs) are resistant to apoptosis triggered by the ER stress inducer thapsigargin. In addition, E2F1 deficiency results in enhanced phosphorylation of eukaryotic translation initiation factor $2{\alpha}$ ($elF2{\alpha}$). These results therefore indicate that E2F1 deficiency increases phosphorylation of $elF2{\alpha}$ in response to ER stress triggered by thapsigargin, and suggest that the reduction in ER stress-induced apoptosis in E2F1-deficient cells is related to the high level of $elF2{\alpha}$ phosphorylation.

• Animal cells and systems
• /
• v.1 no.4
• /
• pp.637-640
• /
• 1997

Raf-1, a cytoplasmic serine/threonine protein kinase, serves as a central intermediate in many signaling pathways in cell proliferation, differentiation, and development. In this study, we investigated that B-raf, Drosophila homolog of the human c-raf-1, is involved in ultraviolet (UV) responsive events by using hypomorphic mutant $D-raf^{c110}$ and Draf-lacZ transgenic fly. At first, effect of UV damage on the survival of wild-type and $D-raf^{C110}$ strains was examined. In terms of $1/LD_{50}$ value, the relative ratio of UV sensitivities of wild-type versus $D-raf^{C110}$ strain was 1 : 2.2. By using quantitative $\beta$-galactosidase activity analysis, transcriptional activity of the D-raf gene promoter was also examined in UV-irradiated Draf-lacZ transgenic larvae. UV irradiation increased the expression of lacZ reporter gene in Draf-lacZ transgenic fly. However, in $D-raf^{C110}$ strain the transcriptional activity of D-raf gene promoter by UV irradiation was extensively reduced. Results obtained in this study suggest that D-raf plays a role in UV response, leading to better survival of Drosophila to UV damage.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.18
• /
• pp.7505-7513
• /
• 2014

Several toxic substances have been detected in plants which are responsible for animal and human diseases. Bracken fern (Pteridium aquilinum) is one example, widely distributed in many parts of the world. It is known to cause cancer in humans and other animals. In fact, man can be directly or indirectly exposed to the danger by consuming fern, contaminated water, milk, meat, and spore inhalation. Experimental studies have shown an association between bracken exposure and gastric cancer, and research has shown genotoxic and cytotoxic effects in vitro. This paper describes and reviews toxic, carcinogenic, genotoxic/cytotoxic, and immunomodulatory effects of bracken and included possible toxic agents. The chemistry of Ptaquiloside (PT) reactions is emphasized, along with bracken problems in livestock, possible pathways of exposure in man, and control for human health.