• Journal of Pharmacopuncture
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• v.20 no.3
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• pp.158-172
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• 2017

Nigella sativa (N. sativa, family Ranunculaceae) is a medicinal plant that has been widely used for centuries throughout the world as a natural remedy. A wide range of chemical compounds found in N. sativa expresses its vast therapeutic effects. Thymoquinone (TQ) is the main component (up to 50%) in the essential oil of N. sativa. Also, pinene (up to 15%), p-cymene (40%), thymohydroquinone (THQ), thymol (THY), and dithymoquinone (DTQ) are other pharmacologically active compounds of its oil. Other terpenoid compounds, such as carvacrol, carvone, 4-terpineol, limonenes, and citronellol, are also found in small quantities in its oil. The main pharmacological characteristics of this plant are immune system stimulatory, anti-inflammatory, hypotensive, hepatoprotective, antioxidant, anti-cancer, hypoglycemic, anti-tussive, milk production, uricosuric, choleretic, anti-fertility, and spasmolytic properties. In this regard, we have searched the scientific databases PubMed, Web of Science, and Google Scholar with keywords of N. sativa, anti-cancer, apoptotic effect, antitumor, antioxidant, and malignancy over the period from 2000 to 2017. The effectiveness of N. sativa against cancer in the blood system, kidneys, lungs, prostate, liver, and breast and on many malignant cell lines has been shown in many studies, but the molecular mechanisms behind that anti-cancer role are still not clearly understood. From among the many effects of N. sativa, including its anti-proliferative effect, cell cycle arrest, apoptosis induction, ROS generation, anti-metastasis/anti-angiogenesis effects, Akt pathway control, modulation of multiple molecular targets, including p53, p73, STAT-3, PTEN, and $PPAR-{\gamma}$, and activation of caspases, the main suggestive anti-cancer mechanisms of N. sativa are its free radical scavenger activity and the preservation of various anti-oxidant enzyme activities, such as glutathione peroxidase, catalase, and glutathione-S-transferase. In this review, we highlight the molecular mechanisms of apoptosis and the anti-cancer effects of N. sativa, with a focus on its molecular targets in apoptosis pathways.

• Journal of Korean Academy of Nursing
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• v.53 no.2
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• pp.236-248
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• 2023

Purpose: Nursing informatics competency is used to manage and improve the delivery of safe, high-quality, and efficient healthcare services in accordance with best practices and professional and regulatory standards. This study examined the relationship between nursing informatics competency (NIC), nursing care left undone, and nurse reported quality of care (NQoC) and nursing productivity. A path model for their effects on nursing productivity among clinical nurses was also established. Methods: Data were collected using structured questionnaires answered by 192 nurses working in a tertiary hospital located in J city, Korea, and analyzed using SPSS/WIN 23.0 and AMOS 21.0 program. Results: The fit indices of the alternative path model satisfied recommended levels χ² = .11 (p = .741), normed χ² (χ² /df) = .11, SRMR = .01, RMSEA = .00, GFI = 1.00, NFI = 1.00, AIC = 18.11. Among the variables, NIC (β = .44, p < .001), NQoC (β = .35, p < .001) had a direct effect on nursing productivity. Due to the mediating effect of NQoC on the relationship between NIC and nursing productivity, the effect size was .14 (95% CI .08~.24). Meanwhile, nursing care left undone through NQoC in the relationship between NIC and nursing productivity, has a significant mediation effect (estimate .01, 95% CI .00~.03). The explanatory power of variables was 44.0%. Conclusion: Education and training for enhancing NIC should be provided to improve nursing productivity, quality of care and to reduce missed nursing care. Furthermore, monitoring the quality of nursing care and using it as a productivity index is essential.

• Journal of dental hygiene science
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• v.23 no.4
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• pp.264-270
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• 2023

Background: Resin-based dental materials release residual monomers or other substances from incomplete polymerization into the oral cavity, thereby causing adverse biological effects on oral tissue. 10-Methacryloyloxydecyl dihydrogen phosphate (10-MDP), an acidic monomer containing dihydrogen phosphate and methacrylate groups, is the most commonly used component of resin-based dental materials, such as restorative composite resins, dentin adhesives, and resin cements. Although previous studies have reported the cytotoxicity and biocompatibility in various cultured cells, the effects of resin monomers on cellular aging have not been reported to date. Therefore, this study aimed to investigate the effects of the resin monomer 10-MDP on cellular senescence and inflamm-aging in vitro. Methods: After stimulation with 10-MDP, MC3T3-E1 osteoblast-like cells were examined for cell viability by WST-8 assay and reactive oxygen species (ROS) production by flow cytometry. The protein and mRNA levels of molecular markers of aging were determined by western blotting and RT-PCR analysis, respectively. Results: Treatment with 0.05 to 1 mM 10-MDP for 24 hours reduced the survival of MC3T3-E1 cells in a concentration-dependent manner. The intracellular ROS levels in the 10-MDP-treated experimental group were significantly higher than those in the control group. 10-MDP at a concentration of 0.1 mM increased p53, p16, and p21 protein levels. Additionally, an aging pattern was observed with blue staining due to intracellular senescence-associated beta-galactosidase activity. Treatment with 10-MDP increased the levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-8, however their expression was decreased by mitogen-activated-protein-kinase (MAPK) inhibitors. Conclusion: Taken together, these results suggest that the exposure of osteoblast-like cells to the dental resin monomer 10-MDP, increases the level of cellular senescence and the inflammatory response is mediated by the MAPK pathway.

• Tuberculosis and Respiratory Diseases
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• v.44 no.6
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• pp.1285-1295
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• 1997

Background : EGFR is one of the initial step in signal transduction pathway about multistep carcinogenesis. It is homologous to oncogene erbB-2 and is the receptor for EGF and TGF alpha. EGFR has important role in the growth and differentiation of tumor cells. So, EGFR in non-small cell lung cancer was examined to search for possible evidence as clinical prognostic factor. Methods : To investigate the role of EGFR in lung cancer, the author performed immunohistochemical stain of EGFR on 57 resected primary non-small cell lung cancer specimens. And the author analyzed the correlation between EGFR expression, clinical parameters, Sand $G_1$ phase fraction and survival. Results : 1) EGFR were detected in 56% of total 57 patients (according to histologic type, squamous cancer 50%, adenocarcinoma 63%, large cell cancer 75%) (according to TNM stage, stage I 64%, stage II 38%, stage III 55%) (according to cellular differentiation, well 50%, moderately 52%, poorly 65%). All differences were insignificant 2) Using the flow cytometric analysis, mean S-phase fraction of EGFR (+) and (-) group were 22.3(${\pm}10.5$)%. 18.0(${\pm}10.9$)% (p>0.05), mean $G_1$-phase fraction of EGFR (+) and (-) group were 68.4(${\pm}11.6$)%, 71.1(${\pm}12.8$)%, (p>0.05) 3) Two-year survival rate of EGFR (+) and (-) group were 53%, 84%, median survival time of EGFR (+) and (-) group were 26, 53 months. (p<0.05, Kaplan-Meier, generalized Wilcox) Conclusion : EGFR immunostaining may be a simple and useful method for survival prediction in non-small cell lung cancer.

• Journal of Life Science
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• v.28 no.12
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• pp.1469-1476
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• 2018

Occurrence of the Warburg effect in solid tumors causes resistance to cancer chemotherapy, and targeting energy metabolisms such as aerobic glycolysis is a potential strategy for alternative treatment. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), shifts glucose metabolism from aerobic glycolysis to oxidative phosphorylation (OxPhos) in many cancers. In this study, we investigated the anticancer effect of DCA on a human anaplastic thyroid cancer (ATC) cell line, 8505C. We found that DCA selectively inhibits cell proliferation of the 8505C line but not of a normal thyroid line. In 8505C, the cell cycle was arrested at the G1/S phase with DCA treatment as a result of decreased antiapoptotic proteins such as $HIF1{\alpha}$, PDK1, and Bcl-2 and increased proapoptotic proteins such as Bax and p21. DCA treatment enhanced the production of reactive oxygen species which consequently induced cell cycle arrest and apoptosis. Interestingly, DCA treatment not only reduced lactate production but also increased the expression of sodium-iodine symporter, indicating that it restores the OxPhos of glucose metabolism and the iodine metabolism of the ATC. Taken together, our findings suggest that PDK inhibitors such as DCA could be useful anticancer drugs for the treatment of ATC and may also be helpful in combination with chemotherapy and radiotherapy.

• Journal of Applied Biological Chemistry
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• v.57 no.2
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• pp.103-111
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• 2014

A1E is an extract from traditional Asian medicinal plants that has therapeutic activities against cancers, metabolic disease, and other intractable conditions. However, its mechanism of action on cervical cancer has not been studied. In order to ascertain if A1E would have pronounced anti-cervical cancer effect, cervical cancer cells were incubated with A1E and apoptosis was detected by nuclear morphological changes, annexin V-FITC/PI staining, cell cycle analysis, western blotting, Reverse-transcription polymerase chain reaction, and measurement of mitochondrial membrane potential. Expression of human papiloma virus E6 and E7 oncogenes was down-regulated in A1E-treated cervical cancer cells, while p53 and retinoblastoma protein levels were enhanced. A1E also perturbed cell cycle progression at sub-G1 and altered cell cycle regulatory factors in SiHa cervical cancer cells. A1E activated apoptotic intrinsic pathway markers such as caspase-9, caspase-3 and poly ADP-ribose polymerase, and down-regulated expression of Bcl-2 and Bcl-xl. A1E induced mitochondrial membrane potential collapse and cytochrome c release, and inhibited phosphatidylinositol 3-kinase (PI3K)/Akt, key factors involved in cell survival signaling. Taken all these results, A1E induced apoptosis via activation of the intrinsic pathway and inhibition of the PI3K/Akt survival-signaling pathway in SiHa cervical cancer cells. In conclusion, A1E exerts anti-proliferative action growth inhibition on cervical cancer cells through apoptosis which demonstrates its anti-cervical cancer properties.

• Journal of Ginseng Research
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• v.45 no.2
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• pp.295-304
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• 2021

Background: Acute promyelocytic leukemia (APL) is a hematopoietic malignancy driven by promyelocytic leukemia-retinoic acid receptor A (PML-RARA) fusion gene. The therapeutic drugs currently used to treat APL have adverse effects. 20(S)-ginsenoside Rh2 (GRh2) is an anticancer medicine with high effectiveness and low toxicity. However, the underlying anticancer mechanisms of GRh2-induced PML-RARA degradation and apoptosis in human APL cell line (NB4 cells) remain unclear. Methods: Apoptosis-related indicators and PML-RARA expression were determined to investigate the effect of GRh2 on NB4 cells. Z-VAD-FMK, LY294002, and C 87, as inhibitors of caspase, and the phosphatidylinositol 3-kinase (PI3K) and tumor necrosis factor-α (TNF-α) pathways were used to clarify the relationship between GRh2-induced apoptosis and PML-RARA degradation. Results: GRh2 dose- and time-dependently decreased NB4 cell viability. GRh2-induced apoptosis, cell cycle arrest, and caspase3, caspase8, and caspase9 activation in NB4 cells after a 12-hour treatment. GRh2-induced apoptosis in NB4 cells was accompanied by massive production of reactive oxygen species, mitochondrial damage and upregulated Bax/Bcl-2 expression. GRh2 also induced PML/PML-RARA degradation, PML nuclear bodies formation, and activation of the downstream p53 pathway in NB4 cells. Z-VAD-FMK inhibited caspase activation and significantly reversed GRh2-induced apoptosis and PML-RARA degradation. GRh2 also upregulated TNF-α expression and inhibited Akt phosphorylation. LY294002, an inhibitor of the PI3K pathway, enhanced the antitumor effects of GRh2, and C 87, an inhibitor of the TNF-α pathway, reversed NB4 cell viability, and GRh2-mediated apoptosis in a caspase-8-dependent manner. Conclusion: GRh2 induced caspase-dependent PML-RARA degradation and apoptosis in NB4 cells via the Akt/Bax/caspase9 and TNF-α/caspase8 pathways.

• Journal of Life Science
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• v.28 no.7
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• pp.778-785
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• 2018

Autophagy is a complex signaling process and has been implicated in tumor suppression and anticancer therapy resistance. Autophagy can produce tumor-suppressive effect by inducing autophagic cell death, either in collaboration with apoptosis. In this current study, we found that celecoxib (CCB), a nonsteroidal anti-inflammatory drug (NSAID) with multifaceted effects, induced autophagy including enhanced LC3 conversion (LC3-I to LC3-II) and reduced autophagy substrate protein p62 level in multidrug-resistant (MDR) cancer cells. CCB sensitized human multidrug resistant (MDR) cancer cells to the ansamycin-based HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinoid ansamycin, which causes the degradation of several oncogenic and signaling proteins, by inducing autophagic cell death and apoptosis. CCB significantly augmented 17-AAG-mediated level of LC3-II/LC-I, indicating the combined effect of 17-AAG and CCB on the induction of autophagy. Autophagic degradation of mutant p53 (mutp53) and activation of caspase-3 in 17-AAG-treated MDR cells were accelerated by CCB. Inhibition of caspase-3-mediated apoptotic pathway by Z-DEVD-FMK, a caspase-3 inhibitor, did not completely block CCB-induced cell death in MCF7-MDR cells. In addition, treatment of MDR cells with Z-DEVD-FMK failed to prevent activation of autophagy by combined treatment with 17-AAG and CCB. Based on our findings, the ability of clinically used drug CCB to induce autophagy has important implications for its development as a sensitizing agent in combination with Hsp90 inhibitor of MDR cancer.

• Journal of Acupuncture Research
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• v.27 no.4
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• pp.39-53
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• 2010

목적 : 퇴행성 관절염은 염증성 사이토카인인 IL-$1\beta$에 의해 연골관절이 파괴되고 이로 인해 염증성 사이토카인이 더욱 증가하는 질환이다. 퇴행성 관절염을 치료하기 위해서는 연골 파괴를 가속화시키는 catabolic cytokines의 활성을 줄이고, 성장인자인 anabolic factor의 활성을 증가시는 연골 보호 작용이 있어야 한다. 본 연구에서는 독활 승마 처방(OAH19T)이 catabolic/anabolic 대사 조절에 어떤 영향을 미치는지와 그 신호 전달 기전에 대해 연구하였다. 또한 OAH19T를 구성하는 단미재 및 임상에서 사용되는 COX-2 inhibitor인 Celebrex(CEL)와 효능을 비교 실험하였다. 방법 : 배양된 세포에 IL-$1\beta$로 자극한 후 (1) glycosaminoglycan(GAG)의 분해 억제 정도, (2) OAH19T와 CEL에 대하여 MMP-1과 MMP-3의 유전자 발현 및 활성 억제, (3) Aggrecan 및 Aggrecanases의 유전자 발현 및 활성 억제, (4) OAH19T의 growth factor의 조절 능력, (5) MAPK pathway 등을 RT-PCR(reverse transcriptase-polymerase chain reaction), ELISA(Enzyme-linked immunosorbent assay), western blot, viability 측정을 통해 검증했다. 결과 : 사람 관절 세포에서 (1) 독활 승마 각각의 단미재, 임상에서 사용중인 셀레콕시브(CEL), 조인스보다 실험 약물(OAH19T)이 저농도에서 GAG 분해 억제 효과가 우수하였고, 부탄올로 분획한 OAH19B와는 동등한 효과를 보였다. (2) OAH19T는 IL-$1\beta$에 의하여 활성화된 MMP-1과 MMP-3의 발현을 모두 억제하였으나, CEL은 MMP-1의 발현은 억제하였으나 MMP-3의 발현은 억제하지 못하였다. (3) OAH19T는 IL-$1\beta$에 의하여 손상된 Aggrecan을 회복시켰으며 이는 활성화된 Aggrecanase-1과 Aggrecanase-2를 억제시킴으로써 나타난 결과이다. 그러나 CEL의 경우, 손상된 Aggrecan을 회복시키지 못하였다. (4) 배양된 세포는 IL-$1\beta$에 의하여 TGF-$\beta$II및 TGF-$\beta$ receptor II의 발현이 억제되었으나, OAH19T는 TGF-$\beta$II및 TGF-$\beta$ receptor II의 발현을 회복시켜 OAH19T가 anabolic한 조절능력이 있음을 시사한다. 그러나 CEL의 경우 growth factor에 대한 조절 능력이 없었다. (5) 대사 조절 작용에 대한 기전으로서 MAPK pathway에 대해서 연구한 결과 IL-$1\beta$에 의하여 유도된 pERK, pp38 kinase의 활성은 억제하였고, pJNK의 활성은 변하지 않았다. 또한 OAH19T는 연골 세포에 독성이 없었으며 IL-$1\beta$에 의해 유도된 세포 증식만을 억제시켰다. 이 결과로, OAH19T가 OA chondrocyte의 탈분화 및 세포 고사를 억제하여 연골보호 및 회복 효과가 있음을 알 수 있었다. 결론 : OAH19T는 이를 구성하는 단미재 및 CEL보다 연골보호 효과가 월등하였고, 이러한 연골보호 효과는 catabolic cytokines/growth factors의 균형으로 대사조절을 통해 연골세포의 탈분화 및 세포 고사를 억제하여 연골보호 및 회복 효과가 있음을 알 수 있었다.

• Tuberculosis and Respiratory Diseases
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• v.57 no.5
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• pp.449-460
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• 2004

Background : PS-341 is a novel, highly selective and potent proteasome inhibitor, which showed cytotoxicity against some tumor cells. Its anti-tumor activity has been suggested to be associated with modulation of the expression of apoptosis-associated proteins, such as p53, $p21^{WAF/CIP1}$, $p27^{KIP1}$, NF-${\kappa}B$, Bax and Bcl-2. c-Jun N-terminal kinase (JNK) and glycogen synthase kinase-$3{\beta}$ (GSK-$3{\beta}$) are important modulators of apoptosis. However, their role in PS-341-induced apoptosis is unclear. This study was undertaken to elucidate the role of JNK and GSK-$3{\beta}$ in the PS-341-induced apoptosis in lung cancer cells. Method : NCI-H157 and A549 cells were used in the experiments. The cell viability was assayed using the MTT assay and apoptosis was evaluated by proteolysis of PARP. The JNK activity was measured by an in vitro immuno complex kinase assay and by phosphorylation of endogenous c-Jun. The protein expression was evaluated by Western blot analysis. Dominant negative JNK1 (DN-JNK1) and GSK-$3{\beta}$ were overexpressed using plasmid and adenovirus vectors, respectively. Result : PS-341 reduced the cell viability via apoptosis, activated JNK and increased the c-Jun expression. Blocking of the JNK activation by overexpression of DN-JNK1, or pretreatment with SP600125, suppressed the apoptosis induced by PS-341. The activation of caspase 3 was mediated by JNK activation. Blocking of the caspase 3 activation suppressed PS-341-induced apoptosis. PS-341 activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, but its blockade enhanced the PS-341-induced cell death via apoptosis. GSK-$3{\beta}$ was inactivated by PS-341 via the PI3K/Akt pathway. Overexpression of constitutively active GSK-$3{\beta}$ enhanced PS-341-induced apoptosis; in contrast, this was suppressed by dominant negative GSK-$3{\beta}$ (DN-GSK-$3{\beta}$). Inactivation of GSK-$3{\beta}$ by pretreatment with lithium chloride or the overexpression of DN-GSK-$3{\beta}$ suppressed both the JNK activation and c-Jun up-regulation induced by PS-341. Conclusion : The JNK/caspase pathway is involved in PS-341-induced apoptosis, which is negatively regulated by the PI3K/Akt-mediated inactivation of GSK-$3{\beta}$ in lung cancer cells.