• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.475-481
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• 2014

Background: Pereskia sacharosa is a genus of cacti widely used in folk medicine for cancer-related treatment. Anti-proliferative effects have been studied in recent years against colon, breast, cervical and lung cancer cell lines, with promising results. We here extended study of anti-proliferative effects to a blood malignancy, leukemia. Materials and Methods: Two leukemic cell lines, MV4-11 (acute myeloid leukemia) and K562 (chronic myeloid leukemia), were studied. $IC_{50}$ concentrations were determined and apoptosis and cell cycle regulation were studied by flow cytometric analysis. The expression of apoptosis and cell-cycle related regulatory proteins was assessed by Western blotting. Results: P sacharosa inhibited growth of MV4-11 and K562 cells in a dose-dependent manner. The mode of cell death was via induction of intrinsic apoptotic pathways and cell cycle arrest. There was profound up-regulation of cytochrome c, caspases, p21 and p53 expression and repression of Akt and Bcl-2 expression in treated cells. Conclusions: These results suggest that P sacharosa induces leukemic cell death via apoptosis induction and changes in cell cycle checkpoint, thus deserves further study for anti-leukemic potential.

• BMB Reports
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• 제53권8호
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• pp.419-424
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• 2020

Bee venom (BV), secreted from the venom gland of the honey bee, contains several biological active compounds. BV has been widely used as a traditional medicine for treating human disease, including cancer. In this study, we have shown the molecular mechanism underlying the therapeutic effect of BV on cancer. Treatment with BV reduced the proliferation of cervical-cancer cells in a dose- and time-dependent manner. Interestingly, the killing effect of BV was specific to HPV-positive cervical-cancer cell lines, such as Caski and HeLa cells, and not to HPV-negative cervical-cancer cells (C33A). BV reduced the expression of HPV E6 and E7 at RNA and protein levels, leading to an increase in the expression of p53 and Rb in Caski and HeLa cells. Further, BV decreased the levels of cell-cycle proteins, such as cyclin A and B, and increased the levels of cell-cycle inhibitors, such as p21 and p27. BV significantly induced apoptosis and inhibited wound healing and migration of cervical-cancer cells. It also upregulated the expression of pro-apoptotic BAX and downregulated the expression of anti-apoptotic Bcl-2 and Bcl-XL. Cleavage of caspase-3, caspase-9, and PARP were also induced by BV treatment, whereas the phosphorylation of mitogenic signaling-related proteins, such as AKT, JNK, p38, and ERK, were downregulated. Our results indicate that BV has a therapeutic selectivity for HPV-positive malignant cells, so further clinical studies are needed to assess its clinical application.

• 한국식품과학회지
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• 제52권1호
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• pp.81-88
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• 2020

PGSE의 혈당조절 효과를 평가하기 위하여 제2형 당뇨 동물모델을 이용하여 8주간의 동물실험을 진행한 결과, 고농도 PGSE(600 mg/kg)의 투여는 경구 포도당 내성 및 혈당 수준을 유의적으로 감소시켰으며(p<0.05), 당화혈색소도 유의적으로 낮은 수준을 유지시켰다(p<0.05). 또한, 혈청 인슐린과 렙틴 농도 역시 대조군과 비교하여 PGSE 고농도 처리군에서 유의적으로 감소하였다(p<0.05). PGSE 투여는 db/db 마우스의 골격근에서 인슐린 의존적 세포신호전달경로를 유의적으로 활성화시켰으며, AMPK 인산화를 촉진시키고, 골격근내 포도당 흡수를 위한 GLUT4의 세포막으로의 전이를 대조군 대비 약 1.7배 증가시켰다. 이러한 결과를 근거로 할 때 PGSE는 항 당뇨병 치료제로서의 잠재적 가능성을 가진 것으로 판단된다.

• 대한의생명과학회지
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• 제20권2호
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• pp.85-95
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• 2014

Activation of the epidermal growth factor receptor (EGFR) and downstream signaling pathways have been implicated in causing resistance to EGFR-targeted therapy in solid tumors, including the head and neck tumors. To investigate the mechanism of antiproliferation to EGFR inhibition in oral cancer, we compared EGFR tyrosine kinase inhibitor (Gefitinib, Iressa, ZD1839) with respect to its inhibitory effects on three kinases situated downstream of EGFR: MAPK, Akt, and glycogen synthase kinase-$3{\beta}$ (GSK-$3{\beta}$). We have demonstrated that ZD1839 induces growth arrest and apotosis in oral cancer cell lines by independent of EGFR-mediated signaling. An exposure of oral cancer cells to ZD1839 resulted in a dose dependent up-regulation of the cyclin-dependent kinase inhibitor p21 and p27, down regulation of cyclin D1, inactivation of GSK-$3{\beta}$ and of active MAPK. In resistant cells, GSK-$3{\beta}$ is constitutively active and its activity is negatively regulated primarily through Ser 9 phosphorylation and further enhanced by Tyr216 phosphorylation. These results showed that the resistance to the antiproliferative effects of ZD1839, in vitro was associated with uncoupling between EGFR and MAPK inhibition, and that GSK-$3{\beta}$ activation and degradation of its target cyclin D1 were indicators of high cell sensitivity to ZD1839. In conclusion, our data show that the uncoupling of EGFR with mitogenic pathways can cause resistance to EGFR inhibition in oral cancer.

• Animal cells and systems
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• 제16권4호
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• pp.274-279
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• 2012

Thymoquinone (TQ), a drug extracted from the black seeds of Nigella sativa, has been shown to exhibit anti-inflammatory, anti-oxidant, and anti-neoplastic effects in numerous cancer cells. The effects of TQ on cyclooxygenase-2 (COX-2) expression and prostaglandin $E_2$ ($PGE_2$) production in MDA-MB-231, however, remain poorly understood. Western blot analysis and immunofluorescence staining were performed to study the expression levels of inflammation regulatory proteins in MDA-MB-231. $PGE_2$ assay was conducted to explore the TQ-induced production of $PGE_2$. In this study, we investigated the effects of TQ on COX-2 expression and $PGE_2$ production in MDA-MB-231. TQ significantly induced COX-2 expression and increased $PGE_2$ production in a dose-dependent manner, as determined by a Western blot analysis and $PGE_2$ assay. Furthermore, the activation of Akt and p38 kinase, respectively, was up-regulated in TQ treated cells. Inhibition of p38 kinase with SB203580 and PI3kinase (PI3K) with LY294002 abolished TQ-caused COX-2 expression and decreased $PGE_2$ production. These results collectively demonstrate that TQ effectively modulates COX-2 expression and $PGE_2$ production via PI3K and p38 kinase pathways in the human breast cancer cell line MDA-MB-231.

• 한국환경성돌연변이발암원학회지
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• 제25권1호
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• pp.40-46
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• 2005

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) displays high toxicity in animals and has been implicated in human carcinogenesis. Although the mechanism of carcinogenesis by TCDD is unclear, it is considered to be a non-genotoxic compound and tumor promoter. In our experiment, we investigated the effects of TCDD on gene expression in mouse skin carcinogenesis. We used cDNA microarray to detect the differential gene expression in tumors induced in hairless mouse skin by MNNG plus TCDD protocol. We found that erb-2, c-ets2 and p27$^{kip1}$ were significantly up-regulated, but TNFR2, AKT-l, integrin $\beta$l, maspin, IGF-l, c-raf-l, Rb were significantly down-regulated, in tumor region, respectively. We also found that the expression of 53 genes involved in cen cycle, signal transduction, apoptosis, adhesion molecule, angiogenesis, and invasion, were changed two fold more, in tumor surrounding region. These data suggest that TCDD alters the expression of a large array of genes involved in apoptosis, cytokine production and angiogenesis in mouse skin carcinogenesis.

• BMB Reports
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• 제52권8호
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• pp.520-525
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• 2019

Dihydroartemisinin (DHA) has been reported to possess anti-cancer activity against many cancers. However, the pharmacologic effect of DHA on HBV-positive hepatocellular carcinoma (HCC) remains unknown. Thus, the objective of the present study was to determine whether DHA could inhibit the proliferation of HepG2.2.15 cells and uncover the underlying mechanisms involved in the effect of DHA on HepG2.2.15 cells. We found that DHA effectively inhibited HepG2.2.15 HCC cell proliferation both in vivo and in vitro. DHA also reduced the migration and tumorigenicity capacity of HepG2.2.15 cells. Regarding the underlying mechanisms, results showed that DHA induced cellular senescence by up-regulating expression levels of proteins such as p-ATM, p-ATR, ${\gamma}-H_2AX$, P53, and P21 involved in DNA damage response. DHA also induced autophagy (green LC3 puncta gathered together and LC3II/LC3I ratio increased through AKT-mTOR pathway suppression). Results also revealed that DHA-induced autophagy was not linked to senescence or cell death. TPP1 (telomere shelterin) overexpression could not rescue DHA-induced anticancer activity (cell proliferation). Moreover, DHA down-regulated TPP1 expression. Gene knockdown of TPP1 caused similar phenotypes and mechanisms as DHA induced phenotypes and mechanisms in HepG2.2.15 cells. These results demonstrate that DHA might inhibit HepG2.2.15 cells proliferation through inducing cellular senescence and autophagy.

• Journal of Ginseng Research
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• 제47권4호
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• pp.493-505
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• 2023

In recent years, an increasing number of reports have explored the wound healing mechanism of these two traditional Chinese herbal medicines- Panax ginseng and Panax notoginseng, but there is no systematic research on the related core functions and different mechanisms in the treatment of wound healing up to now. Based on network pharmacology and meta-analysis, the present work aimed to comprehensively review the commonality and diversity of P. ginseng and P. notoginseng in wound healing. In this study, a wound healing-related "ingredients-targets" network of two herbs was constructed. Thereafter, meta-analysis of the multiple target lists by Metascape showed that these two medicines significantly regulated blood vessel development, responses to cytokines and growth factors and oxygen levels, cell death, cell proliferation and differentiation, and cell adhesion. To better understand the discrepancy between these two herbs, it was found that common signaling pathways including Rap1, PI3K/AKT, MAPK, HIF-1 and Focal adhesion regulated the functions listed above. In parallel, the different pathways including renin-angiotensin system, RNA transport and circadian rhythm, autophagy, and the different metabolic pathways may also explained the discrepancies in the regulation of the above-mentioned functions, consistent with the Traditional Chinese Medicine theory about the effects of P. ginseng and P. notoginseng.

• Biomolecules & Therapeutics
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• 제27권6호
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• pp.522-529
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• 2019

M1/M2 polarization of immune cells including microglia has been well characterized. It mediates detrimental or beneficial roles in neuroinflammatory disorders including cerebral ischemia. We have previously found that sphingosine 1-phospate receptor subtype 1 ($S1P_1$) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between $S1P_1$ and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of $S1P_1$ is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether $S1P_1$ was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing $S1P_1$ activity with its functional antagonist, AUY954 (5 mg/kg, p.o.), attenuated mRNA upregulation of M1 polarization markers in post-ischemic brain at 1 day and 3 days after tMCAO challenge. Similarly, suppressing $S1P_1$ activity with AUY954 administration inhibited M1-polarizatioin-relevant $NF-{\kappa}B$ activation in post-ischemic brain. Particularly, $NF-{\kappa}B$ activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through $S1P_1$ in post-ischemic brain mainly occurred in activated microglia. Suppressing $S1P_1$ activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that $S1P_1$ could also influence M2 polarization in post-ischemic brain. Finally, suppressing $S1P_1$ activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevant Akt, all of which were downstream pathways following $S1P_1$ activation. Overall, these results revealed $S1P_1$-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.

• 한국식품영양학회지
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• 제26권4호
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• pp.806-813
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• 2013

본 연구는 짚신나물 열수 추출물의 ${\alpha}$-glucosidase 저해 활성을 측정하고, 분화된 근육세포에서 glucose 이용과 인슐린 신호전달에 미치는 영향을 분석하였다. 짚신나물 열수 추출물($10mg/m{\ell}$)은 ${\alpha}$-glucosidase 활성을 67% 저해하였으며, 같은 농도의 양성대조구인 acarbose(63%)와 유사한 저해 효과를 보였다. 짚신나물 열수 추출물이 ${\alpha}$-glucosidase에 의한 단당류 생성을 저해함으로 식사 후 혈당이 급격히 상승하는 것을 억제하는데 효과적인 소재로 이용 가능성을 확인하였다. 또한 근육세포에서 인슐린 저항성을 유발하기 위해 지방산(1 mM, palmitic acid)를 처리하였고, glucose의 세포내 유입이 감소되는 것을 확인하였다. 지방산 처리 세포 모델에서 짚신나물 열수 추출물($10{\mu}g/m{\ell}$)은 glucose 이용을 유의적으로 회복시켜 주었다. Normal 상태의 배양조건에서 근육세포의 포도당 이용능은 짚신나물 열수 추출물($100{\mu}g/m{\ell}$) 처리에 의해 유의적으로 증가하였다. 근육세포 내로 glucose 유입은 운반 단백질인 Glut4를 통해 이루어지며, 이것은 인슐린이 신호전달을 통해 조절한다. 짚신나물 열수 추출물의 세포 내 glucose 이용 증가 효과는 인슐린 신호전달 관련 분자인 Akt 유전자와 단백질 발현을 증가시킨 것과 관련되는 것으로 추정된다. 결론적으로, 짚신나물 열수 추출물은 소화기관에서의 탄수화물 흡수 저해와 근육세포 내 glucose 이용 증가를 통해 혈당 조절 및 당 대사 개선에 긍정적인 영향을 미치고 있음을 확인하였다.