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13 pages, 3845 KiB

Open AccessArticle

Vitamin D Suppresses Ovarian Cancer Growth and Invasion by Targeting Long Non-Coding RNA CCAT2

by Liye Wang, Shuang Zhou and Bin Guo

Int. J. Mol. Sci. 2020, 21(7), 2334; https://doi.org/10.3390/ijms21072334 - 27 Mar 2020

Cited by 23 | Viewed by 3636

Ovarian cancer is the most deadly gynecologic cancer among women worldwide. Poor response to current treatment makes it necessary to discover new diagnostic biomarkers to detect the cancer early and develop new and effective prevention strategies. Calcitriol, the active metabolite of vitamin D, [...] Read more.

Ovarian cancer is the most deadly gynecologic cancer among women worldwide. Poor response to current treatment makes it necessary to discover new diagnostic biomarkers to detect the cancer early and develop new and effective prevention strategies. Calcitriol, the active metabolite of vitamin D, protects against multiple cancers through unelucidated mechanisms. The oncogenic long non-coding RNA (lncRNA) CCAT2 (colon cancer associated transcript 2) is overexpressed in ovarian cancer. Here, we foundd that calcitriol inhibited CCAT2 expression in ovarian cancer cell lines. Treatment with calcitriol inhibited ovarian cancer cell proliferation, migration, and invasion. As a result of CCAT2 inhibition, calcitriol decreased the binding of transcription factor TCF7L2 (TCF4) to the MYC promoter, resulting in the repression of c-Myc protein expression. Our results suggest a novel anti-cancer mechanism of vitamin D by targeting CCAT2 in ovarian cancer. The findings may help develop vitamin D as a practical and inexpensive nutraceutical for ovarian cancer prevention. Full article

(This article belongs to the Special Issue Nutraceuticals in Cancer and Disease Prevention)

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16 pages, 1972 KiB

Open AccessArticle

Novel and Stable Dual-Color IL-6 and IL-10 Reporters Derived from RAW 264.7 for Anti-Inflammation Screening of Natural Products

by Papawee Saiki, Yasuhiro Kawano, Yoshihiro Nakajima, Leo J. L. D. Van Griensven and Koyomi Miyazaki

Int. J. Mol. Sci. 2019, 20(18), 4620; https://doi.org/10.3390/ijms20184620 - 18 Sep 2019

Cited by 7 | Viewed by 3483

Abstract

Our previous study suggested that the interleukin (IL)-6 and IL-10 could serve as good biomarkers for chronic inflammatory disease. We previously established an IL-6 and IL-10 reporters assay that could examine reporter activity along with the reference gene in LPS-induced RAW 264.7 cells. [...] Read more.

Our previous study suggested that the interleukin (IL)-6 and IL-10 could serve as good biomarkers for chronic inflammatory disease. We previously established an IL-6 and IL-10 reporters assay that could examine reporter activity along with the reference gene in LPS-induced RAW 264.7 cells. In this study, we described new and stable RAW 264.7 derived dual-color IL-6/gapdh and IL-10/gapdh reporters. This assay allowed us to easily determine relative IL-6 and IL-10 levels with 96-well plate within one step. We evaluated the relative IL-6 and IL-10 levels in the LPS-induced stable cells testing 52 natural products by real-time bioluminescence monitoring and time-point determination using a microplate luminometer. The relative IL-6 and IL-6/IL-10 values decreased by the crude ethanol extracts from nutmeg and by 1′S-1′-acetoxychavicol from greater galangal using real-time bioluminescence monitoring. At the same time, the relative IL-10 was induced. The relative IL-6 and IL-6/IL-10 decreased by crude ethanol extracts from nutmeg and 1′S-1′-acetoxychavicol acetate at 6 h. Only crude ethanol extract from nutmeg induced IL-10 at 6 h. We suggested that the use of these stable cells by real-time monitoring could serve as a screening assay for anti-inflammatory activity and may be used to discover new drugs against chronic inflammatory disease. Full article

(This article belongs to the Special Issue Nutraceuticals in Cancer and Disease Prevention)

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14 pages, 4072 KiB

Open AccessArticle

Flexicaulin A, An ent-Kaurane Diterpenoid, Activates p21 and Inhibits the Proliferation of Colorectal Carcinoma Cells through a Non-Apoptotic Mechanism

by Yixuan Xia, Chu Shing Lam, Wanfei Li, Md. Shahid Sarwar, Kanglun Liu, Kwan Ming Lee, Hong-Jie Zhang and Siu Wai Tsang

Int. J. Mol. Sci. 2019, 20(8), 1917; https://doi.org/10.3390/ijms20081917 - 18 Apr 2019

Cited by 4 | Viewed by 3170

Abstract

Natural products, explicitly medicinal plants, are an important source of inspiration of antitumor drugs, because they contain astounding amounts of small molecules that possess diversifying chemical entities. For instance, Isodon (formerly Rabdosia), a genus of the Lamiaceae (formerly Labiatae) family, has been [...] Read more.

Natural products, explicitly medicinal plants, are an important source of inspiration of antitumor drugs, because they contain astounding amounts of small molecules that possess diversifying chemical entities. For instance, Isodon (formerly Rabdosia), a genus of the Lamiaceae (formerly Labiatae) family, has been reported as a rich source of natural diterpenes. In the current study, we evaluated the in vitro anti-proliferative property of flexicaulin A (FA), an Isodon diterpenoid with an ent-kaurane structure, in human carcinoma cells, by means of cell viability assay, flow cytometric assessment, quantitative polymerase chain reaction array, Western blotting analysis, and staining experiments. Subsequently, we validated the in vivo antitumor efficacy of FA in a xenograft mouse model of colorectal carcinoma. From our experimental results, FA appears to be a potent antitumor molecule, since it significantly attenuated the proliferation of human colorectal carcinoma cells in vitro and restricted the growth of corresponsive xenograft tumors in vivo without causing any adverse effects. Regarding its molecular mechanism, FA considerably elevated the expression level of p21 and induced cell cycle arrest in the human colorectal carcinoma cells. While executing a non-apoptotic mechanism, we believe the antitumor potential of FA opens up new horizons for the therapy of colorectal malignancy. Full article

(This article belongs to the Special Issue Nutraceuticals in Cancer and Disease Prevention)

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14 pages, 3615 KiB

Open AccessArticle

Dehydroabietic Acid Suppresses Inflammatory Response Via Suppression of Src-, Syk-, and TAK1-Mediated Pathways

by Eunji Kim, Young-Gyu Kang, Yong-Jin Kim, Tae Ryong Lee, Byong Chul Yoo, Minkyeong Jo, Ji Hye Kim, Jong-Hoon Kim, Donghyun Kim and Jae Youl Cho

Int. J. Mol. Sci. 2019, 20(7), 1593; https://doi.org/10.3390/ijms20071593 - 29 Mar 2019

Cited by 40 | Viewed by 4107

Abstract

Dehydroabietic acid (DAA) is a naturally occurring diterpene resin acid derived from coniferous plants such as Pinus and Picea. Various bioactive effects of DAA have been studied including antibacterial, antifungal, and anticancer activities. However, the anti-inflammatory mechanism of DAA remains unclear. We [...] Read more.

Dehydroabietic acid (DAA) is a naturally occurring diterpene resin acid derived from coniferous plants such as Pinus and Picea. Various bioactive effects of DAA have been studied including antibacterial, antifungal, and anticancer activities. However, the anti-inflammatory mechanism of DAA remains unclear. We evaluated the anti-inflammatory effect of DAA in macrophage cell lines. Dehydroabietic acid clearly reduced nitric oxide (NO) production and inflammatory gene expression decreased according to RT-PCR results. Dehydroabietic acid displayed anti-inflammatory activity at the transcriptional level in results from NF-κB- or AP-1-mediated luciferase assays. To identify the DAA target protein, we investigated NF-κB and AP-1 pathways by Western blotting analysis. Dehydroabietic acid suppressed the activity of proto-oncogene tyrosine protein kinase (Src) and spleen tyrosine kinase (Syk) in the NF-κB cascade and transforming growth factor beta-activated kinase 1 (TAK1) in the AP-1 cascade. Using overexpression strategies, we confirmed that DAA targeted these kinases. Our findings demonstrate the anti-inflammatory effects and molecular mechanism of DAA. This suggests that DAA has potential as a drug or supplement to ameliorate inflammation. Full article

(This article belongs to the Special Issue Nutraceuticals in Cancer and Disease Prevention)

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16 pages, 4441 KiB

Open AccessArticle

Immunomodulatory Effects of (24R)-Pseudo-Ginsenoside HQ and (24S)-Pseudo-Ginsenoside HQ on Cyclophosphamide-Induced Immunosuppression and Their Anti-Tumor Effects Study

by Zeng Qi, Lixue Chen, Zhuo Li, Zijun Shao, Yuli Qi, Kun Gao, Songxin Liu, Yinshi Sun, Pingya Li and Jinping Liu

Int. J. Mol. Sci. 2019, 20(4), 836; https://doi.org/10.3390/ijms20040836 - 15 Feb 2019

Cited by 33 | Viewed by 3773

Abstract

(24R)-pseudo-ginsenoside HQ (R-PHQ) and (24S)-pseudo-ginsenoside HQ (S-PHQ) are the main metabolites of (20S)-ginsenoside Rh₂ (Rh₂) in vivo. In this study, we found that Rh₂, R-PHQ, and S-PHQ upregulated the innate and adaptive immune response in cyclophosphamide (CTX) induced-immunocompromised [...] Read more.

(24R)-pseudo-ginsenoside HQ (R-PHQ) and (24S)-pseudo-ginsenoside HQ (S-PHQ) are the main metabolites of (20S)-ginsenoside Rh₂ (Rh₂) in vivo. In this study, we found that Rh₂, R-PHQ, and S-PHQ upregulated the innate and adaptive immune response in cyclophosphamide (CTX) induced-immunocompromised mice as evidenced by the number of leukocytes, cellular immunity, and phagocytosis of macrophages. Spleen T-lymphocyte subpopulations and the serum cytokines level were also balanced in these immunosuppressed mice. Furthermore, co-administration with R-PHQ or S-PHQ did not compromise the antitumor activity of CTX in the hepatoma H22-bearing mice. Treatment with R-PHQ and S-PHQ clearly induced the apoptosis of tumor cells, significantly increased the expression of Bax, and remarkably inhibited the expression of Bcl-2 and vascular endothelial growth factor (VEGF) in H22 tumor tissues. The anti-tumor activity of R-PHQ and S-PHQ could be related to the promotion of tumor apoptosis and inhibition of angiogenesis and may involve the caspase and VEGF signaling pathways. This study provides a theoretical basis for further study on R-PHQ and S-PHQ. Full article

(This article belongs to the Special Issue Nutraceuticals in Cancer and Disease Prevention)

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17 pages, 6680 KiB

Open AccessArticle

Boldine Improves Kidney Damage in the Goldblatt 2K1C Model Avoiding the Increase in TGF-β

by Gonzalo I. Gómez and Victoria Velarde

Int. J. Mol. Sci. 2018, 19(7), 1864; https://doi.org/10.3390/ijms19071864 - 25 Jun 2018

Cited by 25 | Viewed by 4753

Abstract

Boldine, a major aporphine alkaloid found in the Chilean boldo tree, is a potent antioxidant. Oxidative stress plays a detrimental role in the pathogenesis of kidney damage in renovascular hypertension (RVH). The activation of the renin-angiotensin system (RAS) is crucial to the development [...] Read more.

Boldine, a major aporphine alkaloid found in the Chilean boldo tree, is a potent antioxidant. Oxidative stress plays a detrimental role in the pathogenesis of kidney damage in renovascular hypertension (RVH). The activation of the renin-angiotensin system (RAS) is crucial to the development and progression of hypertensive renal damage and TGF-β is closely associated with the activation of RAS. In the present study, we assessed the effect of boldine on the progression of kidney disease using the 2K1C hypertension model and identifying mediators in the RAS, such as TGF-β, that could be modulated by this alkaloid. Toward this hypothesis, rats (n = 5/group) were treated with boldine (50 mg/kg/day, gavage) for six weeks after 2K1C surgery (pressure ≥ 180 mmHg). Kidney function was evaluated by measuring of proteinuria/creatininuria ratio (U prot/U Crea), oxidative stress (OS) by measuring thiobarbituric acid reactive substances (TBARS). The evolution of systolic blood pressure (SBP) was followed weekly. Alpha-smooth muscle actin (α-SMA) and Col III were used as markers of kidney damage; ED-1 and osteopontin (OPN) were used as markers of inflammation. We also explored the effect in RAS mediators, such as ACE-1 and TGF-β. Boldine treatment reduced the UProt/UCrea ratio, plasma TBARS, and slightly reduced SBP in 2K1C hypertensive rats, producing no effect in control animals. In 2K1C rats treated with boldine the levels of α-SMA, Col III, ED-1, and OPN were lower when compared to 2K1C rats. Boldine prevented the increase in ACE-1 and TGF-β in 2K1C rats, suggesting that boldine reduces kidney damage. These results suggest that boldine could potentially be used as a nutraceutic. Full article

(This article belongs to the Special Issue Nutraceuticals in Cancer and Disease Prevention)

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25 pages, 1364 KiB

Open AccessReview

Nutraceutical Boom in Cancer: Inside the Labyrinth of Reactive Oxygen Species

by Maura Calvani, Amada Pasha and Claudio Favre

Int. J. Mol. Sci. 2020, 21(6), 1936; https://doi.org/10.3390/ijms21061936 - 12 Mar 2020

Cited by 50 | Viewed by 7844

Abstract

In recent years, epidemiological studies have shown that food is a very powerful means for maintaining a state of well-being and for health prevention. Many degenerative, autoimmune and neoplastic diseases are related to nutrition and the nutrient–organism interaction could define the balance between [...] Read more.

In recent years, epidemiological studies have shown that food is a very powerful means for maintaining a state of well-being and for health prevention. Many degenerative, autoimmune and neoplastic diseases are related to nutrition and the nutrient–organism interaction could define the balance between health and disease. Nutrients and dietary components influence epigenetic phenomena and modify drugs response; therefore, these food–host interactions can influence the individual predisposition to disease and its potential therapeutic response. Do nutraceuticals have positive or negative effects during chemotherapy? The use of nutraceutical supplements in cancer patients is a controversial debate without a definitive conclusion to date. During cancer treatment, patients take nutraceuticals to alleviate drug toxicity and improve long-term results. Some nutraceuticals may potentiate the effect of cytotoxic chemotherapy by inducing cell growth arrest, cell differentiation, and alteration of the redox state of cells, but in some cases, high levels of them may interfere with the effectiveness of chemotherapy, making cancer cells less reactive to chemotherapy. In this review, we highlighted the emerging opinions and data on the pros and cons on the use of nutraceutical supplements during chemotherapy. Full article

(This article belongs to the Special Issue Nutraceuticals in Cancer and Disease Prevention)

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26 pages, 1186 KiB

Open AccessReview

An Overview on the Anticancer Activity of Azadirachta indica (Neem) in Gynecological Cancers

by Marius Alexandru Moga, Andreea Bălan, Costin Vlad Anastasiu, Oana Gabriela Dimienescu, Carmen Daniela Neculoiu and Claudia Gavriș

Int. J. Mol. Sci. 2018, 19(12), 3898; https://doi.org/10.3390/ijms19123898 - 05 Dec 2018

Cited by 44 | Viewed by 12790

Abstract

In recent years, a wide range of studies have pointed out the importance of nutraceuticals as reservoirs of therapeutic compounds for several diseases, including cancer. This study is centered on the role of some nutraceuticals as anticancer agents and on their efficiency in [...] Read more.

In recent years, a wide range of studies have pointed out the importance of nutraceuticals as reservoirs of therapeutic compounds for several diseases, including cancer. This study is centered on the role of some nutraceuticals as anticancer agents and on their efficiency in the oncological gynecological field. Gynecological cancers include cervical, ovarian, and breast neoplasia and these are the major causes of morbidity and mortality in the female population. Cervical neoplasia affects sexually active women aged between 30 and 40 years and is considered the second leading cause of death for women worldwide. Epidemiological studies have shown a strong association of this cancer with human papilloma virus (HPV) infection, independent of any others risk factors. Ovarian cancer represents about 4% of all women’s cancers and breast neoplasia registers 52.8 new cases per 100,000 women annually. Since ancient times, herbal therapies have shown a wide range of beneficial effects and a high potential for safeguarding human health. Azadirachta indica (Neem) is a medicinal plant of Indian origin, a tree with more of 140 isolated compounds and at least 35 biologically active principles that have shown an important influence as tumor suppressors by interfering with the carcinogenesis process. Used for centuries in Asia as a natural remedy for cancer, neem compounds present in bark, leaves, flowers, and seed oil have been shown to possess properties such as chemopreventive capacity, apoptotic activities, immunomodulatory effects, and induction of p53-independent apoptosis. The current study is a systematic literature review based on the anticarcinogenic potential of neem compounds in gynecological cancers. Full article

(This article belongs to the Special Issue Nutraceuticals in Cancer and Disease Prevention)

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