Hiroshi Nishida’s research while affiliated with Shimane Institute Of Health Science and other places

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Publications (50)


Chemical structures of squalene (A) and SQOOH isomers (B).
Representative LC−MS/MS chromatograms demonstrating the analysis of SQOOH isomers in human skin surface lipids (A) and in vitro singlet oxygen oxidation products of squalene (B). The following MRM pairs were utilized for the analysis of each SQOOH isomer: m/z 465.4 > 433.5, 2‐OOH‐SQ; m/z 465.4 > 395.3, 3‐OOH‐SQ; m/z 465.4 > 365.3, 6‐OOH‐SQ; m/z 465.4 > 297.2, 10‐OOH‐SQ; m/z 465.4 > 181.1, 7‐OOH‐SQ; m/z 465.4 > 229.2, 11‐OOH‐SQ.
Quantitative values of each SQOOH isomer in human skin surface lipids. Data are expressed as means ± SE (n = 5).
Representative LC−MS/MS chromatograms demonstrating the analysis of SQOOH isomers in shark liver oil supplements (A and B) and in vitro free radical oxidation products of squalene (C). The following MRM pairs were utilized for the analysis of each SQOOH isomer: m/z 465.4 > 433.5, 2‐OOH‐SQ; m/z 465.4 > 395.3, 3‐OOH‐SQ; m/z 465.4 > 365.3, 6‐OOH‐SQ; m/z 465.4 > 297.2, 10‐OOH‐SQ; m/z 465.4 > 181.1, 7‐OOH‐SQ; m/z 465.4 > 229.2, 11‐OOH‐SQ.
Quantitative values of each SQOOH isomer in various shark liver oil supplement samples. Data are expressed as means ± SE (n = 3).
Evaluation of squalene oxidation mechanisms in human skin surface lipids and shark liver oil supplements
  • Article
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August 2019

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213 Reads

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13 Citations

Naoki Shimizu

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Kiyotaka Nakagawa

Squalene is a terpenoid found in human skin surface lipids (SSLs) and foods that possesses beneficial properties. However, since oxidation of squalene causes various complications, it is necessary to identify the mechanisms by which squalene is oxidized. In this study, we aimed to determine the oxidation mechanisms of squalene in SSLs and shark liver oil (SLO) supplements by the analysis of squalene monohydroperoxide (SQOOH) isomers, on the basis of our previous finding that different oxidation mechanisms yield different SQOOH isomers. Liquid chromatography–tandem mass spectrometry analysis of SQOOH isomers revealed that squalene in human SSLs was oxidized by singlet oxygen oxidation, whereas squalene in SLO was oxidized mainly by free radicals. As a result, we have presented the first evidence suggesting that the analysis of SQOOH isomers enables estimation of oxidation mechanisms. Estimating oxidation mechanisms by analyzing SQOOH isomers may provide a foundation for the prevention of skin diseases and food deterioration via regulation of squalene oxidation.

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The Adjuvant Effect of Squalene, an Active Ingredient of Functional Foods, on Doxorubicin-Treated Allograft Mice

June 2019

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95 Reads

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23 Citations

Many functional foods or physiologically active ingredients derived from plants and animals are actively being investigated for their role in chronic disease prevention. Squalene (SQ) is found as active ingredient in the functional foods predominantly present in olive oil and shark liver oil. It is known that during chemotherapy anticancer drugs induce inflammation. SQ has been thought to prevent and suppress inflammation; however, there is little direct evidence available. We examined the adjuvant effect of SQ on tumor-transplanted mice along with anticancer drug doxorubicin (DOX). SQ significantly suppressed the DOX-induced increase in prostaglandin E2 (PGE2) concentration (P < 0.05) in plasma of tumor-bearing mice. SQ inhibited the numbers of writhing response (P < 0.05), formalin-induced pain and decreased COX-2 and substance P expression in the tumor tissue compared to control mice and also enhanced the antitumor efficacy of DOX in allograft mice. Thus, SQ reduces inflammation through modulation of PGE2 production indicating its potential as an adjuvant during chemotherapy in tumor-bearing mice.


Pork Loin Treated with High Hydrostatic Pressure as a Food Processing Technology: Subacute Toxicity of the Freeze-Dried Powder and Cytotoxicity of the Methanol Extracts

September 2017

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27 Reads

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1 Citation

Food Safety

High hydrostatic pressure (HP) treatment is used in food processing owing to its sterilization effect. Meat or meat products are sterilized and become tender by HP processing. Therefore, the variety of HP-processed meat products has increased worldwide. However, little is known about the safety of HP-processed meat products. The aim of this study was to determine the effects of HP processing and HP combined with 0.4 M sodium carbonate treatment (HP-Na) on pork loins and to evaluate the subacute toxicity and cytotoxicity of these processing methods. In an in vivo study, we performed 90- and 180-day feeding tests in mice and did not detect any adverse effects in HP-processed and HP-Na-processed pork loins. In addition, we evaluated the cytotoxicity of HP-processed meats, and did not observe any obvious toxicity associated with pork loin extracts in vitro. These results suggest that HP is not associated with risk factors during processing. Fullsize Image


Cytotoxic compounds against cancer cells from Bombyx mori inoculated with Cordyceps militaris

February 2017

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46 Reads

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9 Citations

Bioscience Biotechnology and Biochemistry

Two compounds, 3′-deoxyinosine and cordycepin, were isolated from Bombyx mori inoculated with Cordyceps militaris. In the bioassay examining cytotoxicity against cancer cells, both compounds showed toxicity against A549, PANC-1, and MCF-7 cancer cells.


Synergistic Anti-cancer Effect of Rice Bran Oil Componentsこめ油成分を活用した相乗的ながん抑制効果

January 2017

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5 Reads

Oleoscience

Rice bran oil contains various bioactive compounds, including tocotrienol (T3; unsaturated vitamin E), ferulic acid (FA), γ-oryzanol, β-sitosterol, and thus much attention has been focused on the health benefits of its components. We previously demonstrated that T3 has potent anti-tumor activity, and that δ-T3 has the most potent anti-cancer activity (i.e., antiangiogenesis and telomerase inhibition) of the four T3 isomers. Since the bioavailability of orally ingested T3 is lower than that of tocopherol (well-known vitamin E), several studies are in progress to screen for molecules that can synergize with T3 in order to augment its potency. In this review, we summarize the current status of synergistic effects of rice bran oil components, especially T3 and FA, on cancer cell growth and cellular telomerase.


A Combination of δ-Tocotrienol and Ferulic Acid Synergistically Inhibits Telomerase Activity in DLD-1 Human Colorectal Adenocarcinoma Cells

December 2016

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23 Reads

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28 Citations

Journal of Nutritional Science and Vitaminology

Rice bran is a rich source of functional compounds, including tocotrienol (T3) and ferulic acid (FA). We previously investigated the anti-cancer properties of T3, and reported on the potent inhibitory effects of δ-T3 on angiogenesis and telomerase activity. In this study, we examined the synergistic suppressive effects of the combination of δ-T3 and FA on telomerase activity in DLD-1 human colorectal adenocarcinoma cells. Co-treatment with δ-T3 and FA significantly decreased cellular telomerase activity compared to treatment with δ-T3 alone, whereas FA alone had no inhibitory effect. Co-treatment with δ-T3 and FA also synergistically down-regulated the expression of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, indicating that the enzymatic activity of telomerase is controlled at the transcriptional level. FA significantly increased the intracellular concentration of δ-T3, suggesting that FA improved the bioavailability of δ-T3, thereby increasing the inhibitory potency of δ-T3 on telomerase. FA may be a promising candidate for augmenting the anti-cancer activity of δ-T3. © 2016, Center for Academic Publications Japan. All rights reserved.


The Fruit of Acanthopanax Senticosus (Rupr. Et Maxim) Harms, or Goka, Improves Insulin Resistance in High-Fat Diet Fed Obese Mice

November 2016

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11 Reads

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3 Citations

Free Radical Biology and Medicine

Insulin resistance is a risk factor for metabolic disease including type 2 diabetes and dyslipidemia that is induced by obesity associated chronic inflammation and oxidative stress. Therefore, the treatments of the inflammation and/or oxidative stress are important to improve the insulin resistance. Acanthopanax Senticosus (Rupr. et Maxim) Harms (Goka) has been applied to traditional Chinese medicine, due to its anti-inflammatory and anti-oxidative effects (though detailed information are not available to date). Thus, Goka might lead to the improvement in the status of insulin resistance. The aim of the present study was to investigate whether Goka fruit (GF) improves insulin resistance via the suppression of inflammatory mediators and oxidative stress. After eight weeks induction of high-fat diet, mice were divided into four groups; vehicle (HFD), HFD-GF (500 mg/kg and 1000 mg/kg), and HFD-metformin (MET) (300 mg/kg) for 12 weeks of oral administration, respectively. Insulin tolerance test revealed that HFD-GF groups significantly decreased plasma glucose level than HFD. HFD-GF group exhibited significant reduction of hepatic lipid accumulation rather than HFD. In the adipose tissues, expression of cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-α) were tend to decreased by HFD-GF administration rather than HFD. Thiobarbituric acid reactive substance (TBARS) in HFD-GF were tend to lower than that of the HFD group. These results suggest that GF improved the HFD induced insulin resistance through the alleviate obesity associated inflammation and oxidative stress in the peripheral tissue.


Figure 3. Epidermal growth factor receptor (EGFR) and its downstream signaling proteins. EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; JAK, Janus kinase; STAT, signal transducer and activator of transcription; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase; Akt, protein kinase B; P, phosphorylation. Arrows and perpendicular lines indicate activation/induction and inhibition/suppression, respectively.
Figure 4. Crosstalk between EGFR and nuclear factor-κB (NF-κB) signaling pathway. PGE 2 , prostaglandin E 2 ; IκB, inhibitors of κB; IKK, IκB kinase; COX-2, cyclooxygenase-2; mTOR, mammalian target of rapamycin; Ub, ubiquitylation; PLA 2 , phosphorlipase A 2 ; P, phosphorylation. Arrows and perpendicular lines indicate activation/induction and inhibition/suppression, respectively.  
Figure 5. Metabolic pathway of γ-T3. The second and fourth cycles of β-oxidation are needed for 2,4-dienoyl-CoA reductase (A) and 3,2-enoyl-CoA isomerase (B). Arrows and perpendicular lines indicate activation/induction and inhibition/suppression, respectively.  
Figure 5. Metabolic pathway of γ-T3. The second and fourth cycles of β-oxidation are needed for 2,4-dienoyl-CoA reductase (A) and 3,2-enoyl-CoA isomerase (B). Arrows and perpendicular lines indicate activation/induction and inhibition/suppression, respectively.  
Synergistic Anticancer Effect of Tocotrienol Combined with Chemotherapeutic Agents or Dietary Components: A Review

September 2016

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12,938 Reads

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47 Citations

International Journal of Molecular Sciences

Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, apoptosis induction, antiangiogenesis, anti-metastasis, nuclear factor-?B suppression, and telomerase inhibition. Owing to a difference in the affinity of T3 and Toc for the ?-tocopherol transfer protein, the bioavailability of orally ingested T3 is lower than that of Toc. Furthermore, cellular uptake of T3 is interrupted by coadministration of ?-Toc in vitro and in vivo. Based on this, several studies are in progress to screen for molecules that can synergize with T3 in order to augment its potency. Combinations of T3 with chemotherapeutic drugs (e.g., statins, celecoxib, and gefitinib) or dietary components (e.g., polyphenols, sesamin, and ferulic acid) exhibit synergistic actions on cancer cell growth and signaling pathways. In this review, we summarize the current status of synergistic effects of T3 and an array of agents on cancer cells, and discuss their molecular mechanisms of action. These combination strategies would encourage further investigation and application in cancer prevention and therapy.


The fruit of Acanthopanax senticosus (Rupr. et Maxim) Harms improves insulin resistance and hepatic lipid accumulation by modulation of liver AMP-activated protein kinase activity and lipogenic gene expression in high-fat-diet-fed obese mice

September 2016

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53 Reads

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33 Citations

Nutrition Research

Obesity-associated insulin resistance is a major risk factor for most metabolic diseases, including dyslipidemia and type 2 diabetes. Acanthopanax senticosus (Rupr. et Maxim) Harms (Goka) root has been used in traditional Chinese Medicine for treatment of diabetes and other conditions; however, little is known about the effects of Goka fruit (GF). GF is rich in anthocyanin, which has beneficial effects on obesity and insulin resistance via activation of AMP-activated protein kinase (AMPK). We hypothesized that GF can improve obesity-associated insulin resistance. The aim of the present study was to investigate whether GF improves insulin resistance in high-fat diet (HFD)-induced obese mice. HFD mice treated with GF (500 mg/kg and 1000 mg/kg) for 12 weeks showed an improved glucose tolerance and insulin sensitivity, as well as reduced plasma insulin, and liver lipid accumulation. Moreover, GF administration to HFD mice resulted in downregulation of fatty acid synthase expression and upregulation of cholesterol 7-alpha-hydroxylase expression in the liver. Notably, AMPK phosphorylation in the liver increased after GF administration. In summary, GF supplementation improved obesity-associated insulin resistance and hepatic lipid accumulation through modulation of AMPK activity and lipid metabolism-associated gene expression.


Squalene Inhibits ATM-Dependent Signaling in γIR-Induced DNA Damage Response through Induction of Wip1 Phosphatase

January 2016

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164 Reads

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16 Citations

Ataxia telangiectasia mutated (ATM) kinase plays a crucial role as a master controller in the cellular DNA damage response. Inhibition of ATM leads to inhibition of the checkpoint signaling pathway. Hence, addition of checkpoint inhibitors to anticancer therapies may be an effective targeting strategy. A recent study reported that Wip1, a protein phosphatase, de-phosphorylates serine 1981 of ATM during the DNA damage response. Squalene has been proposed to complement anticancer therapies such as chemotherapy and radiotherapy; however, there is little mechanistic information supporting this idea. Here, we report the inhibitory effect of squalene on ATM-dependent DNA damage signals. Squalene itself did not affect cell viability and the cell cycle of A549 cells, but it enhanced the cytotoxicity of gamma-irradiation (γIR). The in vitro kinase activity of ATM was not altered by squalene. However, squalene increased Wip1 expression in cells and suppressed ATM activation in γIR-treated cells. Consistent with the potential inhibition of ATM by squalene, IR-induced phosphorylation of ATM effectors such as p53 (Ser15) and Chk1 (Ser317) was inhibited by cell treatment with squalene. Thus, squalene inhibits the ATM-dependent signaling pathway following DNA damage through intracellular induction of Wip1 expression.


Citations (40)


... As a natural antioxidant, squalene protects against the oxidation of PUFAs to varying degrees. Thus, for example, a previous study showed that squalene protected against PUFAs oxidation by up to 50%, implying that squalene may protect PUFAs by binding to singlet oxygen or free radicals (Shimizu et al., 2019). ...

Reference:

How lipids, as important endogenous nutrient components, affect the quality of aquatic products: An overview of lipid peroxidation and the interaction with proteins
Evaluation of squalene oxidation mechanisms in human skin surface lipids and shark liver oil supplements

... It is a major constituent (12%) of human sebum, and is present in various tissues, contributing to skin hydration and protection [30]. Due to its widespread occurrence and beneficial properties, squalene has been extensively studied and used in industries such as pharmaceuticals, cosmetics, and food [8,31,32]. ...

The Adjuvant Effect of Squalene, an Active Ingredient of Functional Foods, on Doxorubicin-Treated Allograft Mice
  • Citing Article
  • June 2019

... Its active ingredients include glycosides, polysaccharides, flavonoids, lignans, triterpenoids, and organic acids (4). Modern pharmacology has revealed that AS can regulate immunity, treat cardiovascular system diseases, and has antiinflammatory, antitumor, and anti-oxidation effects (5). Glycosides repel insects, have antibacterial properties, and can improve sleep (6). ...

The Fruit of Acanthopanax Senticosus (Rupr. Et Maxim) Harms, or Goka, Improves Insulin Resistance in High-Fat Diet Fed Obese Mice
  • Citing Article
  • November 2016

Free Radical Biology and Medicine

... Two compounds were isolated from Bombyx mori L. infected with the fungus Cordyceps militaris i.e., 3′-deoxyinosine and cordycepin. Both these compounds showed cytotoxic activity against A549, PANC-1, and MCF-7 cancer cells (Qiu et al., 2017). The peptide, cecropin A isolated from B. mori has shown two activities-antimicrobial and antitumor (esophageal cancer cells) (Ramos-Martín et al., 2022). ...

Cytotoxic compounds against cancer cells from Bombyx mori inoculated with Cordyceps militaris

Bioscience Biotechnology and Biochemistry

... In general, some of the molecular targets and pathways affected by T3 in humans cancer cell lines appear to be common regardless of the type of the malignancy, such as induction of cell death through apoptosis, 9,10,26,33,38,40,42,[44][45][46][49][50][51][52][54][55][56][57]61,[63][64][65] followed by inhibiting proliferation through inhibition of cell cycle [9][10][11]26,34,35,37,40,43,[45][46][47][48][49][54][55][56][57]60,61,65 or inhibition of angiogenesis, 43,60 cell migration and invasion 10,45,60,62,65 (Figure 3). In a smaller number of studies, the T3 appear to exert the anticancer effects through antiglycolytic effect, 36 suppressing cancer stem cells, 33 antioxidant and synergism with other compounds and antineoplastic therapeutic drugs. ...

A Combination of δ-Tocotrienol and Ferulic Acid Synergistically Inhibits Telomerase Activity in DLD-1 Human Colorectal Adenocarcinoma Cells
  • Citing Article
  • December 2016

Journal of Nutritional Science and Vitaminology

... Although the precise mechanism by which tocotrienols exert their cytotoxic effects is not directly addressed in this study, the existing evidence suggests that tocotrienols may induce oxidative stress, activate the apoptotic signaling pathways, inhibit the activation of transcription factors such as NF-κB, and suppress growth receptor signaling [27]. Additionally, tocotrienols appear to have relative selectivity for cancer cells, with reduced toxicity toward normal cells [26], and have a synergistic anticancer effect when combined with chemotherapeutic agents such as gefitinib [28]. ...

Synergistic Anticancer Effect of Tocotrienol Combined with Chemotherapeutic Agents or Dietary Components: A Review

International Journal of Molecular Sciences

... The trough value was basically below the lower limit of quantification, and the concentration of each compound did not show a cumulative trend in the normal and model groups after multiple administrations of ESF extract from day 2 to day 6. ESF could improve obesity-related lipid and glucose metabolism disorders and prevent T2DM [16]. The pathogenesis of T2DM is related to oxidative stress, inflammation, adipokines, and insulin secretion disorders [17]. ...

The fruit of Acanthopanax senticosus (Rupr. et Maxim) Harms improves insulin resistance and hepatic lipid accumulation by modulation of liver AMP-activated protein kinase activity and lipogenic gene expression in high-fat-diet-fed obese mice
  • Citing Article
  • September 2016

Nutrition Research

... Squalene, shows excellent antioxidant properties (Kojima et al., 1981;Martínez-Beamonte et al., 2018;Tatewaki et al., 2016). Due to the properties of high cell membrane absorption, high bioavailability, and relatively low cost, plant-derived SQ has the potential to be applied as a feed additive for pigs Tatewaki et al., 2016). ...

Squalene Inhibits ATM-Dependent Signaling in γIR-Induced DNA Damage Response through Induction of Wip1 Phosphatase

... Acanthopanax senticosus (A. senticosus), belonging to the family Araliaceae, genus Acanthopanax, is widely distributed throughout northern Asia, especially in northeastern China, the Russian Far East, Japan, and Korea [1]. A. senticosus is used as an analogy with ginseng, also known as Siberian ginseng, a famous traditional Chinese herb, which is rich in polysaccharides, polyphenols, flavonoids and saponins, and other active ingredients, and, therefore, has very positive pharmacological effects, mainly in enhancing the immunity and antioxidant capacity of animal organisms [2][3][4], anti-stress [5], protecting the nervous system and cardiac muscle cells [6], enhancing anti-inflammatory and antibacterial effects [7,8], and hypoglycemic effects [9]. ...

Anti-hyperlipidemic effect of Acanthopanax senticosus (Rupr. et Maxim) Harms leaves in high-fat diet fed mice
  • Citing Article
  • December 2015

... acephala DC.) ( Figure 1) is a new variety of vegetable created by crossbreeding kale and brussel sprouts (Brassica oleracea species). Its anti-obesity effects were previously demonstrated in mice fed a high-fat diet containing 5% freeze-dried Petit vert [10]; however, the composition and identity of the active compounds present in Petit vert remain unclear. Since only the leafy side shoots of Petit vert are harvested, the outer leaves, which are of high nutritional value, are typically discarded because they contain rough fibers. ...

Anti-obesitic Effect of Petit Vert on Mice Fed a High-fat Diet
  • Citing Article
  • August 2011

Nihon Eiyō Shokuryō Gakkai shi = Nippon Eiyō Shokuryō Gakkaishi = Journal of Japanese Society of Nutrition and Food Science