β-Hydroxybutyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5 in human renal cortical epithelial cells

Mikami, Daisuke; Kobayashi, Mamiko; Uwada, Junsuke; Yazawa, Takashi; Kamiyama, Kazuko; Nishimori, Kazuhisa; Nishikawa, Yudai; Morikawa, Yukie; Yokoi, Seiji; Takahashi, Naoki; Kasuno, Kenji; Taniguchi, Tadatsugu; Iwano, Masayuki

doi:10.1016/j.lfs.2019.03.008

Cited by 25 publications

(11 citation statements)

References 31 publications

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“…β-HB is not only a metabolic intermediate but also possesses a variety of signaling functions (37). It is known to downregulate caspase-3 and to significantly increase the expression of Bcl-2 (38,39). Epoxyeicosatrienoic acids (EETs) are biologically active epoxide derivatives products of arachidonic acid that are formed by cytochrome P450 (CYP) epoxygenases, and they exhibit potent antiinflammatory properties and vascular-protecting effects (40,41).…”

Section: Discussionmentioning

confidence: 99%

Chinese medicine Bazi Bushen capsule improves lipid metabolism in ovariectomized female ApoE−/− mice

Huang

Hu²,

Chang³

et al. 2020

Ann Palliat Med

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Background: Dyslipidemia is one of the mechanisms of atherosclerosis (AS). Depletion of estrogen plays a key role in the pathogenesis of postmenopausal AS in women, and the blood lipid levels of women are closely related to endogenous estrogen levels. Phytoestrogens (PEs) exert estrogenic effects, including protection against AS, without the adverse effects of estrogen administration. Bazi Bushen capsule (BZBS) is a traditional Chinese medicine herbal compound prescription that has been shown to contain 11 unique PEs.In the present study, we assessed the effects of BZBS against lipid metabolism disorders.Methods: All ApoE -/mice underwent ovary ligation and bilateral ovariectomy (Ovx) to induce surgical menopause (Ovx/ApoE -/mice), whereas the C57BL/6J mice underwent sham surgery (needle threading).Ovx/ApoE -/mice were given a high-fat diet without estrogen and C57BL/6J mice were given a normal diet for 12 weeks. Ovx/ApoE -/mice treated with G1, a highly selective G-protein-coupled estrogen receptor1 (GPER1) agonist with proven activity against AS, were used as positive controls. Estrogen levels were measured and uterine atrophy index was calculated to determine the success of the model. Serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured in each group. The orthogonal projections to latent structures discriminant analysis (OPLS-DA) model was used to separate the groups, MetaboAnalyst was then used to analyze the metabolic pathway, and the most representative metabolites were finally identified.Results: Removal of bilateral ovaries resulted in successful surgical menopause models, where BZBS increased estrogen levels but did not increase the risk of uterine proliferation. BZBS attenuated dyslipidemia, including decreased TG, TC, and LDL-C levels, but increased HDL-C levels. The OPLS-DA model successfully distinguished the groups with good predictive ability and revealed their tendency to separate from each other. MetaboAnalyst suggested that both the G1 group and high-dose BZBS (HD-BZ) could improve the effect of lipid metabolism: the glycerophospholipid metabolism pathway was mainly improved by the G1 group, while the inositol phosphate metabolism pathway was mainly improved by the HD-BZ group. For the four compounds with the highest content, the concentrations of docosahexaenoic acid (DHA), 3-hydroxybutyric acid, and 5(Z), 8(Z), 11(Z)-eicosatrienoic acid were dramatically lower in the model group compared to the control group. Lysophosphatidylethanolamine (18:0) was higher in the model group than in the control group. BZBS corrected these effects.Conclusions: BZBS treatment reduced serum lipid levels and improved fatty acid metabolism in high-fat diet-fed, surgically induced menopausal ApoE -/mice.

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Section: Discussionmentioning

confidence: 99%

Chinese medicine Bazi Bushen capsule improves lipid metabolism in ovariectomized female ApoE−/− mice

Huang

Hu²,

Chang³

et al. 2020

Ann Palliat Med

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“…[34][35][36] 4-Hydroxybutyric acid, like other ketone bodies, is a fatty acid derivative molecule that is produced in the liver and increases in fasting or exercise and serves as an energy source. 37 It has been also stated that the increase in the amount of 4-hydroxybutyric acid is related to the up-regulation of fatty acid oxidation defined OC tumors and metastases. 38 An increase in the amount of fatty acid required in the case of lipogenesis has been reported in many malignancies such as ovarian and breast cancer because of membrane formation in the cells.…”

Section: Discussionmentioning

confidence: 99%

“…L-arginine is a nitrogen source for nitric oxide needed by immune cells in defense mechanisms. 37 It is also involved in urea synthesis to synthesize creatine and maintain the whole body nitrogen balance. 61 In addition, as it is necessary for cellular growth, rapid growth conditions such as malignancy differ significantly from healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

Discovery of metabolomic biomarkers for discriminating platinum-sensitive and platinum-resistant ovarian cancer by using GC-MS

Eroglu

Tunug

Geckil

et al. 2021

Eur J Mass Spectrom (Chichester)

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This study aims to determine ovarian cancer (OC) patients with platinum resistance for alternative treatment protocols by using metabolomic methodologies. Urine and serum samples of platinum-resistant and platinum-sensitive OC were analyzed using GC-MS. After data processing of GC-MS raw data, multivariate analyses were performed to interpret complex data for biologically meaningful information and to identify the biomarkers that cause differences between two groups. The biomarkers were verified after univariate, multivariate, and ROC analysis. Finally, metabolomic pathways related to group separations were specified. The results of biomarker analysis showed that 3,4-dihydroxyphenylacetic acid, 4-hydroxybutyric acid, L-threonine, D- mannose, and sorbitol metabolites were potential biomarkers in urine samples. In serum samples, L-arginine, linoleic acid, L-glutamine, and hypoxanthine were identified as important biomarkers. R2Y, Q2, AUC, sensitivity and specificity values of platinum-resistant and sensitive OC patients’ urine and serum samples were 0.85, 0.545, 0.844, 91.30%, 81.08 and 0.570, 0.206, 0.743, 77.78%, 74.28%, respectively. In metabolic pathway analysis of urine samples, tyrosine metabolism and fructose and mannose metabolism were found to be statistically significant (p < 0.05) for the discrimination of the two groups. While 3,4-dihydroxyphenylacetic acid, L-tyrosine, and fumaric acid metabolites were effective in tyrosine metabolism. D-sorbitol and D-mannose metabolites were significantly important in fructose and mannose metabolism. However, seven metabolomic pathways were significant (p < 0.05) in serum samples. In terms of p-value, L-glutamine in the nitrogen metabolic pathway from the first three pathways; L-glutamine and pyroglutamic acid metabolites in D-glutamine and D-glutamate metabolism. In the arginine and proline metabolic pathway, L-arginine, L-proline, and L-ornithine metabolites differed significantly between the two groups.

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“…However, controversial results have been reported concerning acetylation of histone H3 with CDDP treatment. On the one hand, CDDP reduces levels of histone H3 acetylation in the injured kidney tissue [ 46 , 65 ]; however, another study demonstrated an increase in histone H3 acetylation after CDDP treatment in human renal cortical epithelial (HRCE) cells [ 66 ]. Although HDACs inhibitors do not prevent the DNA adducts formation and the initial damage response, they can interfere with the subsequent signaling [ 67 ].…”

Section: Cisplatin Nephrotoxicity and Histone Modificationsmentioning

confidence: 99%

“…Additionally, HDAC6 inhibition by trichostatin A (TSA) reduces the renal pathological damage caused by CDDP treatment [ 65 ]. Finally, reduction of HDAC4 and HDAC5 with LMK-235 blocks the caspase-3 cleavage in HRCE cells [ 66 ]. The use of TSA, valproate (VPA) or suberoylanilide hydroxamic acid (SAHA) can confer kidney protection during CDDP treatment by H3K27 acetylation and IL-9 down-regulation [ 62 ], increase of BMP-7 [ 63 ], AMWAP [ 68 , 69 ] and PSTPIP2 [ 70 ]; increased CREB phosphorylation [ 71 ], reduction of caspase-3 activation [ 71 ] or by autophagy stimulation [ 72 ].…”

Section: Cisplatin Nephrotoxicity and Histone Modificationsmentioning

confidence: 99%

Epigenetic Mechanisms Involved in Cisplatin-Induced Nephrotoxicity: An Update

Loren

Saavedra

et al. 2021

Pharmaceuticals

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Cisplatin is an antineoplastic drug used for the treatment of many solid tumors. Among its various side effects, nephrotoxicity is the most detrimental. In recent years, epigenetic regulation has emerged as a modulatory mechanism of cisplatin-induced nephrotoxicity, involving non-coding RNAs, DNA methylation and histone modifications. These epigenetic marks alter different signaling pathways leading to damage and cell death. In this review, we describe how different epigenetic modifications alter different pathways leading to cell death by apoptosis, autophagy, necroptosis, among others. The study of epigenetic regulation is still under development, and much research remains to fully determine the epigenetic mechanisms underlying cell death, which will allow leading new strategies for the diagnosis and therapy of this disease.

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β-Hydroxybutyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5 in human renal cortical epithelial cells

Cited by 25 publications

References 31 publications

Chinese medicine Bazi Bushen capsule improves lipid metabolism in ovariectomized female ApoE−/− mice

Chinese medicine Bazi Bushen capsule improves lipid metabolism in ovariectomized female ApoE−/− mice

Discovery of metabolomic biomarkers for discriminating platinum-sensitive and platinum-resistant ovarian cancer by using GC-MS

Epigenetic Mechanisms Involved in Cisplatin-Induced Nephrotoxicity: An Update

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