The Experts below are selected from a list of 828 Experts worldwide ranked by ideXlab platform
Mitsuru Shindo - One of the best experts on this subject based on the ideXlab platform.
-
Bongkrekic Acid facilitates glycolysis in cultured cells and induces cell death under low glucose conditions
Biochemistry and biophysics reports, 2019Co-Authors: Arihiro Kano, Takuma Iwasaki, Mitsuru ShindoAbstract:Abstract Bongkrekic Acid (BKA) inhibits adenine nucleotide translocator (ANT) and suppresses ADP/ATP exchange in the mitochondrial inner membrane. Previously, we demonstrated that BKA exhibited cytotoxic effects on 4T1 tumor cells, depending on the cell number in the culture, but not on NIH3T3 cells. However, the cause of this differential sensitivity was unelucidated. Here we demonstrate that BKA reduced the O2 consumption in both cell lines and increased the mitochondrial membrane potential, thereby facilitating glucose consumption. BKA reduced cellular ATP in 4T1 cells in a dose-dependent manner but not in NIH3T3 cells. The cellular ATP of 4T1 cells was decreased with a reduced glucose concentration in the media, but that of NIH3T3 cells remained constant. We also demonstrated that BKA-induced cell death in both cell lines in low glucose media; however, the susceptibility to the reduced glucose concentration was slightly higher in 4T1 cells, which may be attributed to the difference in the dependency on glycolysis as their energy source. These results indicate that 4T1 tumor cells rely heavily on glucose for energy production. Our data demonstrate that BKA disturbs ATP production in mitochondria and increases the susceptibility to a low glucose condition.
-
Synthesis and evaluation of simplified functionalized Bongkrekic Acid analogs
Tetrahedron, 2018Co-Authors: Satoshi Fujita, Masaki Suyama, Kenji Matsumoto, Atsushi Yamamoto, Takenori Yamamoto, Yuka Hiroshima, Takayuki Iwata, Arihiro Kano, Yasuo Shinohara, Mitsuru ShindoAbstract:Abstract Bongkrekic Acid (BKA) is a strong inhibitor of adenine nucleotide translocase (ANT), inducing inhibition of adenosine triphosphate synthesis. We designed and synthesized simplified benzene-ring-containing BKA analogs. The key reaction is the one-pot double Sonogashira reaction, which forms the main skeleton. The analogs were efficiently synthesized in 8–10 longest linear sequence steps. This synthetic method can be applied for the preparation of other analogs having different combinations of carbon chain lengths. Furthermore, the allyloxy group on the benzene ring can be easily replaced by other functional groups. Our preliminary biological evaluation based on mitochondrial inhibitory effects revealed the high potency of the analogs bearing the same carbon chain length as that of BKA. In particular, the prefunctionalized analogs are potential ANT inhibitors.
-
A Novel Bongkrekic Acid Analog-Mediated Modulation of the Size of Lipid Droplets: Evidence for the Appearance of Smaller Adipocytes.
Biological & pharmaceutical bulletin, 2017Co-Authors: Hiroyuki Okazaki, Mitsuru Shindo, Satoshi Fujita, Masaki Suyama, Kenji Matsumoto, Shuso Takeda, Hiroyuki Ishii, Yukimi Takemoto, Hironori AramakiAbstract:Thiazolidinediones (TZDs) are known as peroxisome proliferator-activated receptor γ (PPARγ) activators, and are used in the treatment of diabetes. Although the usefulness of TZDs has been demonstrated, some of their side effects are becoming an obstacle to their clinical applicability; edema is known to be evoked by the "structural characteristics" of TZD, but not by the PPARγ activation. Thus, novel therapeutic modalities (i.e., non-TZD-type PPARγ activators) having different structures to those of TZDs are desired. We previously identified Bongkrekic Acid (BKA) as a PPARγ activator using the human breast cancer MCF-7 cell line as a model system. In the present study, we newly synthesized BKA analogs and examined the usefulness of BKA and its analogs as PPARγ activators in differentiated adipocyte cells. Among the chemicals investigated, one of the BKA analogs (BKA-#2) strongly stimulated PPARγ and the differentiation of 3T3-L1 cells similar to pioglitazone, a positive control. Furthermore, BKA-#2 reduced the size of lipid droplets in the mature adipocyte cells. The possible modulation mechanism by BKA-#2 is discussed.
-
Bongkrekic Acid as a Warburg Effect Modulator in Long-term Estradiol-deprived MCF-7 Breast Cancer Cells.
Anticancer research, 2016Co-Authors: Shuso Takeda, Mitsuru Shindo, Kenji Matsumoto, Hiroyuki Okazaki, Taichi Himeno, Kazuhiro Kakizoe, Taichi Kudo, Hironori AramakiAbstract:Background/aim An in vitro cell model of long-term estrogen-deprived MCF-7 (LTED) cells has been utilized to analyze the re-growth mechanisms of breast cancers treated with blockers for estrogen receptor α (ERα) signaling. Bongkrekic Acid (BKA) is a natural toxin isolated from coconut tempeh contaminated with the bacterium Burkholderia cocovenans. Materials and methods LTED cells, MCF-7 cells and MDA-MB-231 cells were employed in the study. After treatment with BKA (chemically synthesized; purity: >98%), several biochemical analyses were carried out. Results LTED cells were categorized into an oxidative phenotype. When LTED cells were treated with BKA, lactate dehydrogenase A (LDH-A)/pyruvate dehydrogenase kinase 4 (PDK4) were down-regulated, thereby prompting the aggressive use of glucose via mitochondrial oxidative phosphorylation and induction of cell death responses. These effects of BKA were not observed in the other breast cancer cells analyzed. Conclusion We suggest the potential of BKA as an experimental tool for the analysis of cancer biology in LTED cells.
-
Molecular Design, Synthesis, and Evaluation of Novel Potent Apoptosis Inhibitors Inspired from Bongkrekic Acid
2016Co-Authors: Katsuhiro Okuda, Keisuke Hasui, Kenji Matsumoto, Masato Abe, Mitsuru ShindoAbstract:Bongkrekic Acid (BKA) is an inhibitor of adenine nucleotide translocase (ANT). Since inhibition of ANT is connected to the inhibition of cytochrome c release from mitochondria, which then results in the suppression of apoptosis, it has been used as a tool for the mechanistic investigation of apoptosis. BKA consists of a long carbon chain with two asymmetric centers, a nonconjugated olefin, two conjugated dienes, three methyl groups, a methoxyl group, and three carboxylic Acids. This complicated chemical structure has caused difficulties in synthesis, supply, and biochemical mechanistic investigations. In this study, we designed and synthesized more simple tricarboxylic Acids that were inspired by the molecular structure of BKA. Their cytotoxicity and apoptosis-preventing activity in HeLa cells and the effect on the mitochondrial inner membrane potential (ΔΨm) in HL-60 cells were then evaluated. All tested tricarboxylic Acid derivatives including BKA showed little toxicity against HeLa cells. BKA and two of the synthesized derivatives significantly suppressed staurosporine (STS)-induced reductions in cell viability. Furthermore, STS-induced ΔΨm collapse was significantly restored by pretreatment with BKA and a tricarboxylic Acid derivative. Other derivatives, in which one of three carboxylic Acids was esterified, exhibited potent toxicity, especially a derivative bearing a carbon chain of the same length as that of BKA. In conclusion, we have developed a new lead compound as an apoptosis inhibitor bearing three carboxylic Acids connected with the proper length of a long carbon chain
Christian Hertweck - One of the best experts on this subject based on the ideXlab platform.
-
Biosynthesis of the Respiratory Toxin Bongkrekic Acid in the Pathogenic Bacterium Burkholderia gladioli
Chemistry & Biology, 2012Co-Authors: Nadine Moebius, Barbara Rohm, Kirstin Scherlach, Claudia Ross, Martin Roth, Christian HertweckAbstract:Summary Bongkrekic Acid (BA), an infamous respiratory toxin of the pathogenic bacterium Burkholderia gladioli , causes lethal intoxications when tempe bongkrek is produced with contaminated Rhizopus oligosporus cultures. Genome sequencing of B. gladioli pathovar cocovenenans unveiled the genetic basis for BA biosynthesis, and pointed to a homologous bon gene cluster in a B. gladioli strain from an infected rice plant. For functional genetics in B. gladioli λ Red recombination was established. Dissection of the modular type I polyketide synthase (a trans -AT PKS) provided insights into complex polyketide assembly. Isoprenoid-like β-branching events and a six-electron oxidation of a methyl group to a carboxylic Acid give rise to the unique branched tricarboxylic fatty Acid. The role of the cytochrome P450 monooxygenase, BonL, was proven by structural elucidation of deoxyBongkrekic Acid from a mutant.
-
Biosynthesis of the mitochondrial adenine nucleotide translocase (ATPase) inhibitor Bongkrekic Acid in Burkholderia gladioli.
Organic & Biomolecular Chemistry, 2010Co-Authors: Barbara Rohm, Kirstin Scherlach, Christian HertweckAbstract:Biosynthetic studies with (13)C-labelled acetates and methionine revealed that the infamous, food-related toxin Bongkrekic Acid from Burkholderia gladioli is a polyketide with acetate-derived beta-branches and a carboxylate terminus derived from the methyl group of an acetate.
Jiann Ruey Hong - One of the best experts on this subject based on the ideXlab platform.
-
Giant seaperch iridovirus (GSIV) induces mitochondria-mediated cell death that is suppressed by Bongkrekic Acid and cycloheximide in a fish cell line
Virus research, 2015Co-Authors: Xin Yu Chen, C M Wen, Jiann Ruey HongAbstract:Giant seaperch iridovirus (GSIV) induces cell death by an unknown mechanism. We postulated that this mechanism involves mitochondria-mediated cell death. Cell viability assays revealed a steady increase in dead grouper fin cells (GF-1) after GSIV infection, from 11% at 2 days post-infection (dpi) to 67% at 5 dpi. Annexin V/PI staining revealed GSIV infection induced apoptosis in a steadily increasing fraction of cells, from 4% at 1 dpi to 29% at 5 dpi. Furthermore, post-apoptotic necrosis was apparent at 4 and 5 dpi in the late replication stage. In the early replication stage, JC-1 dye revealed mitochondrial membrane potential (ΔΨm) loss in 42% of infected cells at 1 dpi, increasing to 98% at 3 dpi. Phosphatidylserine (PS) exposure and loss of ΔΨm from apoptosis/necrosis was attenuated by treatment with the adenine nucleotide translocase inhibitor Bongkrekic Acid (BKA) and the protein synthesis inhibitor cyclohexamide (CHX). These data suggest GSIV induces GF-1 apoptotic/necrotic cell death through pathways that require newly synthesized protein and involve the mitochondrial function.
-
betanodavirus induces phosphatidylserine exposure and loss of mitochondrial membrane potential in secondary necrotic cells both of which are blocked by Bongkrekic Acid
Virology, 2006Co-Authors: Shi Ping Chen, Hueylang Yang, Guor Mour Her, Han You Lin, Mei Fen Jeng, Jiann Ruey HongAbstract:In this study, we show how the red spotted grouper nervous necrosis virus (RGNNV) causes loss of mitochondrial membrane potential and promotes host secondary apoptotic necrosis. RGNNV viral proteins such as protein α (42 kDa) and protein A (110 kDa) were quickly expressed between 12 h and 24 h postinfection (p.i.) in GL-av cells. Annexin V staining revealed that the NNV infection of GL-av cells induced phosphatidylserine (PS) externalization and development of bulb-like vesicles (bleb formation) at 24 h p.i. NNV infection also induced DNA fragmentation detectable by TUNEL assay between 12 h (8%) and 72 h (32%) p.i. Bongkrekic Acid (1.6 μM; BKA) blocked permeability of the mitochondrial permeability transition pore, but cyclosporine A (CsA) did not block secondary necrosis. Finally, secondary necrotic cells were not engulfed by neighboring cells. Our data suggest that RGNNV induces apoptotic death via opening the mitochondrial permeability transition pore thereby triggering secondary necrosis in the mid-apoptotic phase.
Antonio Toninello - One of the best experts on this subject based on the ideXlab platform.
-
carbenoxolone induces oxidative stress in liver mitochondria which is responsible for transition pore opening
Endocrinology, 2005Co-Authors: Mauro Salvi, Cristina Fiore, Valentina Battaglia, M Palermo, Decio Armanini, Antonio ToninelloAbstract:Carbenoxolone (Cbx), a derivative of glycyrrhetinic Acid, which has been found to affect mineralocorticoid and glucocorticoid receptors, induces swelling and membrane potential collapse when added to Ca2+-loaded liver mitochondria at 10 μm concentrations. These effects are strictly correlated with hydrogen peroxide generation, increase in oxygen uptake, and sulfhydryl and pyridine nucleotide oxidation. Cyclosporin A, Bongkrekic Acid, and N-ethylmaleimide completely abolish all the above-described effects, suggesting that Cbx can be considered an inducer of mitochondrial permeability transition by means of oxidative stress. Cbx can also trigger the apoptotic pathway because the above events are also correlated with the loss of cytochrome c. These effects are probably related to the conjugated carbonyl oxygen in C-11, which produces reactive oxygen species by interacting with the mitochondrial respiratory chain, mainly at the level of complex I but, most likely, also with complex III. The oxidative stress i...
-
Menadione induces a low conductance state of the mitochondrial inner membrane sensitive to Bongkrekic Acid.
Free radical biology & medicine, 2004Co-Authors: Antonio Toninello, Mauro Salvi, Matthias Schweizer, Christoph RichterAbstract:Abstract When rat liver mitochondria are allowed to cycle Ca2+ and are incubated in the presence of the pro-oxidant menadione, they undergo swelling, membrane potential (ΔΨ) collapse, and ion release. These effects, which are inhibited by cyclosporin A (CsA), are fully consistent with the opening of the so-called permeability transition pore. However, when Ca2+ cycling is abolished by EGTA, the mitochondria remain energized (ΔΨ collapse and swelling are avoided), but Ca2+ efflux, promoted by the chelating agent, is stimulated by menadione. This stimulation goes together with the release of Mg2+, K+, and adenine nucleotides (AdN) and is inhibited by Bongkrekic Acid (BKA). The effect of menadione is also characterized by biphasic NAD(P)H oxidation which becomes monophasic in the presence of BKA, CsA, or EGTA and by the oxidation of thiol groups not restrained by the above-mentioned inhibitors. These results suggest that BKA acts indirectly by preserving in the matrix a critical amount of AdN without modifying the monophasic oxidation of pyridine nucleotides by menadione. A critical number of thiol groups also seems to be involved in the phenomenon. Their oxidation most probably causes a conformational change on adenine nucleotide translocase with the opening of the “low-conductance state” of the mitochondrial permeability transition, resulting in ion permeability without ΔΨ disruption and mitochondrial swelling.
Kenji Matsumoto - One of the best experts on this subject based on the ideXlab platform.
-
Synthesis and evaluation of simplified functionalized Bongkrekic Acid analogs
Tetrahedron, 2018Co-Authors: Satoshi Fujita, Masaki Suyama, Kenji Matsumoto, Atsushi Yamamoto, Takenori Yamamoto, Yuka Hiroshima, Takayuki Iwata, Arihiro Kano, Yasuo Shinohara, Mitsuru ShindoAbstract:Abstract Bongkrekic Acid (BKA) is a strong inhibitor of adenine nucleotide translocase (ANT), inducing inhibition of adenosine triphosphate synthesis. We designed and synthesized simplified benzene-ring-containing BKA analogs. The key reaction is the one-pot double Sonogashira reaction, which forms the main skeleton. The analogs were efficiently synthesized in 8–10 longest linear sequence steps. This synthetic method can be applied for the preparation of other analogs having different combinations of carbon chain lengths. Furthermore, the allyloxy group on the benzene ring can be easily replaced by other functional groups. Our preliminary biological evaluation based on mitochondrial inhibitory effects revealed the high potency of the analogs bearing the same carbon chain length as that of BKA. In particular, the prefunctionalized analogs are potential ANT inhibitors.
-
A Novel Bongkrekic Acid Analog-Mediated Modulation of the Size of Lipid Droplets: Evidence for the Appearance of Smaller Adipocytes.
Biological & pharmaceutical bulletin, 2017Co-Authors: Hiroyuki Okazaki, Mitsuru Shindo, Satoshi Fujita, Masaki Suyama, Kenji Matsumoto, Shuso Takeda, Hiroyuki Ishii, Yukimi Takemoto, Hironori AramakiAbstract:Thiazolidinediones (TZDs) are known as peroxisome proliferator-activated receptor γ (PPARγ) activators, and are used in the treatment of diabetes. Although the usefulness of TZDs has been demonstrated, some of their side effects are becoming an obstacle to their clinical applicability; edema is known to be evoked by the "structural characteristics" of TZD, but not by the PPARγ activation. Thus, novel therapeutic modalities (i.e., non-TZD-type PPARγ activators) having different structures to those of TZDs are desired. We previously identified Bongkrekic Acid (BKA) as a PPARγ activator using the human breast cancer MCF-7 cell line as a model system. In the present study, we newly synthesized BKA analogs and examined the usefulness of BKA and its analogs as PPARγ activators in differentiated adipocyte cells. Among the chemicals investigated, one of the BKA analogs (BKA-#2) strongly stimulated PPARγ and the differentiation of 3T3-L1 cells similar to pioglitazone, a positive control. Furthermore, BKA-#2 reduced the size of lipid droplets in the mature adipocyte cells. The possible modulation mechanism by BKA-#2 is discussed.
-
Bongkrekic Acid as a Warburg Effect Modulator in Long-term Estradiol-deprived MCF-7 Breast Cancer Cells.
Anticancer research, 2016Co-Authors: Shuso Takeda, Mitsuru Shindo, Kenji Matsumoto, Hiroyuki Okazaki, Taichi Himeno, Kazuhiro Kakizoe, Taichi Kudo, Hironori AramakiAbstract:Background/aim An in vitro cell model of long-term estrogen-deprived MCF-7 (LTED) cells has been utilized to analyze the re-growth mechanisms of breast cancers treated with blockers for estrogen receptor α (ERα) signaling. Bongkrekic Acid (BKA) is a natural toxin isolated from coconut tempeh contaminated with the bacterium Burkholderia cocovenans. Materials and methods LTED cells, MCF-7 cells and MDA-MB-231 cells were employed in the study. After treatment with BKA (chemically synthesized; purity: >98%), several biochemical analyses were carried out. Results LTED cells were categorized into an oxidative phenotype. When LTED cells were treated with BKA, lactate dehydrogenase A (LDH-A)/pyruvate dehydrogenase kinase 4 (PDK4) were down-regulated, thereby prompting the aggressive use of glucose via mitochondrial oxidative phosphorylation and induction of cell death responses. These effects of BKA were not observed in the other breast cancer cells analyzed. Conclusion We suggest the potential of BKA as an experimental tool for the analysis of cancer biology in LTED cells.
-
Molecular Design, Synthesis, and Evaluation of Novel Potent Apoptosis Inhibitors Inspired from Bongkrekic Acid
2016Co-Authors: Katsuhiro Okuda, Keisuke Hasui, Kenji Matsumoto, Masato Abe, Mitsuru ShindoAbstract:Bongkrekic Acid (BKA) is an inhibitor of adenine nucleotide translocase (ANT). Since inhibition of ANT is connected to the inhibition of cytochrome c release from mitochondria, which then results in the suppression of apoptosis, it has been used as a tool for the mechanistic investigation of apoptosis. BKA consists of a long carbon chain with two asymmetric centers, a nonconjugated olefin, two conjugated dienes, three methyl groups, a methoxyl group, and three carboxylic Acids. This complicated chemical structure has caused difficulties in synthesis, supply, and biochemical mechanistic investigations. In this study, we designed and synthesized more simple tricarboxylic Acids that were inspired by the molecular structure of BKA. Their cytotoxicity and apoptosis-preventing activity in HeLa cells and the effect on the mitochondrial inner membrane potential (ΔΨm) in HL-60 cells were then evaluated. All tested tricarboxylic Acid derivatives including BKA showed little toxicity against HeLa cells. BKA and two of the synthesized derivatives significantly suppressed staurosporine (STS)-induced reductions in cell viability. Furthermore, STS-induced ΔΨm collapse was significantly restored by pretreatment with BKA and a tricarboxylic Acid derivative. Other derivatives, in which one of three carboxylic Acids was esterified, exhibited potent toxicity, especially a derivative bearing a carbon chain of the same length as that of BKA. In conclusion, we have developed a new lead compound as an apoptosis inhibitor bearing three carboxylic Acids connected with the proper length of a long carbon chain
-
Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues
Chemistry (Weinheim an der Bergstrasse Germany), 2015Co-Authors: Kenji Matsumoto, Yukiko Sato, Yoshifumi Aso, Satoshi Fujita, Masaki Suyama, Hiroshi Matsuo, Takuya Moriwaki, Satoshi Muroshita, Keishi Monda, Katsuhiro OkudaAbstract:Bongkrekic Acid (BKA), isolated from the bacterium Burkholderia cocovenenans, is an inhibitor of adenine nucleotide translocator, which inhibits apoptosis, and is thus an important tool for the mechanistic investigation of apoptosis. An efficient total synthesis of BKA has been achieved by employing a three-component convergent strategy based on Kocienski-Julia olefination and Suzuki-Miyaura coupling. It is noteworthy that segment B has been prepared as a new doubly functionalized coupling partner, which contributes to shortening of the number of steps. Torquoselective olefination with an ynolate has also been applied for the efficient construction of an unsaturated ester. Furthermore, it is revealed that 1-methyl-2-azaadamantane N-oxyl is an excellent reagent for final oxidation to afford BKA in high yield. Based on the total synthesis, several BKA analogues were prepared for structure-activity relationship studies, which indicated that the carboxylic Acid moieties were essential for the apoptosis inhibitory activity of BKA. More easily available BKA analogues with potent apoptosis inhibitory activity were also developed.