• The Korean Journal of Physiology and Pharmacology
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• v.26 no.5
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• pp.325-333
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• 2022

Heart failure (HF) has become one of the severe public health problems. The detailed role of mitochondrial function in HF was still unclear. Benzoylaconine (BAC) is a traditional Chinese medicine, but its role in HF still needs to be explored. In this study, oxygen-glucose deprivation and reperfusion (OGD/R) was executed to mimic the injury of H9C2 cells in HF. The viability of H9C2 cells was assessed via MTT assay. OGD/R treatment markedly decreased the viability of H9C2 cells, but BAC treatment evidently increased the viability of OGD/R-treated H9C2 cells. The apoptosis of H9C2 was enhanced by OGD/R treatment but suppressed by BAC treatment. The mitochondrial membrane potential was evaluated via JC-1 assay. BAC improved the mitochondrial function and suppressed oxidative stress in OGD/R-treated H9C2 cells. Moreover, Western blot analysis revealed that the protein expression of p-AMPK and PGC-1α were reduced in OGD/R-treated H9C2 cells, which was reversed by BAC. Rescue assays indicated that AMPK attenuation reversed the BAC-mediated protective effect on OGD/R-treated cardiomyocytes. Moreover, BAC alleviated myocardial injury in vivo. In a word, BAC modulated the mitochondrial function in OGD/R-induced cardiomyocyte injury by activation of the AMPK/PGC-1 axis. The findings might provide support for the application of BAC in the treatment of HF.

• BMB Reports
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• v.53 no.2
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• pp.100-105
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• 2020

While liver histopathology is heterogeneous in diabetes, the underlying mechanisms remain unclear. We investigated whether glycemic variation resulting from differential diets can induce heterogeneity in diabetic liver and the underlying molecular mechanisms. We generated end-stage non-obese diabetic model rats by subtotal-pancreatectomy in male Sprague-Dawley rats and ad libitum diet for 7 weeks (n = 33). The rats were then divided into three groups, and fed a standard- or a low-protein diet (18 or 6 kcal%, respectively), for another 7 weeks: to maintain hyperglycemia, 11 rats were fed ad libitum (18AL group); to achieve euglycemia, 11 were calorie-restricted (18R group), and 11 were both calorie- and protein-restricted with the low-protein diet (6R group). Overnight-fasted liver samples were collected after the differential diets together with sham-control (18S group), and histology and molecular changes were compared. Hyperglycemic-18AL showed glycogenic hepatopathy (GH) without steatosis, with the highest GSK-3β inactivation because of Akt activation during hyperglycemia; mitochondrial function was not impaired, compared to the 18S group. Euglycemic-18R showed neither GH nor steatosis, with intermediate GSK-3β activation and mitochondrial dysfunction. However, euglycemic-6R showed both GH and steatosis despite the highest GSK-3β activity and no molecular evidence of increased lipogenesis or decreased ApoB expression, where mitochondrial dysfunction was highest among the groups. In conclusion, heterogeneous liver histopathology developed in end-stage non-obese diabetic rats as the glycemic levels varied with differential diets, in which protein content in the diets as well as glycemic levels differentially influenced GSK-3β activity and mitochondrial function in insulin-deficient state.

• BMB Reports
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• v.48 no.10
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• pp.539-540
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• 2015

It has been proposed that the selective elimination of cancer stem cells (CSCs) using targeted therapy could greatly reduce tumor growth, recurrence, and metastasis. To develop effective therapeutic targets for CSC elimination, we aimed to define the properties of CSC mitochondria, and identify CSC-mitochondria-specific targets in colon cancer. We found that colon CSCs utilize mitochondrial oxidative phosphorylation (OXPHOS) to produce ATP. We also found that forkhead box protein 1 (FOXM1)-induced peroxiredoxin 3 (PRDX3) maintains the mitochondrial function, and the FOXM1/PRDX3 mitochondrial pathway maintains survival of colon CSCs. Furthermore, FOXM1 induces CD133 (PROM1/prominin 1) expression, which maintains the stemness of colon CSCs. Together, our findings indicate that FOXM1, PRDX3, and CD133 are potential therapeutic targets for the elimination of CSCs in colon cancer.

• BMB Reports
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• v.55 no.10
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• pp.494-499
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• 2022

PTEN-induced putative kinase 1 (PINK1) is a serine/threonine kinase that phosphorylates several substrates and exerts neuroprotective effects against stress-induced apoptotic cell death. Mutations in PINK1 have been linked to autosomal recessive forms of Parkinson's disease (PD). Mitophagy is a type of autophagy that selectively promotes mitochondrial turnover and prevents the accumulation of dysfunctional mitochondria to maintain cellular homeostasis. Toll-interacting protein (Tollip) was initially identified as a negative regulator of IL-1β receptor signaling, suppressing inflammatory TLR signaling cascades. Recently, Tollip has been reported to play a role in autophagy and is implicated in neurodegeneration. In this study, we determined whether Tollip was functionally linked to PINK1-mediated mitophagy. Our results demonstrated that Tollip promoted the mitochondrial processing of PINK1 and altered the localization of PINK1, predominantly to the cytosol. This action was attributed to increased binding of PINK1 to mitochondrial processing peptidase β (MPPβ) and the subsequent increase in MPPβ-mediated mitochondrial PINK1 cleavage. Furthermore, Tollip suppressed mitophagy following carbonyl cyanide m-chlorophenylhydrazone-induced mitochondrial dysfunction. These findings suggest that Tollip inhibits mitophagy via the PINK1/parkin pathway upon mitochondrial damage, leading to the blockade of PINK1-mediated neuroprotection.

• Journal of Ginseng Research
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• v.46 no.6
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• pp.750-758
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• 2022

Background: Mild cognitive impairment (MCI) is a transitional condition between normality and dementia. Ginseng is known to have effects on attenuating cognitive deficits in neurogenerative diseases. Ginsenosides are the main bioactive component of ginseng, and their protein targets have not been fully understood. Furthermore, no thorough analysis is reported in ginsenoside-related protein targets in MCI. Methods: The candidate protein targets of ginsenosides in brain tissues were identified by drug affinity responsive target stability (DARTS) coupled with label-free liquid chromatography-mass spectrometry (LC-MS) analysis. Network pharmacology approach was used to collect the therapeutic targets for MCI. Based on the above-mentioned overlapping targets, we built up a proteineprotein interaction (PPI) network in STRING database and conducted gene ontology (GO) enrichment analysis. Finally, we assessed the effects of ginseng total saponins (GTS) and different ginsenosides on mitochondrial function by measuring the activity of the mitochondrial respiratory chain complex and performing molecular docking. Results: We screened 2526 MCI-related protein targets by databases and 349 ginsenoside-related protein targets by DARTS. On the basis of these 81 overlapping genes, enrichment analysis showed the mitochondria played an important role in GTS-mediated MCI pharmacological process. Mitochondrial function analysis showed GTS, protopanaxatriol (PPT), and Rd increased the activities of complex I in a dose-dependent manner. Molecular docking also predicted the docking pockets between PPT or Rd and mitochondrial respiratory chain complex I. Conclusion: This study indicated that ginsenosides might alleviate MCI by targeting respiratory chain complex I and regulating mitochondrial function, supporting ginseng's therapeutic application in cognitive deficits.

• Journal of the Korean Magnetic Resonance Society
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• v.16 no.1
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• pp.22-33
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• 2012

Tid1, belonging to the Hsp40/DnaJ family of proteins, functions as a cochaperone of cytosolic and mitochondrial Hsp70 proteins. In particular, the N-terminal J-domain of Tid1 (Tid1-JD) constitutes the major binding sites for proteinprotein interactions with client proteins, including p53, as well as its partner chaperone, Hsp70. In the present study, soluble, recombinant protein of Tid1-JD could be obtained by using the pCold vector system, and backbone NMR assignments were completed using the isotope $[^{13}C/^{15}N]$-enriched protein. Far-UV CD result implied that Tid1-JD is an ${\alpha}$-helical protein and the secondary structure determined using chemical shift data sets indentified four ${\alpha}$-helices with a loop region containing the HPD (conserved tripeptide of His, Pro and Asp) motif. Additionally, NMR spectra under different conditions implied that the HPD motif, which is a critical region for protein-protein interactions of Tid1-JD, would possess dynamic properties.

• Bulletin of the Korean Chemical Society
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• v.35 no.2
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• pp.419-424
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• 2014

The pro-apoptotic BCL-2 family protein BID activates BAK and/or BAX, which form oligomeric pores in the mitochondrial outer membrane. This results in the release of cytochrome c into the cytoplasm, initiating the apoptotic cascade. Here, we utilized liposomes encapsulating sulfo-rhodamine at a controlled temperature to improve upon a previously reported assay system with enhanced sensitivity and specificity for measuring membrane permeabilization by BID-dependent BAK activation. BAK activation was inhibited by BCL-$X_L$ protein but not by a mutant protein with impaired anti-apoptotic activity. With the assay system, we screened a chemical library and identified several compounds including trifluoperazine, a mitochondrial apoptosis-induced channel blocker. It inhibited BAK activation by direct binding to BAK and blocking the oligomerization of BAK.

• Interdisciplinary Bio Central
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• v.5 no.4
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• pp.9.1-9.7
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• 2013

Introduction: Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial heat shock protein (HSP), which belongs to HSP90 family. It plays important roles in regulating mitochondrial integrity, protecting against oxidative stress, and inhibiting cell death. Recent studies suggest that TRAP1 is linked to mitochondria and its metabolism. In this study, we established TRAP1 transgenic mice and performed partial hepatectomy (PH) on wild-type (WT) and TRAP1 transgenic mice to investigate the function of TRAP1 during liver regeneration. Results and Discussion: We found that TRAP1 was highly expressed in liver as well as kidney. In addition, liver regeneration slightly decreased together with increased fatty liver and inflammation at 72 hr after PH in TRAP1 transgenic mice compared with WT control group mice. Concomitantly, we observed decreased levels of p38 protein in TRAP1 transgenic mice compared with WT control group mice. These results suggest that TRAP1 plays a critical role in liver energy balance by regulating lipid accumulation during liver regeneration. Conclusions and Prospects: To our knowledge, we reported, for the first time, that liver regeneration slightly reduced together with increased fat accumulations after PH in TRAP1 transgenic mice compared with WT control group mice. Concomitantly, we observed decreased levels of p38 protein in TRAP1 transgenic mice compared with WT control group mice. Overexpression of TRAP1 might affect liver regeneration via disturbing mitochondrial function leading to fatty liver in vivo.

• Parasites, Hosts and Diseases
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• v.56 no.5
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• pp.515-519
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• 2018

Triatoma rubrofasciata is a wide-spread vector of Chagas disease in Americas. In this study, we completed the mitochondrial genome sequencing of T. rubrofasciata. The total length of T. rubrofasciata mitochondrial genome was 17,150 bp with the base composition of 40.4% A, 11.6% G, 29.4% T and 18.6% C. It included 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and one control region. We constructed a phylogenetic tree on the 13 protein-coding genes of T. rubrofasciata and other 13 closely related species to show their phylogenic relationship. The determination of T. rubrofasciata mitogenome would play an important role in understanding the genetic diversity and evolution of triatomine bugs.

• Molecules and Cells
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• v.42 no.4
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• pp.292-300
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• 2019

Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert anti-inflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.