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Background Antimicrobial resistance has been considered one of the greatest threats to human health, according to the World Health Organization (WHO). Gram-negative bacteria, especially carbapenem-resistant Enterobacteriaceae (CRE), drive this alarming trend.Among CRE pathogens, carbapenem-resistant Klebsiella pneumonia (CRKP) has recently been reported as a highly infectious one responsible of a high mortality and morbility in adults and immunocompromised patients. Additionally, CRKP-related infections are challenging to treat, as carbapenems are the last resort of antibiotics. Therefore, developing novel drugs with different mechanism of action from the existing drugs is urgently required to defeat this lethal menace. In these circumstances, probiotics intended for being a potential choice to be a therapeutic candidate and inhibit the pathogens. Thus, our research team has been focusing on probiotics for a long time to develop potential anti-CRKP drug agents. Methods After such efforts, we finally found a novel Lactobacillus sakei PMC104 derived from kimchi, a probiotic strain suitable for treating CRE infection. Next, as part of our expansion into therapeutic development, we did media optimization at food grade and then established a scale-up process to pilot scale. A lyophilizate was then obtained, which was subsequently used in a mouse model infected with CRKP. Results Data showed that treatment with L. sakei powder remarkably diminished the body weight loss, mortality, and illness severity in CRKP-infected mice which shows the preventive effect of our PMC 104 against CRKP infection. Discussion Our results exhibit the potential therapeutic effect of our candidate probiotic strain opposed to the CRKP, advocating that L. sakei can be congested as an antimicrobial candidate for treating CRKP infections. However, extensive studies such as toxicity tests and clinical trials are still needed to develop it as a new anti-CRE therapeutic agent.

The biological process of aging is thought to result in part from accumulation of senescent cells in organs. However, the present study identified that the numbers of full-senescent cells were not increased in normal elderly tissue. Instead, fibroblasts and smooth muscle cells that were neither proliferative nor fully senescent were prevalent in tissues of the elderly, which we termed “mid-old” cells. Upregulation of pro-inflammatory genes (IL1β, SAA1) and downregulation of anti-inflammatory genes (SLIT2, CXCL12) were detected in mid-old cells. In the stroma, SAA1 promotes development of the inflammatory microenvironment via upregulation of MMP9, which decreases the stability of epithelial cells present on the basement membrane, decreasing epithelial cell function. Strikingly, the microenvironmental change and the functional decline of mid-old cells could be rejuvenated by a young cell-originated protein, SLIT2. We provided the functional reverse of mid-old cells rather than elimination of senescent cells as a new concept about rejuvenation.

Abstract Deregulated mitochondrial energetics is a metabolic hallmark of cancer cells. However, the causative mechanism of the bioenergetic deregulation is not clear. In this study, we show that somatic copy number alteration (SCNA) of mitoribosomal protein (MRP) genes is a key mechanism of bioenergetic deregulation in hepatocellular carcinoma (HCC). Association analysis between the genomic and transcriptomic profiles of 82 MRPs using The Cancer Genome Atlas-Liver HCC database identified eight key SCNA-dependent MRPs: MRPS31, MRPL10, MRPL21, MRPL15, MRPL13, MRPL55, and DAP3. MRPS31 was the only downregulated MRP harboring a DNA copy number (DCN) loss. MRPS31 loss was associated specifically with the DCN losses of many genes on chromosome 13q. Survival analysis revealed a unique dependency of HCC on the MRPS31 deficiency, showing poor clinical outcome. Subclass prediction analysis using several public classifiers indicated that MRPS31 loss is linked to aggressive HCC phenotypes. By employing hepatoma cell lines with SCNA-dependent MRPS31 expression (JHH5, HepG2, Hep3B, and SNU449), we demonstrated that MRPS31 deficiency is the key mechanism, disturbing the whole mitoribosome assembly. MRPS31 suppression enhanced hepatoma cell invasiveness by augmenting MMP7 and COL1A1 expression. Unlike the action of MMP7 on extracellular matrix destruction, COL1A1 modulated invasiveness via the ZEB1-mediated epithelial-to-mesenchymal transition. Finally, MRPS31 expression further stratified the high COL1A1/DDR1-expressing HCC groups into high and low overall survival, indicating that MRPS31 loss is a promising prognostic marker. Significance Our results provide new mechanistic insight for mitochondrial deregulation in HCC and present MRPS31 as a novel biomarker of HCC malignancy.

Organismal aging is accompanied by a host of progressive metabolic alterations and an accumulation of senescent cells, along with functional decline and the appearance of multiple diseases. This implies that the metabolic features of cell senescence may contribute to the organism's metabolic changes and be closely linked to age-associated diseases, especially metabolic syndromes. However, there is no clear understanding of senescent metabolic characteristics. Here, we review key metabolic features and regulators of cellular senescence, focusing on mitochondrial dysfunction and anabolic deregulation, and their link to other senescence phenotypes and aging. We further discuss the mechanistic involvement of the metabolic regulators mTOR, AMPK, and GSK3, proposing them as key metabolic switches for modulating senescence. [BMB Reports 2019; 52(1): 5-12].

Mitochondrial respiratory defects have been implicated in cancer progression and metastasis, but how they control tumor cell aggressiveness remains unclear. Here, we demonstrate that a mitochondrial respiratory defect induces nuclear factor-erythroid 2 like 1 (NFE2L1) expression at the transcriptional level via reactive oxygen species (ROS)-mediated STAT3 activation. We identified syntaxin 12 (STX12) as an effective downstream target of NFE2L1 by performing cDNA microarray analysis after the overexpression and depletion of NFE2L1 in hepatoma cells. Bioinformatics analysis of The Cancer Genome Atlas Liver Hepatocellular carcinoma (TCGA-LIHC) open database (n = 371) also revealed a significant positive association (r = 0.3, p = 2.49 &times, 10&minus, 9) between NFE2L1 and STX12 expression. We further demonstrated that STX12 is upregulated through the ROS/STAT3/NFE2L1 axis and is a key downstream effector of NFE2L1 in modulating hepatoma cell invasiveness. In addition, gene enrichment analysis of TCGA-LIHC also showed that epithelial&ndash, mesenchymal transition (EMT)-related core genes are significantly upregulated in tumors co-expressing NFE2L1 and STX12. The positive association between NFE2L1 and STX12 expression was validated by immunohistochemistry of the hepatocellular carcinoma tissue array. Finally, higher EMT gene enrichment and worse overall survival (p = 0.043) were observed in the NFE2L1 and STX12 co-expression group with mitochondrial defect, as indicated by low NDUFA9 expression. Collectively, our results indicate that NFE2L1 is a key mitochondrial retrograde signaling-mediated primary gene product enhancing hepatoma cell invasiveness via STX12 expression and promoting liver cancer progression.

Mitochondrial DNA (mtDNA) mutations are often observed in various cancer types. Although the correlation between mitochondrial dysfunction and cancer malignancy has been demonstrated by several studies, further research is required to elucidate the molecular mechanisms underlying accelerated tumor development and progression due to mitochondrial mutations. We generated an mtDNA-depleted cell line, ρ⁰, via long-term ethidium bromide treatment to define the molecular mechanisms of tumor malignancy induced by mitochondrial dysfunction. Mitochondrial dysfunction in ρ⁰ cells reduced drug-induced cell death and decreased the expression of pro-apoptotic proteins including p53. The p53 expression was reduced by activation of nuclear factor-κB that depended on elevated levels of free calcium in HCT116/ρ⁰ cells. Overall, these data provide a novel mechanism for tumor development and drug resistance due to mitochondrial dysfunction. [BMB Reports 2018; 51(6): 296-301].

Impaired mitochondrial oxidative phosphorylation (OXPHOS) capacity, accompanied by enhanced glycolysis, is a key metabolic feature of cancer cells, but its underlying mechanism remains unclear. Previously, we reported that human hepatoma cells that harbor OXPHOS defects exhibit high tumor cell invasiveness via elevated claudin-1 (CLN1). In the present study, we show that OXPHOS-defective hepatoma cells (SNU354 and SNU423 cell lines) exhibit reduced expression of mitochondrial ribosomal protein L13 (MRPL13), a mitochondrial ribosome (mitoribosome) subunit, suggesting a ribosomal defect. Specific inhibition of mitoribosomal translation by doxycycline, chloramphenicol, or siRNA-mediated MRPL13 knockdown decreased mitochondrial protein expression, reduced oxygen consumption rate, and increased CLN1-mediated tumor cell invasiveness in SNU387 cells, which have active mitochondria. Interestingly, we also found that exogenous lactate treatment suppressed MRPL13 expression and oxygen consumption rate and induced CLN1 expression. A bioinformatic analysis of the open RNA-Seq database from The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) cohort revealed a significant negative correlation between MRPL13 and CLN1 expression. Moreover, in patients with low MRPL13 expression, two oxidative metabolic indicators, pyruvate dehydrogenase B expression and the ratio of lactate dehydrogenase type B to type A, significantly and negatively correlated with CLN1 expression, indicating that the combination of elevated glycolysis and deficient MRPL13 activity was closely linked to CLN1-mediated tumor activity in LIHC. These results suggest that OXPHOS defects may be initiated and propagated by lactate-mediated mitoribosomal deficiencies and that these deficiencies are critically involved in LIHC development.

As senescence develops, cells sequentially acquire diverse senescent phenotypes along with simultaneous multistage gene reprogramming. It remains unclear what acts as the key regulator of the collective changes in gene expression at initiation of senescent reprogramming. Here we analyzed time series gene expression profiles obtained in two different senescence models in human diploid fibroblasts: replicative senescence and H2O2-induced senescence. Our results demonstrate that suppression of DNA methyltransferase 1 (DNMT1)-mediated DNA methylation activity was an initial event prior to the display of senescent phenotypes. We identified seven DNMT1-interacting proteins, ubiquitin-like with PHD and ring finger domains 1 (UHRF1), EZH2, CHEK1, SUV39H1, CBX5, PARP1, and HELLS (also known as LSH (lymphoid-specific helicase) 1), as being commonly down-regulated at the same time point as DNMT1 in both senescence models. Knockdown experiments revealed that, among the DNMT1-interacting proteins, only UHRF1 knockdown suppressed DNMT1 transcription. However, UHRF1 overexpression alone did not induce DNMT1 expression, indicating that UHRF1 was essential but not sufficient for DNMT1 transcription. Although UHRF1 knockdown effectively induced senescence, this was significantly attenuated by DNMT1 overexpression, clearly implicating the UHRF1/DNMT1 axis in senescence. Bioinformatics analysis further identified WNT5A as a downstream effector of UHRF1/DNMT1-mediated senescence. Senescence-associated hypomethylation was found at base pairs −1569 to −1363 from the transcription start site of the WNT5A gene in senescent human diploid fibroblasts. As expected, WNT5A overexpression induced senescent phenotypes. Overall, our results indicate that decreased UHRF1 expression is a key initial event in the suppression of DNMT1-mediated DNA methylation and in the consequent induction of senescence via increasing WNT5A expression.

Summary Mitochondrial ribosomes (mitoribosomes), the specialized translational machinery for mitochondrial genes, exclusively encode the subunits of the oxidative phosphorylation (OXPHOS) system. Although OXPHOS dysfunctions are associated with hepatic disorders including hepatocellular carcinoma (HCC), their underlying mechanisms remain poorly elucidated. In this study, we aimed to investigate the effects of mitoribosome defects on OXPHOS and HCC progression. By generating a gene signature from HCC transcriptome data, we developed a scoring system, i.e., mitoribosome defect score (MDS), which represents the degree of mitoribosomal defects in cancers. The MDS showed close associations with the clinical outcomes of patients with HCC and with gene functions such as oxidative phosphorylation, cell-cycle activation, and epithelial-mesenchymal transition. By analyzing immune profiles, we observed that mitoribosomal defects are also associated with immunosuppression and evasion. Taken together, our results provide new insights into the roles of mitoribosome defects in HCC progression., Graphical Abstract, Highlights • A set of down-regulated MRPs in HCC cause mitoribosomal defects • Mitoribosomal defects are linked to aggressive molecular features and poor prognosis • Mitoribosomal defects in HCC are associated with immunosuppression and evasion • TGF-β signaling pathway is a crucial mechanism to mediate mitoribosomal defects in HCC, Immunology; Cancer Systems Biology; Cancer

Cellular senescence is a process by which cells enter a state of permanent cell cycle arrest. It is commonly believed to underlie organismal aging and age-associated diseases. However, the mechanism by which cellular senescence contributes to aging and age-associated pathologies remains unclear. Recent studies showed that senescent cells exert detrimental effects on the tissue microenvironment, generating pathological facilitators or aggravators. The most significant environmental effector resulting from senescent cells is the senescence-associated secretory phenotype (SASP), which is constituted by a strikingly increased expression and secretion of diverse pro-inflammatory cytokines. Careful investigation into the components of SASPs and their mechanism of action, may improve our understanding of the pathological backgrounds of age-associated diseases. In this review, we focus on the differential expression of SASP-related genes, in addition to SASP components, during the progress of senescence. We also provide a perspective on the possible action mechanisms of SASP components, and potential contributions of SASP-expressing senescent cells, to age-associated pathologies. [BMB Reports 2015; 48(10): 549-558]

Aerobic glycolysis and mitochondrial dysfunction are key metabolic features of cancer cells, but their interplay during cancer development remains unclear. We previously reported that human hepatoma cells with mitochondrial defects exhibit down-regulated lactate dehydrogenase subunit B (LDHB) expression. Here, using several molecular and biochemical assays and informatics analyses, we investigated how LDHB suppression regulates mitochondrial respiratory activity and contributes to liver cancer progression. We found that transcriptional LDHB down-regulation is an upstream event during suppressed oxidative phosphorylation. We also observed that LDHB knockdown increases inhibitory phosphorylation of pyruvate dehydrogenase (PDH) via lactate-mediated PDH kinase (PDK) activation and thereby attenuates oxidative phosphorylation activity. Interestingly, monocarboxylate transporter 1 was the major lactate transporter in hepatoma cells, and its expression was essential for PDH phosphorylation by modulating intracellular lactate levels. Finally, bioinformatics analysis of the hepatocellular carcinoma cohort from The Cancer Genome Atlas revealed that a low LDHB/LDHA ratio is statistically significantly associated with poor prognostic outcomes. A low ratio was also associated with a significant enrichment in glycolysis genes and negatively correlated with PDK1 and 2 expression, supporting a close link between LDHB suppression and the PDK–PDH axis. These results suggest that LDHB suppression is a key mechanism that enhances glycolysis and is critically involved in the maintenance and propagation of mitochondrial dysfunction via lactate release in liver cancer progression.

Populations are aging and most older adults suffer from multiple chronic diseases, raising the risk of functional limitations and dependency. This phenomenon is worldwide, and poses to the world a challenge of poor quality of life and increased healthcare costs. Healthy aging framework is a solution to counter such dismal prospects. Although we should consider diverse aspects of healthy aging, such as physical, cognitive and emotional aging, there has been great progress in understanding healthy aging theoretically, resulting in convergent principles on healthy aging. Despite these converging principles of healthy aging, setting up and implementing policies to enhance healthy aging is a challenge as we should take into account of diversities of the population, community, and environment. In this symposium, the authors will review theoretical aspects of healthy aging, and then will introduce practical applications and experiences of policymaking pertaining to frailty and dementia, two major barriers to healthy aging.

Gemigliptin is a selective DPP4 inhibitor used to treat type 2 diabetes. The objective of this study was to evaluate the pharmacokinetics (PKs) of gemigliptin, rosuvastatin, and irbesartan monotherapies and combination therapies.Randomized, open-label, three-treatment, six-sequence, three-period, crossover studies were performed on healthy male volunteers. The three treatments were: 50 mg gemigliptin alone; 20 mg rosuvastatin (part A) or 300 mg irbesartan alone (part B); and rosuvastatin or irbesartan with concomitant gemigliptin. Each drug was administered as part of once daily, 7 day, repeated dosing regimens with a 14 day washout period.NCT01823133 (part A) and NCT01825850 (part B).The primary PK parameters - Cmax and AUCτ - were compared to the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) that were determined for the combination therapies and monotherapies.A total of 60 participants were administered the study drugs, and 52 participants (27 participants in part A; 25 participants in part B) were analyzed as part of the PK dataset. In part A, the GMRs (gemigliptin + rosuvastatin/gemigliptin) of the Cmax and AUCτ values of gemigliptin were 0.955 (90% CI = 0.874-1.044) and 1.023 (90% CI = 0.991-1.057), and those of rosuvastatin were 1.012 (90% CI = 0.946-1.084) and 1.086 (90% CI = 1.032-1.142), respectively. In part B, the GMRs of the Cmax and AUCτ values of gemigliptin were 1.046 (90% CI = 0.964-1.134) and 1.035 (90% CI = 1.005-1.065), and those of irbesartan were 0.966 (90% CI = 0.897-1.040) and 1.050 (90% CI = 0.993-1.111), respectively. The limitations of this study include its relatively short treatment period and small sample size, as only healthy participants were included.Gemigliptin does not affect the PK properties of rosuvastatin or irbesartan; also, rosuvastatin and irbesartan do not affect the PKs of gemigliptin.

The purpose of the study was to examine the image types of the traditional child rearing by mothers with infancy and early childhood through Q-methodology. To conduct that, Q-group was first formed from mothers who raised their child in traditional way after their brainstorming about the method and interviewing them. Based on the subject`s shared statements, Q-standard was made with 40 subjects. The 40 subjects were asked to grade each statement from one to nine and then their responses were analyzed by QUANL program. The image types were classified into 4 groups. There were `Type 1: Relationship-oriented parenting through harmony` `Type 2: Archetypal Parenting based on the Korean traditional values,` `Type 3: Practice-oriented Parenting to respect life,` and `Type 4: Attachment Parenting modern variants necessary.` This study serves as a momentum to see the impact of traditional child rearing on modern child upbringing by examining mother`s viewpoints on traditional child rearing.

Osteoblasts are specialized mesenchymal cells that are responsible for bone formation. In this study, we examine the role of GATA4 in osteoblast differentiation. GATA4 was abundantly expressed in preosteoblast cells and gradually down-regulated during osteoblast differentiation. Overexpression of GATA4 in osteoblastic cells inhibited alkaline phosphatase activity and nodule formation in osteogenic conditioned cell culture system. In addition, overexpression of GATA4 attenuated expression of osteogenic marker genes, including Runx2, alkaline phosphatase, bone sialoprotein, and osteocalcin, all of which are important for osteoblast differentiation and function. Overexpression of GATA4 attenuated Runx2 promoter activity, whereas silencing of GATA4 increased Runx2 induction. We found that GATA4 interacted with Dlx5 and subsequently decreased Dlx5 binding activity to Runx2 promoter region. Our data suggest that GATA4 acts as a negative regulator in osteoblast differentiation by downregulation of Runx2. [BMB Reports 2014; 47(8): 463-468]

Many solid tumor cells exhibit mitochondrial respiratory impairment; however, the mechanisms of such impairment in cancer development remain unclear. Here, we demonstrate that SNU human hepatoma cells with declined mitochondrial respiratory activity showed decreased expression of mitochondrial 8-oxoguanine DNA glycosylase/lyase (mtOGG1), a mitochondrial DNA repair enzyme; similar results were obtained with human hepatocellular carcinoma tissues. Among several OGG1-2 variants with a mitochondrial- targeting sequence (OGG1-2a, -2b, -2c, -2d, and -2e), OGG1-2a was the major mitochondrial isoform in all examined hepatoma cells. Interestingly, hepatoma cells with low mtOGG1 levels showed delayed cell growth and increased intracellular reactive oxygen species (ROS) levels. Knockdown of OGG1-2 isoforms in Chang-L cells, which have active mitochondrial respiration with high mtOGG1 levels, significantly decreased cellular respiration and cell growth, and increased intracellular ROS. Overexpression of OGG1-2a in SNU423 cells, which have low mtOGG1 levels, effectively recovered cellular respiration and cell growth activities, and decreased intracellular ROS. Taken together, our results suggest that mtOGG1 plays an important role in maintaining mitochondrial respiration, thereby contributing to cell growth of hepatoma cells.

Transforming growth factor β1 (TGF β1) induces Mv1Lu cell senescence by persistently producing mitochondrial reactive oxygen species (ROS) through decreased complex IV activity. Here, we investigated the molecular mechanism underlying the effect of TGF β1 on mitochondrial complex IV activity. TGF β1 progressively phosphorylated the negative regulatory sites of both glycogen synthase kinase 3 (GSK3) α and β, corresponding well to the intracellular ROS generation profile. Pre-treatment of N -acetyl cysteine, an antioxidant, did not alter this GSK3 phosphorylation (inactivation), whereas pharmacological inhibition of GSK3 by SB415286 significantly increased mitochondrial ROS, implying that GSK3 phosphorylation is an upstream event of the ROS generation. GSK3 inhibition by SB415286 decreased complex IV activity and cellular O 2 consumption rate and eventually induced senescence of Mv1Lu cell. Similar results were obtained with siRNA-mediated knockdown of GSK3. Moreover, we found that GSK3 not only exists in cytosol but also in mitochondria of Mv1Lu cell and the mitochondrial GSK3 binds complex IV subunit 6b which has no electron carrier and is topologically located in the mitochondrial intermembrane space. Involvement of subunit 6b in controlling complex IV activity and overall respiration rate was proved with siRNA-mediated knockdown of subunit 6b. Finally, TGF β1 treatment decreased the binding of the subunit 6b to GSK3 and subunit 6b phosphorylation. Taken together, our results suggest that GSK3 inactivation is importantly involved in TGF β1-induced complex IV defects through decreasing phosphorylation of the subunit 6b, thereby contributing to senescence-associated mitochondrial ROS generation.

Aerobic lactate production of which the final step is executed by lactate dehydrogenase (LDH) is one of the typical phenotypes in invasive tumor development. However, detailed mechanism of how LDH links to cancer cell invasiveness remains unclear. This study shows that suppressed LDHB expression plays a critical role in hepatoma cell invasiveness by inducing claudin-1 (Cln-1), a tight junction protein, via mitochondrial respiratory defects. First, we found that all the SNU human hepatoma cells with increased glycolytic lactate production have the defective mitochondrial respiratory activity and the Cln-1-mediated high invasive activity. Similar results were also obtained with human hepatocellular carcinoma tissues. Unexpectedly, the increased lactate production was due to LDH isozyme shifts to LDH5 by LDHB down-expression rather than LDHA induction, implying the importance of LDHB modulation. Second, LDHB knockdown did not only trigger Cln-1 induction at the transcriptional level, but also induced respiratory impairment. Interestingly, most respiratory inhibitors except KCN induced Cln-1 expression although complex I inhibition by rotenone was most effective on Cln-1 induction. Respiratory defect-mediated Cln-1 induction was further confirmed by knockdown of NDUFA9, one of complex I subunits. Finally, ectopic expression of LDHB attenuated the invasiveness of both SNU 354 and 449 cells whereas LDHB knockdown significantly augmented the invasiveness of Chang cells with Cln-1induction. The increased invasive activity by LDHB modulation was clearly reversed by knocking-down Cln-1. Taken together, our results suggest that LDHB suppression plays an important role in triggering or maintaining the mitochondrial defects and then contributes to cancer cell invasiveness by inducing Cln-1 protein.

Many cancer cells require more glycolytic adenosine triphosphate production due to a mitochondrial respiratory defect. However, the roles of mitochondrial defects in cancer development and progression remain unclear. To address the role of transcriptomic regulation by mitochondrial defects in liver cancer cells, we performed gene expression profiling for three different cell models of mitochondrial defects: cells with chemical respiratory inhibition (rotenone, thenoyltrifluoroacetone, antimycin A, and oligomycin), cells with mitochondrial DNA depletion (Rho0), and liver cancer cells harboring mitochondrial defects (SNU354 and SNU423). By comparing gene expression in the three models, we identified 10 common mitochondrial defect–related genes that may be responsible for retrograde signaling from cancer cell mitochondria to the intracellular transcriptome. The concomitant expression of the 10 common mitochondrial defect genes is significantly associated with poor prognostic outcomes in liver cancers, suggesting their functional and clinical relevance. Among the common mitochondrial defect genes, we found that nuclear protein 1 (NUPR1) is one of the key transcription regulators. Knockdown of NUPR1 suppressed liver cancer cell invasion, which was mediated in a Ca2+ signaling–dependent manner. In addition, by performing an NUPR1-centric network analysis and promoter binding assay, granulin was identified as a key downstream effector of NUPR1. We also report association of the NUPR1–granulin pathway with mitochondrial defect–derived glycolytic activation in human liver cancer. Conclusion: Mitochondrial respiratory defects and subsequent retrograde signaling, particularly the NUPR1–granulin pathway, play pivotal roles in liver cancer progression. (Hepatology 2015;62:1174-1189)

Although mitochondrial dysfunction has been implicated in tumor metastasis, it is unclear how it regulates tumor cell aggressiveness. We have reported previously that human hepatoma cells harboring mitochondrial defects have high tumor cell invasion activity via increased claudin-1 (Cln-1) expression. In this study, we demonstrated that mitochondrial respiratory defects induced Cln-1 transcription via reactive oxygen species (ROS)-mediated heat shock factor 1 (HSF1) activation, which contributed to hepatoma invasiveness. We first confirmed the inverse relationship between mitochondrial defects and Cln-1 induction in SNU hepatoma cells and hepatocellular carcinoma tissues. We then examined five different respiratory complex inhibitors, and complex I inhibition by rotenone most effectively induced Cln-1 at the transcriptional level. Rotenone increased both mitochondrial and cytosolic ROS. In addition, rotenone-induced Cln-1 expression was attenuated by N-acetylcysteine, an antioxidant, and exogenous H2O2 treatment was enough to increase Cln-1 transcription, implying the involvement of ROS. Next we found that ROS-mediated HSF1 activation via hyperphosphorylation was the key event for Cln-1 transcription. Moreover, the Cln-1 promoter region (from −529 to +53) possesses several HSF1 binding elements, and this region showed increased promoter activity and HSF1 binding affinity in response to rotenone treatment. Finally, we demonstrated that the invasion activity of SNU449 cells, which harbor mitochondrial defects, was blocked by siRNA-mediated HSF1 knockdown. Taken together, these results indicate that mitochondrial respiratory defects enhance Cln-1-mediated hepatoma cell invasiveness via mitochondrial ROS-mediated HSF1 activation, presenting a potential role for HSF1 as a novel mitochondrial retrograde signal-responsive transcription factor to control hepatoma cell invasiveness.

Frailty is a hallmark of vulnerability in older adults predisposed to adverse health outcomes, posing as a major threat to healthy aging. Community-based interventions targeting the pre-frail and frail elderly tend to show beneficial effects on frailty status. A growing body of evidence suggests that exercise interventions may be effective in enhancing physical function and performance. Evidence on the benefits of nutrition by itself is, however, inconclusive. A combined exercise and nutritional intervention appears to be more effective. More recently, multi-component interdisciplinary interventions that combine exercise, nutrition, cognitive training, and comprehensive geriatric assessment appear promising. To enhance our understanding of effective preventive interventions for frailty, larger scale clinical trials are needed. This will help to develop individually tailored prevention programs and evidence-based clinical practice guidelines, and to prioritize frailty prevention as one of the key policy agenda for healthy aging.

Although curcumin suppresses the growth of a variety of cancer cells, its poor absorption and low systemic bioavailability have limited its translation into clinics as an anticancer agent. In this study, we show that dimethoxycurcumin (DMC), a methylated, more stable analog of curcumin, is significantly more potent than curcumin in inducing cell death and reducing the clonogenicity of malignant breast cancer cells. Furthermore, DMC reduces the tumor growth of xenografted MDA-MB 435S cells more strongly than curcumin. We found that DMC induces paraptosis accompanied by excessive dilation of mitochondria and the endoplasmic reticulum (ER); this is similar to curcumin, but a much lower concentration of DMC is required to induce this process. DMC inhibits the proteasomal activity more strongly than curcumin, possibly causing severe ER stress and contributing to the observed dilation. DMC treatment upregulates the protein levels of CCAAT-enhancer-binding protein homologous protein (CHOP) and Noxa, and the small interfering RNA-mediated suppression of CHOP, but not Noxa, markedly attenuates DMC-induced ER dilation and cell death. Interestingly, DMC does not affect the viability, proteasomal activity or CHOP protein levels of human mammary epithelial cells, suggesting that DMC effectively induces paraptosis selectively in breast cancer cells, while sparing normal cells. Taken together, these results suggest that DMC triggers a stronger proteasome inhibition and higher induction of CHOP compared with curcumin, giving it more potent anticancer effects on malignant breast cancer cells.

Mitochondrial respiratory defect is a key bioenergetics feature of hepatocellular carcinoma (HCC) cells. However, their involvement and roles in HCC development and progression remain unclear. Recently, we identified 10 common mitochondrial defect (CMD) signature genes that may be induced by retrograde signaling-mediated transcriptional reprogramming in response to HCC mitochondrial defects. HCC patients with enriched expression of these genes had poor prognostic outcomes, such as shorter periods of overall survival and recurrence-free survival. Nuclear protein 1 (NUPR1), a key transcription regulator, was up-regulated by Ca++-mediated retrograde signaling. NUPR1-centric network analysis and a biochemical promoter-binding assay demonstrated that granulin (GRN) is a key downstream effector of NUPR1 for the regulation of HCC cell invasiveness; association analysis of the NUPR1-GRN pathway supported this conclusion. Mitochondrial respiratory defects and retrograde signaling thus play pivotal roles in HCC progression, highlighting the potential of the NUPR1-GRN axis as a novel diagnostic marker and therapeutic target for HCC. [BMB Reports 2015; 48(11): 597-598]

The attachment of specific ligands to the surfaces of nanoparticles is important for medical and biologic imaging. However, covalent modification of nanoparticles has inherent problems in reproducibility because of many factors such as temperature, pH, concentration, and reaction time. Thus, we developed a method for modifying nanoparticles by encapsulation with specific ligand-conjugated amphiphiles. Methods: We synthesized special amphiphiles with a hydrophilic head and a long single-alkyl chain, such as arginine-glycine-aspartic acid-C18, mannose-C18, lactose-C18, and 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid-C18. And then we produced stable quantum dots (QDs) encapsulated with polysorbate 60 (a branched polyethylene glycol head with aC 18 tail) and the synthesized special amphiphiles. The prepared encapsulated QDs were subject to in vitro and in vivo animal biodistribution studies and small-animal PET studies to confirm their specific binding. Results: The encapsulated QDs could specifically bind to target cells in vitro and in vivo and could be labeled with 68 Ga (a positron emitter) easily and with high efficiency. Conclusion: The nanoparticles encapsulated with special amphiphiles could provide a straightforward and novel imaging solution with multimodality and multispecificity.

A highly stereoselective synthesis of (±)-fragranol 1 has been accomplished from the readily available homoallylic alcohol 3 in 11 steps in 10.5% overall yield utilizing an intramolecular ester enolate alkylation as the key step.

The trans-hydrindanone 1 was synthesized from (R)-limonene ( 2 ) in a highly stereoselective manner by an intramolecular ester enolate alkylation and metal-halogen exchange-initiated anionic cyclization.

Angiogenesis is important in the development and progression of cancer, therefore the therapeutic approach based on anti-angiogenesis may represent a promising therapeutic option. KR-31831 is a novel anti-ischemic agent. Previously, we reported the anti-angiogenic activity of KR-31831. In the present study we investigated the molecular mechanisms underlying anti-angiogenic activity of KR-31831. We show that KR-31831 inhibits vascular endothelial growth factor (VEGF)-induced proliferation and tube formation via release of intracellular Ca2+ and phosphorylation of extra-cellular regulated kinase 1/2 (Erk 1/2) in human umbilical vein endothelial cells (HUVECs). Moreover, the expression of VEGF receptor 2 (VEGFR2, known as Flk-1 or KDR) was reduced by the treatment of KR-31831. These results suggest that KR-31831 may have inhibitory effects on tumor angiogenesis through down-regulation of KDR expression.

Backgroung : The incidence of penicillin-resistant streptococcus pneumoniae(PRSP) accounts for almost 70% of all pneumococcal pneumonia cases in Korea. It is still unclear as to whether the efficacy of penicillin or equally active beta-lactam agents is compromised in PRSP pneumonia. This study investigated the prevalence of PRSP in community-acquired pneumonia and its clinical course. Methods : A total of 42 patients with community-acquired pneumococcal pneumonia were evaluated from July 1999 to May 2001. The cultured strains of Streptococcus pneumoniae were divided into susceptible, intermediately resistant, and resistant strains by an E-test, and the effect of the clinical course was investigated. Results : From a total of 42 patients, 22 (52.4%) patients had an intermediate resistance (MIC 0.1-1㎍/ ㎖) and six (14.3%) showed a high resistance (MIC≥2.0㎍/㎖) with current penicillin susceptibility

Background : Tuberculous pleurisy treatments improve symptoms such as fever, chest pain, cough, and prevents the progression to active pulmonary tuberculosis and the development of residual pleural thickening that decrease diaphragm and rib cage movement This study investigated how the degree of residual pleural thickening affects the pulmonary function. Methods : Fifty seven patients who were initially diagnosed as having tuberculous pleurisy, were treated with anti-tuberculous medication for 6 months and had residual pleural thickening between May 1998 and January 2000 at the Eulji university hospital were reviewed. A chest X-ray and pulmonary function test(PFT, Sensormedics 2200) were performed. The predicted value(%) of the forced vital capacity(FVC), forced inspiratory vital capacity(FNC) and total lung capacity(TLC) were measured. The residual pleural thickening was defined the average of the summation in the lateral chest at the level of the imaginary line intersecting from the cardiophrenic angle to the diaphragmatic dome and the lowest part of the costophrenic angle between them. The results were sorted into three grades according to pleural thickness

The trans-hydrindanone 1 was synthesized from (R)-limonene ( 2 ) in a highly stereoselective manner by an intramolecular ester enolate alkylation and metal-halogen exchange-initiated anionic cyclization.

A highly stereoselective synthesis of (±)-fragranol 1 has been accomplished from the readily available homoallylic alcohol 3 in 11 steps in 10.5% overall yield utilizing an intramolecular ester enolate alkylation as the key step.