The correlation of gagging threshold with intra-oral tactile and psychometric profiles in healthy subjects: A pilot study.

Excessive gag reflex could be problematic for adequate dental care. Although various factors may increase the susceptibility to gagging, its contributing factors have not been fully determined. This study aimed to determine whether gag reflex was associated with tactile sensitivity and psychological characteristics. Fifteen volunteers of healthy males and females each were recruited for this study. After completing a questionnaire describing the self-perceived gag reflex activity, a disposable saliva ejector was inserted along the palate into the mouth until gagging was evoked. The ratio of the insertion depth to the palatal length was used as an index for the gagging threshold. The two-point discrimination (TPD) and Semmes-Weinstein monofilament (SWM) tests were performed to assess the tactile sensitivity of the palatal regions (hard palate, anterior and posterior soft palate). The Symptom Checklist-90-Revised was used to investigate the relationship between the gagging threshold and the psychological status. Our findings showed that the gagging threshold had a significant positive correlation with the TPD and SWM thresholds on the hard palate. The psychological profiles of psychoticism and hostility score were also significantly correlated with the gagging threshold. However, there were no significant differences in the tactile and gagging thresholds, as well as the psychological profiles, between males and females. Our results suggested that the tactile sensitivity of the anterior palate is a determining factor for the gagging threshold and implied that the initial response of the oral entry site to stimulation may lead to the development of gag reflex.

A case report of a tongue ulcer presented as the first sign of occult tuberculosis.

BACKGROUND: Tuberculosis (TB) is a serious infectious disease with considerable fatality, typically affecting the pulmonary system and, rarely, other body organs including the oral cavity. Due to the rarity of oral TB, it is frequently overlooked in differential diagnosis of oral lesions. Despite a declining trend in TB incidence in recent years, it is still a major public health problem with high contagiousness, thereby requiring the early diagnosis and prompt treatment. CASE PRESENTATION: A 57-year-old male patient presented with chief complaint of painful ulcer on tip of his tongue. He reported that the ulcer developed without any remarkable event such as mechanical trauma, vesicle formation or systemic illness. His past medical history revealed the TB over 40 years ago, which had reportedly healed after pharmacological treatments. As the ulceration persisted after topical steroid application and careful education about avoiding possible mechanical stimuli, biopsy was performed and histological finding showed typical findings of oral tuberculosis including intense granulomatous inflammatory features with small red rods of mycobacterial organisms as well as epithelioid cells and Langhans giant cells. After suitable antituberculosis treatments, oral tuberculosis ulcer was almost completely healed. We present a case of oral TB affecting tip of the tongue in a patient with a history of pulmonary TB and emphasize the understanding of intraoral manifestations for early diagnosis and prompt treatment of TB. CONCLUSIONS: The present case represented the importance of understanding oral tuberculosis manifestations for dental clinicians who might be frequently the first health care professionals to encounter various oral lesions.

Cellular toxicity driven by high-dose vitamin C on normal and cancer stem cells.

As a powerful antioxidant, vitamin C protects cells from oxidative damage by inhibiting production of free radicals. However, high levels of vitamin C shows cytotoxicity especially on cancerous cells through generating excessive ROS and blocking the energy homeostasis. Although the double-sided character of vitamin C has been extensively studied in many cell types, there is little research on the consequence of vitamin C treatment in stem cells. Here, we identified that high-dose vitamin C shows cellular toxicity on proliferating NSPCs. We also demonstrated that undifferentiated NSPCs are more sensitive to vitamin C-driven DNA damage than differentiated cells, due to higher expression of Glut genes. Finally, we showed that high-dose vitamin C selectively induces DNA damage on cancer stem cells rather than differentiated tumor cells, raising a possibility that vitamin C may be used to target cancer stem cells.

Loss of toll-like receptor 3 aggravates hepatic inflammation but ameliorates steatosis in mice.

The importance of toll-like receptor (TLR) 4 in the pathogenesis of steatohepatitis has been well documented; however, little is known about the role of TLR3. In this study, we determined whether the depletion of TLR3 modulated hepatic injury in mice and further aimed to provide mechanistic insights into the TLR3-mediated modulation of diet-induced hepatic inflammation and fat accumulation. Hepatic steatosis and inflammatory response were induced by feeding wild-type (WT) or TLR3 knockout mice a high-fat diet for 8 weeks. Primary liver resident cells, including hepatocytes, Kupffer cells, and hepatic stellate cells (HSCs), were treated with palmitic acid. TLR3 knockout mice fed a high-fat diet showed severe hepatic inflammation accompanied by nuclear factor-κB and IRF3 activation, which is mainly induced by the activation of Kupffer cells. Decreased TLR4 expression was restored in hepatic mononuclear cells and Kupffer cells in TLR3 knockout mice compared to that in the WT. Moreover, hepatic steatosis was decreased in TLR3 knockout mice. Hepatocytes from TLR3 knockout mice exhibited reduced expression of cannabinoid receptors. HSCs from TLR3 knockout mice showed decreased expression of the enzymes involved in endocannabinoid synthesis. In conclusion, this study suggests that the selective modulation of TLR3 could be a novel therapeutic target for the treatment of hepatic inflammation and steatosis.

The presence of altered craniocervical posture and mobility in smartphone-addicted teenagers with temporomandibular disorders.

[Purpose] Smartphones are widely used by teenagers and adults for various purposes. As teenagers use smartphones more actively than adults, they are more prone to be addicted to smartphones. Furthermore, excessive usage of smartphones can lead to various psychosocial and physical symptoms. [Subjects and Methods] One hundred teenage subjects were recruited and divided into normal and addiction groups, based on the criteria of the smartphone addiction scale-short version questionnaire. Craniocervical posture and mobility were examined by lateral cephalometric analysis and a cervical range of motion instrument. [Results] Cephalometric analysis showed no significant difference in the craniocervical angles of the resting positions of the two groups. However, measurement using an inclinometer revealed a significantly flexed cervical posture while using smartphones and decreased cervical range of motion in the smartphone-addicted teenagers. The clinical profile of temporomandibular disorders revealed that muscular problems were more frequently presented in the smartphone-addicted teenagers. [Conclusion] These findings suggest that smartphone addiction has a negative influence on craniocervical posture and mobility. Further, it can be postulated that smartphone addiction among teenagers may have contributed to the occurrence of myogenous temporomandibular disorders. In conclusion, smartphone-addicted teenagers may be more frequently subjected to muscular disturbance in the craniocervical area, which probably affects the pathologic process of temporomandibular disorders in teenagers.

Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice.

UNLABELLED: The important roles of retinols and their metabolites have recently been emphasized in the interactions between hepatic stellate cells (HSCs) and natural killer (NK) cells. Nevertheless, the expression and role of retinol metabolizing enzyme in both cell types have yet to be clarified. Thus, we investigated the expression of retinol metabolizing enzyme and its role in liver fibrosis. Among several retinol metabolizing enzymes, only alcohol dehydrogenase (ADH) 3 expression was detected in isolated HSCs and NK cells, whereas hepatocytes express all of them. In vitro treatment with 4-methylpyrazole (4-MP), a broad ADH inhibitor, or depletion of the ADH3 gene down-regulated collagen and transforming growth factor-ß1 (TGF-ß1) gene expression, but did not affect α-smooth muscle actin gene expression in cultured HSCs. Additionally, in vitro, treatments with retinol suppressed NK cell activities, whereas inhibition of ADH3 enhanced interferon-γ (IFN-γ) production and cytotoxicity of NK cells against HSCs. In vivo, genetic depletion of the ADH3 gene ameliorated bile duct ligation- and carbon tetrachloride-induced liver fibrosis, in which a higher number of apoptotic HSCs and an enhanced activation of NK cells were detected. Freshly isolated HSCs from ADH3-deficient mice showed reduced expression of collagen and TGF-ß1, but enhanced expression of IFN-γ was detected in NK cells from these mice compared with those of control mice. Using reciprocal bone marrow transplantation of wild-type and ADH3-deficient mice, we demonstrated that ADH3 deficiency in both HSCs and NK cells contributed to the suppressed liver fibrosis. CONCLUSION: ADH3 plays important roles in promoting liver fibrosis by enhancing HSC activation and inhibiting NK cell activity, and could be used as a potential therapeutic target for the treatment of liver fibrosis.

Modulation of synaptic transmission through O-GlcNAcylation.

O-GlcNAcylation is a posttranslational modification where N-acetylglucosamine (O-GlcNAc) is attached and detached from a serine/threonine position by two enzymes: O-GlcNAc transferase and O-GlcNAcase. In addition to roles in diabetes and cancer, recent pharmacological and genetic studies have revealed that O-GlcNAcylation is involved in neuronal function, specifically synaptic transmission. Global alteration of the O-GlcNAc level does not affect basal synaptic transmission while the effect on synaptic plasticity is unclear. Although synaptic proteins that are O-GlcNAcylated are gradually being discovered, the mechanism of how O-GlcNAcylated synaptic protein modulate synaptic transmission has only been reported on CREB, synapsin, and GluA2 subunit of AMPAR. Future research enabling the manipulation of O-GlcNAcylation in individual synaptic proteins should reveal hidden aspects of O-GlcNAcylated synaptic proteins as modulators of synaptic transmission.

Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice.

BACKGROUND & AIMS: The important function of toll-like receptor (TLR) 4 in Kupffer cells and hepatic stellate cells (HSCs) has been well documented in alcoholic liver injury. However, little is known about the role of TLR3. Thus, we tested whether TLR3 activation in HSCs and Kupffer cells could attenuate alcoholic liver injury in vivo, and investigated its possible mechanism in vitro. METHODS: Alcoholic liver injury was achieved by feeding wild type (WT), TLR3 knockout (TLR3(-/-)) and interleukin (IL)-10(-/-) mice with high-fat diet plus binge ethanol drinking for 2 weeks. To activate TLR3, polyinosinic-polycytidylic acid (poly I:C) was injected into mice. For in vitro studies, HSCs and Kupffer cells were isolated and treated with poly I:C. RESULTS: In WT mice, poly I:C treatment reduced alcoholic liver injury and fat accumulation by suppressing nuclear factor-κB activation and sterol response element-binding protein 1c expression in the liver. In addition, freshly isolated HSCs and Kupffer cells from poly I:C-treated mice showed enhanced expression of IL-10 compared to controls. Infiltrated macrophage numbers and the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1 and IL-6 on these cells were decreased after poly I:C treatment. In vitro, poly I:C treatment enhanced the expression of IL-10 via a TLR3-dependent mechanism in HSCs and Kupffer cells. Finally, the protective effects of poly I:C on alcoholic liver injury were diminished in TLR3(-/-) and IL-10(-/-) mice. CONCLUSIONS: TLR3 activation ameliorates alcoholic liver injury via the stimulation of IL-10 production in HSCs and Kupffer cells. TLR3 could be a novel therapeutic target for the treatment of alcoholic liver injury.

CD11b(+) Gr1(+) bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice.

UNLABELLED: Clinical trials and animal models suggest that infusion of bone marrow cells (BMCs) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10(-/-) ) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) BMCs expressed more IL-10 after coculturing with activated HSCs, leading to suppressed expression of collagen and α-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6(-/-) and retinaldehyde dehydrogenase 1(-/-) HSCs. Similar to murine data, human BMCs expressed more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. CONCLUSION: Activated HSCs increase IL-10 expression in BMCs (CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis.

The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis.

Loss of Hippo signaling in Drosophila leads to tissue overgrowth as a result of increased cell proliferation and decreased cell death. YAP (a homolog of Drosophila Yorkie and target of the Hippo pathway) was recently implicated in control of organ size, epithelial tissue development, and tumorigenesis in mammals. However, the role of the mammalian Hippo pathway in such regulation has remained unclear. We now show that mice with liver-specific ablation of WW45 (a homolog of Drosophila Salvador and adaptor for the Hippo kinase) manifest increased liver size and expansion of hepatic progenitor cells (oval cells) and eventually develop hepatomas. Moreover, ablation of WW45 increased the abundance of YAP and induced its localization to the nucleus in oval cells, likely accounting for their increased proliferative capacity, but not in hepatocytes. Liver tumors that developed in mice heterozygous for WW45 deletion or with liver-specific WW45 ablation showed a mixed pathology combining characteristics of hepatocellular carcinoma and cholangiocarcinoma and seemed to originate from oval cells. Together, our results suggest that the mammalian Hippo-Salvador pathway restricts the proliferation of hepatic oval cells and thereby controls liver size and prevents the development of oval cell-derived tumors.

FoxO1 Controls Redox Regulation and Cellular Physiology of BV-2 Microglial Cells.

Microglia are brain-resident macrophage-like cells that play critical roles in diverse pathophysiological conditions, including development, neurogenesis, tissue damage, and pathogenic infection. Identifying molecular switches that govern the fate and function of microglia would be valuable for maintaining brain homeostasis. Forkhead box protein O1 (FoxO1) is the first identified gene in the FoxO family and serves as a potent transcriptional regulator that participates in development, apoptosis, metabolism, and stress response. It has been recently reported that FoxO1 expression is downregulated in human microglia with age, but the role of FoxO1 has not been characterized so far. In the present study, we investigated the molecular function of FoxO1 in microglia by utilizing BV-2 cells. By generating FoxO1-deficient BV-2 microglia through Crispr/Cas9 system, we analyzed the influence of FoxO1 on redox status, metabolism, and polarization of microglia. Our data clearly showed that FoxO1 deficiency suppressed oxidative stress and cell death. In addition, FoxO1 level could modulate metabolic status and polarizing potential of BV-2 microglia. FoxO1 might be a critical element for the regulation of microglial cell physiology and the maintenance of the brain homeostasis.

Non-Coding RNAs as Potential Targets for Diagnosis and Treatment of Oral Lichen Planus: A Narrative Review.

Oral lichen planus (OLP) is a chronic inflammatory disease that is characterized by the infiltration of T cells into the oral mucosa, causing the apoptosis of basal keratinocytes. OLP is a multifactorial disease of unknown etiology and is not solely caused by the malfunction of a single key gene but rather by various intracellular and extracellular factors. Non-coding RNAs play a critical role in immunological homeostasis and inflammatory response and are found in all cell types and bodily fluids, and their expression is closely regulated to preserve normal physiologies. The dysregulation of non-coding RNAs may be highly implicated in the onset and progression of diverse inflammatory disorders, including OLP. This narrative review summarizes the role of non-coding RNAs in molecular and cellular changes in the oral epithelium during OLP pathogenesis.

Anti­tumor properties of FoxO1 in YD­9 oral squamous cell carcinoma cells.

Oral squamous cell carcinoma (OSCC) is a tumor with a poor prognosis and a high recurrence rate. Despite its high annual incidence worldwide, appropriate therapeutic strategies have not yet been developed. Consequently, the 5­year survival rate for OSCC is low when advanced stages or recurrence is diagnosed. Forkhead transcriptional factor O1 (FoxO1) is a key mediator for maintaining cellular homeostasis. FoxO1 can function as a tumor suppressor as well as an oncogene depending on the cancer type. Therefore, the precise molecular functions of FoxO1 need to be validated, considering intracellular factors and the extracellular environment. To the best of our knowledge, however, the roles of FoxO1 in OSCC have not yet been defined. The present study examined FoxO1 levels under pathological conditions (oral lichen planus and oral cancer) and selected an appropriate OSCC cell line (YD­9). Crispr/Cas9 was used to generate FoxO1­deficient YD­9 cells in which the protein levels of phospho ERK and phospho STAT3 were upregulated, promoting cancer proliferation and migration. In addition, FoxO1 reduction increased the levels of the cell proliferation markers phospho H3 (Ser10) and PCNA. FoxO1 loss significantly reduced cellular ROS levels and apoptosis in YD­9 cells. Collectively, the present study demonstrated that FoxO1 exerted an anti­tumor effect by suppressing proliferation and migration/invasion but promoting oxidative stress­linked cell death in YD­9 OSCC cells.

Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice.

UNLABELLED: Activation of innate immunity (natural killer [NK] cell/interferon-γ [IFN-γ]) has been shown to play an important role in antiviral and antitumor defenses as well as antifibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2-week or a 10-week carbon tetrachloride (CCl(4) ) challenge, respectively. Injection of polyinosinic-polycytidylic acid (poly I:C) or IFN-γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2-week CCl(4) model. Such activation was diminished in the 10-week CCl(4) model. Consistent with these findings, the inhibitory effect of poly I:C and IFN-γ on liver fibrosis was markedly reduced in the 10-week versus the 2-week CCl(4) model. In vitro coculture experiments demonstrated that 4-day cultured (early activated) HSCs induce NK cell activation via an NK group 2 member D/retinoic acid-induced early gene 1-dependent mechanism. Such activation was reduced when cocultured with 8-day cultured (intermediately activated) HSCs due to the production of transforming growth factor-ß (TGF-ß) by HSCs. Moreover, early activated HSCs were sensitive, whereas intermediately activated HSCs were resistant to IFN-γ-mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN-γ inhibition of cell proliferation in intermediately activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN-γ signaling and functioning, whereas production of TGF-ß by HSCs inhibited NK cell function and cytotoxicity against HSCs. CONCLUSION: The antifibrogenic effects of NK cell/IFN-γ are suppressed during advanced liver injury, which is likely due to increased production of TGF-ß and expression of SOCS1 in intermediately activated HSCs.

The effect of mucosal dryness on the electrogustometric threshold.

Electrogustometry (EGM) is one of the most useful diagnostic tools widely used to evaluate the taste function by measuring the perception threshold to electrogustatory stimuli on the tongue. However, the effects of oral environments on electrogustometric threshold (EGMT) remain to be established despite its simple applicability. Thus, this study aims to determine the effect of mucosal dryness on EGMT in 68 healthy subjects. The experiment was conducted in two different conditions. First, the baseline EGMT was measured when the dryness of the tongue surface was normal. Second, the EGMT was remeasured after the tongue was intentionally desiccated. The current study showed that the mean of the EGMT was significantly increased when the tongue was desiccated, possibly indicating the reduced sensitivity to electrogustatory stimuli. Such an alteration may be related to the disturbed EGM electrical circuit through the dried mucosa with enhanced impedance. Thus, these findings suggested that mucosal dryness should be considered for better evaluation of gustatory function using EGM.

Effect of Salivary Exosomal miR-25-3p on Periodontitis With Insulin Resistance.

Periodontitis is caused by an oral microbial dysbiosis-mediated imbalance of the local immune microenvironment, which is promoted by insulin resistance and obesity. The prevalence and severity of periodontitis is higher in patients with type 2 diabetes than in healthy individuals, possibly because of differences in immune responses. The level of glycemic control also affects the saliva profile, which may further promote periodontal disease in diabetes patients. Therefore, we compared the salivary exosomal miRNA profiles of patients with type 2 diabetes with those of healthy individuals, and we found that exosomal miR-25-3p in saliva is significantly enriched (by approximately 2-fold, p < 0.01) in obese patients with type 2 diabetes. We also identified CD69 mRNA as a miR-25-3p target that regulates both activation of γδ T cells and the inflammatory response. Knockdown of CD69 increased (by approximately 2-fold) interleukin-17A production of γδ T cells in vitro. To evaluate the role of exosomal miRNA on progression of periodontitis, we analyzed regional immune cells in both periodontal tissues and lymph nodes from mice with periodontitis. We found that diet-induced obesity increased the population of infiltrating pro-inflammatory immune cells in the gingiva and regional lymph nodes of these mice. Treatment with miR-25-3p inhibitors prevented the local in vivo inflammatory response in mice with periodontitis and diet-induced obesity. Finally, we showed that suppression of interleukin 17-mediated local inflammation by a miR-25-3p inhibitor alleviated (by approximately 34%) ligature-induced periodontal alveolar bone loss in mice. Taken together, these data suggest that exosomal miR-25-3p in saliva contributes to development and progression of diabetes-associated periodontitis. Discovery of additional miR-25-3p targets may provide critical insights into developing drugs to treat periodontitis by regulating γδ T cell-mediated local inflammation.

Effect of Aging on Homeostasis in the Soft Tissue of the Periodontium: A Narrative Review.

Aging is characterized by a progressive decline or loss of physiological functions, leading to increased susceptibility to disease or death. Several aging hallmarks, including genomic instability, cellular senescence, and mitochondrial dysfunction, have been suggested, which often lead to the numerous aging disorders. The periodontium, a complex structure surrounding and supporting the teeth, is composed of the gingiva, periodontal ligament, cementum, and alveolar bone. Supportive and protective roles of the periodontium are very critical to sustain life, but the periodontium undergoes morphological and physiological changes with age. In this review, we summarize the current knowledge of molecular and cellular physiological changes in the periodontium, by focusing on soft tissues including gingiva and periodontal ligament.

Ginsenoside F2 induces cellular toxicity to glioblastoma through the impairment of mitochondrial function.

BACKGROUND: Glioblastoma (GBM) is the most aggressive tumor residing within the central nervous system, with extremely poor prognosis. Although the cytotoxic effects of ginsenoside F2 (GF2) on GBM were previously suggested, the precise anti-GBM mechanism of GF2 remains unclear. The aim of this study was to explore the anti-cancer molecular mechanism of GF2 toward human GBM. METHODS: GF2-driven cellular toxicity was confirmed in two different GBM cells, U373 and Hs683. To test mitochondrial impairment driven by GF2, we examined the mitochondrial membrane potential, OCR, and ATP production. An intracellular redox imbalance was identified by measuring the relative ratio of reduced glutathione to oxidized glutathione (GSH/GSSG), glutaredoxin (GLRX) mRNA expression, intracellular NAD+ level, and AMPK phosphorylation status. RESULTS: GF2 increased the percentage of cleaved caspase 3-positive cells and γH2AX signal intensities, confirming that GF2 shows the cytotoxicity against GBM. GO enrichment analysis suggested that the mitochondrial function could be negatively influenced by GF2. GF2 reduced the mitochondrial membrane potential, basal mitochondrial respiratory rate, and ATP production capacity. Our results showed that GF2 downregulated the relative GSH/GSSG, intracellular NAD+ level, and GLRX expression, suggesting that GF2 may alter the intracellular redox balance that led to mitochondrial impairment. CONCLUSION: GF2 reduces mitochondrial membrane potential, inhibits cellular oxygen consumption, activates AMPK signaling, and induces cell death. Our study examined the potential vulnerability of mitochondrial activity in GBM, and this may hold therapeutic promise.

Multiple Functions of Fubp1 in Cell Cycle Progression and Cell Survival.

The discovery of novel and critical genes implicated in malignant development is a topic of high interest in cancer research. Intriguingly, a group of genes named "double-agent" genes were reported to have both oncogenic and tumor-suppressive functions. To date, less than 100 "double-agent" genes have been documented. Fubp1 is a master transcriptional regulator of a subset of genes by interacting with a far upstream element (FUSE). Mounting evidence has collectively demonstrated both the oncogenic and tumor suppressive roles of Fubp1 and the debate regarding its roles in tumorigenesis has been around for several years. Therefore, the detailed molecular mechanisms of Fubp1 need to be determined in each context. In the present study, we showed that the Fubp1 protein level was enriched in the S phase and we identified that Fubp1 deficiency altered cell cycle progression, especially in the S phase, by downregulating the mRNA expression levels of Ccna genes encoding cyclin A. Although this Fubp1-cyclin A axis appears to exist in several types of tumors, Fubp1 showed heterogeneous expression patterns among various cancer tissues, suggesting it exhibits multiple and complicated functions in cancer development. In addition, we showed that Fubp1 deficiency confers survival advantages to cells against metabolic stress and anti-cancer drugs, suggesting that Fubp1 may play both positive and negative roles in malignant development.

Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice.

Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress-induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL-17 production in Th17 cells, GDF15 contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.