Search

Background/aims Heme oxygenase-1 (HO-1) plays a central role in cellular defense against inflammatory insults, and its induction in macrophages potentiates their efferocytic activity. In this study, we explored the potential role of macrophage HO-1 in the resolution of experimentally induced colitis. Methods To induce colitis, male C57BL/6 mice were treated with 2% dextran sulfate sodium (DSS) in the drinking water for 7 days. To investigate efferocytosis, apoptotic colon epithelial CCD 841 CoN cells were coincubated with bone marrow-derived macrophages (BMDMs). Results Administration of the HO-1 inhibitor zinc protoporphyrin IX (ZnPP) blunted the resolution of DSS-induced intestinal inflammation and expression of the proresolving M2 macrophage marker CD206. BMDMs treated with apoptotic colonic epithelial cells showed significantly elevated expression of HO-1 and its regulator Nrf2. Under the same experimental conditions, the proportion of CD206-expressing macrophages was also enhanced. ZnPP treatment abrogated the upregulation of CD206 expression in BMDMs engulfing apoptotic colonic epithelial cells. This result was verified with BMDMs isolated from HO-1-knockout mice. BMDMs, when stimulated with lipopolysaccharide, exhibited increased expression of CD86, a marker of M1 macrophages. Coculture of lipopolysaccharide-stimulated BMDMs with apoptotic colonic epithelial cell debris dampened the expression of CD86 as well as the pro-inflammatory cytokines in an HO-1-dependent manner. Genetic ablation as well as pharmacologic inhibition of HO-1 significantly reduced the proportion of efferocytic BMDMs expressing the scavenger receptor CD36. Conclusions HO-1 plays a key role in the resolution of experimentally induced colitis by modulating the polarization of macrophages.

More than half of the world’s populations are considered to be infected by Helicobacter pylori. It causes a chronic inflammation of the stomach, which is implicated in the pathogenesis of gastric ulcer and cancer. Silibinin, a polyphenolic flavonoid derived from milk thistle, has been known for its hepatoprotective effects, and recent studies have revealed its chemopreventive potential. In the present study, we examined the anti-inflammatory effects of silibinin in human gastric cancer MKN-1 cells and in the stomach of C57BL/6 mice infected by H. pylori. Pretreatment with silibinin attenuated the up-regulation of COX-2 and inducible nitric oxide synthase (iNOS) in H. pylori-infected MKN-1 cells and mouse stomach. In addition, the elevated translocation and DNA binding of NF-κB and STAT3 induced by H. pylori infection were inhibited by silibinin treatment. Moreover, H. pylori infection in combination with high salt diet resulted in dysplasia and hyperplasia in mouse stomach, and these pathological manifestations were substantially mitigated by silibinin administration. Taken together, these findings suggest that silibinin exerts anti-inflammatory effects against H. pylori infection through suppression of NF-κB and STAT3 and subsequently, expression of COX-2 and iNOS.

Obesity is implicated in cardiovascular disease and heart failure. When fatty acids are transported to and not adequately oxidized in cardiac cells, they accumulate, causing lipotoxicity in the heart. Since hepatic progesterone receptor membrane component 1 (Pgrmc1) suppressed de novo lipogenesis in a previous study, it was questioned whether cardiac Pgrmc1 protects against lipotoxicity. Hence, we focused on the role of cardiac Pgrmc1 in basal (Resting), glucose-dominant (Refed) and lipid-dominant high-fat diet (HFD) conditions. Pgrmc1 KO mice showed high FFA levels and low glucose levels compared to wild-type (WT) mice. Pgrmc1 KO mice presented low number of mitochondrial DNA copies in heart, and it was concomitantly observed with low expression of TCA cycle genes and oxidative phosphorylation genes. Pgrmc1 absence in heart presented low fatty acid oxidation activity in all conditions, but the production of acetyl-CoA and ATP was in pronounced suppression only in HFD condition. Furthermore, HFD Pgrmc1 KO mice resulted in high cardiac fatty acyl-CoA levels and TG level. Accordingly, HFD Pgrmc1 KO mice were prone to cardiac lipotoxicity, featuring high levels in markers of inflammation, endoplasmic reticulum stress, oxidative stress, fibrosis, and heart failure. In vitro study, it was also confirmed that Pgrmc1 enhances rates of mitochondrial respiration and fatty acid oxidation. This study is clinically important because mitochondrial defects in Pgrmc1 KO mice hearts represent the late phase of cardiac failure.

Dietary fiber functions as a prebiotic to determine the gut microbe composition. The gut microbiota influences the metabolic functions and immune responses in human health. The gut microbiota and metabolites produced by various dietary components not only modulate immunity but also impact various organs. Although recent findings have suggested that microbial dysbiosis is associated with several respiratory diseases, including asthma, cystic fibrosis, and allergy, the role of microbiota and metabolites produced by dietary nutrients with respect to pulmonary disease remains unclear. Therefore, we explored whether the gut microbiota and metabolites produced by dietary fiber components could influence a cigarette smoking (CS)-exposed emphysema model. In this study, it was demonstrated that a high-fiber diet including non-fermentable cellulose and fermentable pectin attenuated the pathological changes associated with emphysema progression and the inflammatory response in CS-exposed emphysema mice. Moreover, we observed that different types of dietary fiber could modulate the diversity of gut microbiota and differentially impacted anabolism including the generation of short-chain fatty acids, bile acids, and sphingolipids. Overall, the results of this study indicate that high-fiber diets play a beneficial role in the gut microbiota-metabolite modulation and substantially affect CS-exposed emphysema mice. Furthermore, this study suggests the therapeutic potential of gut microbiota and metabolites from a high-fiber diet in emphysema via local and systemic inflammation inhibition, which may be useful in the development of a new COPD treatment plan.

Aberrant activation of Ras has been implicated in aggressiveness of breast cancer. Among Ras isoforms (H-, K-, and N-), H-Ras has been known to be primarily responsible for invasion and metastasis of breast cancer cells. Phosphorylation of serine (Ser) or threonine (Thr) is a key regulatory mechanism responsible for controlling activities and functions of various proteins involved in intracellular signal transduction. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, Pin1 changes the conformation of a subset of proteins phosphorylated on Ser/Thr that precedes proline (Pro). In this study we have found that Pin1 is highly overexpressed in human breast tumor tissues and H-Ras transformed human mammary epithelial (H-Ras MCF10A) and MDA-MB-231 breast cancer cells. Notably, Pin1 directly bound to the activated form of H-Ras harbouring a Ser/Thr-Pro motif. Pharmacologic inhibition of Pin1 reduced clonogenicity of MDA-MB-231 human breast cancer cells. Paclitaxel accelerates apoptosis in Pin1 silenced H-Ras MCF10A cells. MDR genes (MDR1 and MRP4) were significantly downregulated in MDA-MB-231 cells stably silenced for Pin1. We speculate that Pin1 interacts with GTP-H-Ras, thereby upregulating the expression of drug resistance genes, which confers survival advantage and aggressiveness of breast cancer cells under chemotherapy.

Introduction Cognitive impairment is not uncommon in patients with multiple system atrophy (MSA). This study investigated the cortical metabolic changes of MSA and the cortical structure associated with cognitive impairment. Methods The study included probable/definite MSA patients who underwent fluorodeoxyglucose positron emission tomography and cognitive evaluation based on mini-mental status examination (MMSE). Cerebral metabolism of the entire MSA patients (n = 88) was compared with healthy controls (n = 19) by voxel-wise statistical parametric mapping. Eight brain regions of interest (ROIs) were selected accordingly: the dorsolateral prefrontal, medial superior frontal, insular, posterior parietal, precuneus, lateral temporal, medial temporal, and posterior cingulate regions. Using validated population-based norms, MSA patients were divided by MMSE z-scores into MSA with cognitive dysfunction (MSA-D, n = 30) and without cognitive dysfunction (MSA-ND, n = 58). Regional metabolism of the selected ROIs was compared between the MSA-D and MSA-ND groups by logistic regression models. Correlations between the regional metabolism of the selected ROIs and MMSE z-scores were analyzed with a linear regression model. Results Voxel-wise analysis showed hypometabolism in the frontal, temporal, parietal, and limbic areas in MSA patients than in controls. ROI-based comparisons showed that metabolism in the posterior cingulate (P = 0.006) and medial temporal (P = 0.039) regions was significantly lower in the MSA-D than in the MSA-ND group. The degree of posterior cingulate metabolism correlated significantly with MMSE z-score (P = 0.023). Conclusions MSA shows fronto-temporo-parietal cortical involvement. Hypometabolism of the limbic regions is associated with cognitive impairment in MSA.

Korean Red Ginseng (KRG) exerts chemopreventive effects on experimentally induced carcinogenesis through multiple mechanisms. In this study, we investigated effects of KRG on dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced colon carcinogenesis in mice. Male C57BL/6J mice were fed diet containing 1% KRG or a standard diet throughout the experiment. The mouse colitis was induced by administration of 3% DSS in drinking water for 1 week. DSS caused body weight loss, diarrhea, rectal bleeding and colon length shortening, and all these symptoms were ameliorated by KRG treatment. KRG inhibited DSS-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by suppressing activation of nuclear factor-kappa B (NF-κB) and signal transducer and activation of transcription 3 (STAT3). In another experiment, colon carcinogenesis was initiated by single intraperitoneal injection of AOM (10 mg/kg) and promoted by 2% DSS in drinking water. KRG administration relieved the symptoms of colitis and reduced the incidence, the multiplicity and the size of colon tumor. The up-regulation of COX-2, iNOS, c-Myc and Cyclin D1 by AOM plus DSS was attenuated in KRG fed mice which was associated with suppression of NF-κB and STAT3 activation. These results suggest that KRG is a potential candidate for chemoprevention of inflammation-associated cancer in the colon., Graphical abstract Image 1

A Western diet comprising high fat, high carbohydrate, and low fiber content has been suggested to contribute to an increased prevalence of colitis. To clarify the effect of dietary cellulose (an insoluble fiber) on gut homeostasis, for 3 months mice were fed a high-cellulose diet (HCD) or a low-cellulose diet (LCD) based on the AIN-93G formulation. Histologic evaluation showed crypt atrophy and goblet cell depletion in the colons of LCD-fed mice. RNA-sequencing analysis showed a higher expression of genes associated with immune system processes, especially those of chemokines and their receptors, in the colon tissues of LCD-fed mice than in those of HCD-fed mice. The HCD was protective against dextran sodium sulfate-induced colitis in mice, while LCD exacerbated gut inflammation; however, the depletion of gut microbiota by antibiotic treatment diminished both beneficial and non-beneficial effects of the HCD and LCD on colitis, respectively. A comparative analysis of the cecal contents of mice fed the HCD or the LCD showed that the LCD did not influence the diversity of gut microbiota, but it resulted in a higher and lower abundance of Oscillibacter and Akkermansia organisms, respectively. Additionally, linoleic acid, nicotinate, and nicotinamide pathways were most affected by cellulose intake, while the levels of short-chain fatty acids were comparable in HCD- and LCD-fed mice. Finally, oral administration of Akkermansia muciniphila to LCD-fed mice elevated crypt length, increased goblet cells, and ameliorated colitis. These results suggest that dietary cellulose plays a beneficial role in maintaining gut homeostasis through the alteration of gut microbiota and metabolites.

Objective Ceramide is a signaling molecule that contributes to insulin resistance and hepatosteatosis. In the present study, we activated de novo ceramide synthesis by inducing the hepatic expression of Sptlc2 to investigate the role of ceramide in glucose and lipid metabolism. Methods We first constructed an adenovirus containing Sptlc2 (AdSptlc2), which encodes a major catalytic subunit of serine palmitoyltransferase (SPT). We then infected hepatocytes and mice fed a regular diet with AdSptlc2 to activate de novo ceramide biosynthesis. The liver-specific effects of ceramide biosynthesis on glucose and lipid metabolism were investigated by measuring changes in insulin signaling, lipid droplet formation, and very low-density lipoprotein (VLDL) secretion. Results In HepG2 hepatocytes, adenoviral Sptlc2 expression inhibited insulin signaling and increased ceramide levels via activation of c-Jun N-terminal kinase and serine phosphorylation of insulin receptor substrate 1. In contrast, in mice, AdSptlc2 infection decreased plasma glucose levels by downregulating gluconeogenic genes and increased plasma triglyceride levels by increasing VLDL secretion. In mice infected with AdSptlc2, glucose intolerance and insulin sensitivity improved, while pyruvate utilization via gluconeogenesis decreased. Conclusion Hepatic ceramide was found to modulate hepatosteatosis and the insulin response via increased VLDL secretion and inhibition of gluconeogenesis in vivo. Although inhibition of the insulin response was observed in vitro, the compensatory mechanism of relieving ceramide-induced stress and reducing ceramide levels resulted in improvements of glucose and lipid metabolic profiles in vivo. This discrepancy between in vitro and in vivo regulation mechanisms suggests that ceramide plays a role in non-alcoholic fatty liver disease and insulin resistance.

Sirtuin 1 (SIRT1), an NAD+ -dependent histone/protein deacetylase, has multifaceted functions in various biological events such as inflammation, aging and energy metabolism. The role of SIRT1 in carcinogenesis, however, is still under debate. Recent studies have indicated that aberrant overexpression of SIRT1 is correlated with metastasis and poor prognosis in several types of malignancy, including colorectal cancer. In the present study, we found that both SIRT1 and SIRT1 phosphorylated on serine 27 were coordinately upregulated in colon cancer patients' tissues and human colon cancer cell lines. This prompted us to investigate a biological role of phospho-SIRT1 in the context of colon cancer progression. Phosphorylation-defective mutant SIRT1, in which serine 27 was substituted by alanine (SIRT1-S27A), exhibited lower protein stability compared to that of wild-type SIRT1. Notably, human colon cancer (HCT-116) cells harbouring the SIRT1-S27A mutation showed decreased cell proliferation and reduced capability to form xenograft tumor in athymic nude mice, which was accompanied by diminished transcriptional activity of Snail. HCT-116 cells carrying SIRT1-S27A were less capable of deacetylating the Snail protein, with a concomitant decrease in the levels of interleukin (IL)-6 and IL-8 mRNA transcripts. Taken together, these observations suggest that SIRT1 stabilized through phosphorylation on serine 27 exerts oncogenic effects at least partly through deacetylation-dependent activation of Snail and subsequent transcription of IL-6 and IL-8 in human colon cancer cells.

We assessed whether circulating ceramides, which play a role in a number of degenerative changes with aging, significantly differed according to fragility hip fracture (HF) status. We also performed a human study using bone marrow (BM) aspirates, directly reflecting the bone microenvironment, in addition to in vitro experiments. Peripheral blood and BM samples were simultaneously collected from 74 patients 65 years or older at hip surgery for either HF (n = 28) or for other causes (n = 46). Ceramides were measured by liquid chromatography-tandem mass spectrometry. Age was correlated positively with circulating C16:0, C18:0, and C24:1 ceramide levels. Patients with fragility HF had 21.3%, 49.5%, 34.3%, and 22.5% higher plasma C16:0, C18:0, C18:1, and C24:1 ceramide levels, respectively, than those without HF. Higher C16:0, C18:0, C18:1, and C24:1 ceramide levels were positively related to bone resorption markers in both blood and BM samples. Furthermore, in vitro studies showed that C18:0 and C24:1 ceramides directly increased osteoclastogenesis, bone resorption, and expression levels of osteoclast differentiation markers. These results suggested that the association of increased ceramides, especially C18:0 and C24:1, with adverse bone phenotypes in elderly people could be explained mainly by the increase in osteoclastogenesis and bone resorption.

Patients with obstructive sleep apnea (OSA) whose phenotype belongs to a craniofacial vulnerability are referred from sleep doctors to orthodontists. In adults, for osseo-pharyngeal reconstruction (OPR) treatment, permanent maxillomandibular advancement (MMA) surgery and use of a temporary mandibular advancement device (MAD) are applied. This case report demonstrates successful treatment of OSA through application of phased MAD and MMA in a 16-year-old male with craniofacial deformity and residual growth potential. This patient showed skeletal and dentoalveolar changes after 7-year MAD use throughout post-adolescence, which affected the design and timing of subsequent MMA surgery, as well as post-surgical orthodontic strategy. This case report suggests that OPR treatment can be useful for treatment of OSA in post-adolescent patients, from an orthodontic point of view, in close collaboration with sleep doctors for interdisciplinary diagnosis and treatment.

OBJECTIVES To evaluate three-dimensional (3D) craniofacial changes induced by a non-surgical tooth-bone-borne rapid palatal expander (TBB-RPE) according to the symmetrical pattern of expansion, to investigate the 3D changes between the sides in patients with asymmetric expansion, and to identify the related factors of asymmetric expansion. SETTING AND SAMPLE POPULATION Sixty-six patients (mean age: 19.3 ± 5.7 years) treated with TBB-RPE were divided into a symmetric expansion group (Group S, n = 46) or asymmetric expansion group (Group A, n = 20). Group S was subdivided into Group Ss (n = 27), with bilateral frontomaxillary suture (FMS) split, and Group Sn (n = 19), with no FMS split. MATERIALS AND METHODS Pre- and post-expansion cone-beam computed tomography images were superimposed, and the common coordinated system was set. All landmarks were designated as coordinate pairs, and treatment changes were automatically calculated. Analysis of variance was conducted for intergroup comparison of craniofacial changes, and logistic regression analysis was performed to identify the related factors of asymmetric expansion. RESULTS The frequency of asymmetric expansion was 30.3%. Group A with unilateral FMS split showed less craniofacial changes than Group Ss and more changes than Group Sn. Group A exhibited different nasomaxillary displacement between the two halves, showing greater changes in the FMS-split side. Among the tested six variables (age, gender, Angle's classification, unilateral crossbite, maxillary cant and chin deviation), chin deviation was uniquely associated with asymmetric expansion. CONCLUSIONS Tooth-bone-borne rapid palatal expander had a risk of asymmetric expansion, especially in facial asymmetric patients with chin deviation, producing different craniofacial changes from symmetric expansion.

Excessive exposure to solar light, especially its UV component, is a principal cause of photoaging, dermatitis, and photocarcinogenesis. In searching for candidate substances that can effectively protect the skin from photodamage, the present study was conducted with taurine chloramine (TauCl), formed from taurine in phagocytes recruited to inflamed tissue. Irradiation with ultraviolet B (UVB) of 180 mJ/cm2 intensity caused oxidative damage and apoptotic cell death in the murine epidermis. These events were blunted by topically applied TauCl, as evidenced by the lower level of 4-hydroxynonenal-modified protein, reduced proportions of TUNEL-positive epidermal cells, and suppression of caspase-3 cleavage. In addition, the expression of two prototypic inflammatory enzymes, cyclooxygenase-2 and inducible nitric oxide synthase, and transcription of some pro-inflammatory cytokines (Tnf, Il6, Il1b, Il10) were significantly lower in TauCl-treated mice than vehicle-treated control mice. The anti-inflammatory effect of TauCl was associated with inhibition of STAT3 activation and induction of antioxidant enzymes, such as heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1, through activation of nuclear factor erythroid 2-related factor 2.

The aim of this study was to investigate the correlation between the changes in respiratory function and dimensions of the nasomaxillary complex (NMC) and upper airway (UA) compartments after nasomaxillary skeletal expansion (NMSE) treatment for pediatric patients with obstructive sleep apnea (OSA). Nonobese OSA patients (mean age, 13.6 ± 2.9 years; mean body mass index, 18.1 ± 3.0 kg/m2); mean apnea–hypopnea index (AHI, 7.0 ± 5.4 events/h) presenting with transverse nasomaxillary constriction were evaluated before and after NMSE using cone-beam computed tomography (CBCT), home sleep test, and modified pediatric sleep questionnaire (m-PSQ). Paired t tests were performed to examine the treatment-related changes in all the parameters, and a multiple regression analysis adjusted for age and sagittal and vertical skeletal patterns was conducted to determine the dimensional parameters to affect the functional improvement. Among 26 patients, NMSE treatment significantly increased NMC dimensions at all tested levels and all UA compartments in CBCT, except glossopharyngeal airway. Concurrently, AHI, oxygen desaturation index, the lowest oxygen saturation (LSaO2), flow limitation (FL), snoring, and m-PSQ were significantly improved. AHI reduction was correlated with UA enlargement with no correlation with NMC expansion, whereas FL reduction was affected by NMC expansion. The minimal cross-sectional area was the most predictive of functional improvement, presenting correlations with AHI, LSaO2, and m-PSQ. NMSE can be a good treatment for pediatric OSA patients when applied to enhance the nasal and pharyngeal airway patencies beyond the NMC, ultimately to improve pharyngeal collapsibility as well as nasal airflow.

The aim of this study was to investigate the correlation between craniofacial morphology, temporomandibular joint (TMJ) characteristics, and condylar functional movement in patients with facial asymmetry using an up-to-date automated real-time jaw-tracking system. A total of 30 patients with mandibular asymmetry and prognathism were included. Three-dimensional (3D) craniofacial and TMJ morphometric variables were analyzed in images captured using cone-beam computed tomography. Three-dimensional condylar movements were recorded during the opening, protrusion, and laterotrusion of the jaw and divided into those for deviated and non-deviated sides. Overall functional and morphometric variables were compared between the sides by a paired t-test. Pearson’s correlation analysis and factor analysis were also performed. As a result, significant differences were found between the sides in morphometric and functional variables. The condylar path length was significantly longer and steeper on the deviated side during protrusion and lateral excursion. TMJ morphometric asymmetry, more so than the craniofacial morphologic asymmetry, seemed to be reflected in the functional asymmetry, representing different correlations between the sides, as supported by factor analysis. This study provides evidence explaining why the asymmetric condylar path remained unchanged even after orthognathic surgery for the correction of craniofacial asymmetry.

Idiopathic pulmonary fibrosis (IPF) is a serious lung disease characterized by excessive collagen matrix deposition and extracellular remodeling. Signaling pathways mediated by fibrotic cytokine transforming growth factor β1 (TGF-β1) make important contributions to pulmonary fibrosis, but it remains unclear how TGF-β1 alters metabolism and modulates the activation and differentiation of pulmonary fibroblasts. We found that TGF-β1 lowers NADH and NADH/NAD levels, possibly due to changes in the TCA cycle, resulting in reductions in the ATP level and oxidative phosphorylation in pulmonary fibroblasts. In addition, we showed that butyrate (C4), a short chain fatty acid (SCFA), exhibits potent antifibrotic activity by inhibiting expression of fibrosis markers. Butyrate treatment inhibited mitochondrial elongation in TGF-β1-treated lung fibroblasts and increased the mitochondrial membrane potential (MMP). Consistent with the mitochondrial observations, butyrate significantly increased ADP, ATP, NADH, and NADH/NAD levels in TGF-β1-treated pulmonary fibroblasts. Collectively, our findings indicate that TGF-β1 induces changes in mitochondrial dynamics and energy metabolism during myofibroblast differentiation, and that these changes can be modulated by butyrate, which enhances mitochondrial function.

Chemotherapy is a major etiology of cachexia. Ginseng products are known to have various anti-cachectic and health-promoting effects, such as inhibiting inflammation and promoting energy production. In particular, BST204, purified ginseng dry extract, contains multiple ginsenosides that can reduce chemotherapy-related fatigue and toxicity. To investigate the effects of BST204 on the alleviation of chemotherapy-induced cachexia using a multimodal approach. In a CT26 mouse syngeneic colon cancer model, cachexia was predominantly induced by chemotherapy with 5-fluorouracil (5-FU) than by tumor growth. BST204 at a dose of 100 or 200 mg/kg was administered to 5-FU-treated mice. BST204 significantly mitigated the decrease in tumor-excluded body weight (change in 5-FU group and BST204 groups: − 13% vs. − 6% on day 7; − 30% vs. − 20% on day 11), muscle volume (− 19% vs. − 11%), and fat volume (− 91% vs. − 56%). The anti-cachectic effect of BST204 was histologically demonstrated by an improved balance between muscle regeneration and degeneration and a decrease in muscle cross-sectional area reduction. Chemotherapy-induced cachexia was biochemically and metabolically characterized by activated inflammation, enhanced oxidative stress, increased protein degradation, decreased protein stabilization, reduced glucose-mediated energy production, and deactivated glucose-mediated biosynthesis. These adverse effects were significantly improved by BST204 treatment. Overall, our multimodal study demonstrated that BST204 could effectively alleviate chemotherapy-induced cachexia.

Tumor-associated macrophages (TAMs) represent one of the most abundant components of the tumor microenvironment and play important roles in tumor development and progression. TAMs display plasticity and functional heterogeneity as reflected by distinct phenotypic subsets. TAMs with an M1 phenotype have proinflammatory and anti-tumoral properties whereas M2-like TAMs exert anti-inflammatory and pro-tumoral functions. Tumor cell debris generated during chemotherapy can stimulate primary tumor growth and recurrence. According to our previous study, phagocytic engulfment of breast tumor cell debris by TAMs attenuated chemotherapeutic efficacy through the upregulation of heme oxygenase-1 (HO-1). To verify the impact of HO-1 upregulation on the profile of macrophage polarization during cytotoxic therapy, we utilized a syngeneic murine breast cancer (4T1) model in which tumor bearing mice were treated with paclitaxel (PTX). PTX treatment markedly downregulated the surface expression of the M1 marker CD86 in infiltrated TAMs. Notably, there were significantly more cytotoxic CD8+ T cells in tumors of mice treated with PTX plus the HO-1 inhibitor, zinc protophorphyrin IX (ZnPP) than in mice treated with PTX alone. Interestingly, the tumor-inhibiting efficacy of PTX and ZnPP co-treatment was abrogated when macrophages were depleted by clodronate liposomes. Macrophage depletion also decreased the intratumoral CD8+ T cell population and downregulated the expression of Cxcl9 and Cxcl10. The expression of the M1 phenotype marker, CD86 was higher in mice injected with PTX plus ZnPP than that in mice treated with PTX alone. Conversely, the PTX-induced upregulation of the M2 marker gene, Il10 in CD11b+ myeloid cells from 4T1 tumor-bearing mice treated was dramatically reduced by the administration of the HO-1 inhibitor. Genetic ablation of HO-1 abolished the inhibitory effect of 4T1 tumor cell debris on expression of M1 marker genes, Tnf and Il12b, in LPS-stimulated BMDMs. HO-1-deficient BMDMs exposed to tumor cell debris also exhibited a diminished expression of the M2 macrophage marker, CD206. These findings, taken all together, provide strong evidence that HO-1 plays a pivotal role in the transition of tumor-inhibiting M1-like TAMs to tumor-promoting M2-like ones during chemotherapy.

There is a plethora of evidence to support that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately overexpressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains largely undefined. In this study, we found that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the final products of COX-2, induced upregulation of vascular endothelial growth factor (VEGF) and capillary formation and migration through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent heme oxygenase-1 (HO-1) induction in MCF-7 cells. Analysis of the publicly available TCGA data set showed that high mRNA levels of both COX-2 and NRF2 correlated with the poor clinical outcomes in breast cancer patients. Moreover, human tissue analysis showed that the levels of 15d-PGJ2 as well the expression of COX-2, NRF2, and HO-1 were found to be increased in human breast cancer tissues. In conclusion, the elevated levels of 15d-PGJ2 during inflammatory response activate VEGF expression through NRF2-driven induction of HO-1 in human breast cancer cells, proposing a novel mechanism underlying the oncogenic function of 15d-PGJ2.

The pathophysiological mechanisms underpinning OSA are complex and it is no surprise the relationships between craniofacial growth, the airway, and sleep remain controversial in orthodontics. This chapter explores evidence from cases, imaging studies, observational and investigational cohort studies, randomized controlled trials, and systematic reviews that consider the myriad facets of pediatric and adult OSA. In pediatric OSA, certain features are suspected to be associated (e.g., lower facial height, posterior crossbite, small chin, increased ANB and SNB angles, retrognathism, a retrusive mandible, and reduced upper airway width); however, the influence of different types of structures and malocclusions remains unclear. In adult OSA, several correlations have been reported with differing measures of the cranial base, facial height, maxilla and mandible, pharyngeal airway space, the soft palate and tongue, and position of the hyoid bone, but direct causal evidence remains elusive. Evidence shows rapid maxillary expansion impacts the entire nasomaxillary complex, decreases nasal airway resistance, and decreases apnea–hypopnea index in adolescents. Still, long-term evidence is lacking, and no prior guideline has recommended optimal expansion widths or rates to improve symptoms. Research also suggests different orthodontic interventions (e.g., extractions, headgear, and other functional appliances) may impact airway dimensions, but opposing evidence is consid ered.

As upper airway is located below the skull base and behind the face, the growth and developmental changes of craniofacial structures will affect the development of the upper airway and respiratory function. Although craniofacial morphometric diversity is controlled primarily by genetics, it is highly influenced by environmental factors such as head, jaw, and tongue posture and neuromuscular function. It is important to firstly understand the normal growth pattern of cranial base, nasomaxillary complex, mandible, and hyoid affecting the normal development of upper airway in healthy children which varies from year to year. It is still difficult to clarify the cause-and-effect relationship between the craniofacial deformation and abnormal upper airway development; however, it is important to know that further abnormal development of craniofacial structures by delayed growth modification treatment may induce upper airway constriction and secondary development of sleep-disordered breathing. Considering that inherent craniofacial growth might be altered by functional problems of respiratory obstruction, inversely, timely intervention to treat pediatric snoring and obstructive sleep apnea, such as adenotonsillectomy and nasal allergic treatment, should be considered to prevent irreversible craniofacial alteration.

Signal transducer and activator of transcription 3 (STAT3) and nuclear factor-&kappa, B (NF-&kappa, B) are two representative transcription factors that play a critical role in inflammation-associated tumorigenesis through multi-level cooperation. Unlike other types of tumors, breast carcinomas have shown a significant dependency on the non-classical NF-&kappa, B pathway as well as the classical one. The &alpha, subunit of the inhibitor of the &kappa, B kinase (IKK) complex, IKK&alpha, is involved in both classical and non-classical activation of NF-&kappa, B. Although the cross-talk between STAT3 and NF-&kappa, B has been suggested in several studies, the interplay between STAT3 and the regulators of NF-&kappa, B including IKK&alpha, has not been fully clarified yet. In this study, we observed overexpression and co-localization of IKK&alpha, and STAT3 in human breast cancer tissues as well as in H-Ras transformed human breast epithelial (H-Ras MCF-10A) and breast cancer (MDA-MB-231) cells. By utilizing small interfering RNA (siRNA) technology, we were able to demonstrate that STAT3 up-regulated IKK&alpha, but not IKK&beta, or IKK&gamma, in these cells. This was attributable to direct binding to and subsequent stabilization of IKK&alpha, protein by blocking the ubiquitin-proteasome system. Notably, we identified the lysine 44 residue of IKK&alpha, as a putative binding site for STAT3. Moreover, siRNA knockdown of IKK&alpha, attenuated viability, anchorage-independent growth and migratory capabilities of H-Ras MCF-10A cells. Taken together, these findings propose a novel mechanism responsible for NF-&kappa, B activation by STAT3 through stabilization of IKK&alpha, which contributes to breast cancer promotion and progression. Thus, breaking the STAT3-IKK&alpha, alliance can be an alternative therapeutic strategy for the treatment of breast cancer.

Objective To review the study design, type, protocol, and treatment outcomes of miniplate-anchored maxillary protraction (MAMP) in adolescent patients with unilateral or bilateral cleft lip and palate. Setting/sample population Five retrospective and two prospective studies (n=138 patients) were selected as per the inclusion criteria. Materials and methods The study design, type, protocol of MAMP, and the amount of skeletodental change were investigated. Results Two studies adopted type 1 (two miniplates at the infrazygomatic crest with a facemask), four studies adopted type 2 (four miniplates at the infrazygomatic crest and mandibular symphysis and use of intermaxillary elastics), and one study compared the two types. The mean start age was older than 10 years except one study. The mean duration was less than 1 year in two studies, between 1 and 2 years in three studies, and more than 2 years in two studies. The type 1 used 500 g/side for 12-14 hours/day, and the type 2 used three increase methods (100, 200, 250 g/side; 75, 150, 250 g/side; 150, 200, and 250 g/side) for 24 hours/day. The ranges of A point advancement were 0.5°-4.2° in ΔSNA and 1.7-5.6 mm in ΔA-vertical reference plane, respectively. The ranges of rotation of the palatal plane, occlusal plane, and mandibular plane were -1.5° to 2.0°, -2.0° to 2.0°, -1.5° to 3.2°, respectively. The increase of overjet was ranged from 2.3 to 5.8 mm. Conclusion The MAMP therapy is effective for the correction of maxillary hypoplasia in adolescent cleft patients despite different types and protocols.

Biocreative Orthodontic Strategy (BOS) is designed to establish a physiologically stable occlusion in harmony with masticatory and TMJ function and healthy supporting tissues with strategic use of temporary skeletal anchorage devices (TSADs). This narrative review surveys current research that demonstrates how BOS with TSADs uses a target approach to overcome the limitations experienced with conventional orthodontic treatment. A narrative review article including research on TSADs orthodontics in the permanent dentition. This review is a brief survey of five BOS principles for contemporary TSAD orthodontics: elegant selection of TSADs, bracket prescription to enhance TSAD orthodontics, antero-posterior dimension control, transverse dimension control and airway control issues. Severe malocclusion and craniofacial dysmorphology can be treated with Biocreative Orthodontic Strategy with a minimum number of TSADs. In order to achieve successful treatment outcome using TSADs, it is critical to understand the key diagnosis and treatment principles of BOS and how to develop a target approach for the tooth and bone movement.

To suggest an updated interdisciplinary treatment protocol for pediatric obstructive sleep apnea (POSA) based on the integration of craniofacial growth modification into medical and surgical sleep practice.PubMed, Scopus, and Cochrane library were searched up to February 2020 using keywords. Among 184 articles, 80 studies were finally included. An integrated treatment protocol for POSA encompassing craniofacial skeletal management as well as medical and surgical care was attempted.A differential diagnostic workflow for identifying the phenotype of POSA was suggested, and a phenotype-based treatment protocol for POSA was proposed. Despite the lack of high level of evidence, timely skeletal growth modification in three dimensions using craniofacial growth potential could be valuable treatment for upper airway development in POSA patients with craniofacial phenotypic cause.A novel precision treatment protocol will advance clinicians to determine the primary option or to apply the combined strategy for POSA patients.

Persistent activation of STAT3 and Nrf2 is considered to stimulate the aggressive behavior of basal-like breast cancer (BLBC). However, the precise mechanism underlying sustained overactivation of these transcription factors and their roles in breast cancer progression remain elusive. Analysis of the TCGA multi-omics data showed that high levels of STAT3 and Nrf2 mRNA were correlated with elevated expression of P-STAT3Y705 and Nrf2 target proteins in breast cancer patients. Our present study demonstrates a unique interaction between Nrf2 and STAT3 in the maintenance and progression of BLBC. RNA sequencing analysis identified the gene encoding IL-23A upregulated by concurrent binding of STAT3 and Nrf2 to its promoter. IL-23A depletion also showed the similar phenotypic changes to those caused by double knockdown of both transcription factors. In conclusion, the STAT3-Nrf2 interaction accelerates BLBC growth and progression by augmenting IL-23A expression, which underscores the importance of subtype-specific molecular pathways in human breast cancer.

The n-3 fatty acid (FA) has evoked considerable interest as a modifiable factor for maintenance of muscle health owing to its anti-inflammatory properties. To clarify this possibility, we investigated circulating n-3 FA level, a reliable biomarker of FA status in the body, in relation to sarcopenia in a cohort of Asian older adults. Blood samples were collected from 125 participants who underwent comprehensive assessment of muscle mass and function. Serum FA level was measured by gas chromatography/mass spectrometry. Sarcopenia was diagnosed using the cut-off points specified for the Asian population. After adjusting for sex, age, and body mass index, subjects with sarcopenia and those with low muscle strength had 36.5% and 32.4% lower serum n-3 levels (P = 0.040 and 0.030), respectively, than controls. The odds ratios per standard deviation increment in serum n-3 level for sarcopenia and low muscle strength were 0.29 and 0.40 (P = 0.015 and 0.028), respectively. A higher serum n-3 level was significantly associated with greater muscle strength (P = 0.038). These findings suggest a possible protective effect of n-3 FA on human muscle homeostasis. Further well-designed large-scale longitudinal studies are necessary to understand the definite role of circulating n-3 FA level in sarcopenia risk assessment.

ObjectiveTo investigate the frequency distribution of various craniofacial skeletal patterns in a large Korean adult obstructive sleep apnea (OSA) population, and to find a relationship between craniofacial risks and respiratory and sleep characteristics.MethodsA total of 1226 OSA patients (mean age of 44.9±13.3 years) were included in this retrospective cross-sectional study. All subjects were evaluated for gender and age using fourteen polysomnographic, five cephalometric, two comorbid variables, and three self-reported indexes. Frequency analysis was used to screen the distribution of main skeletal patterns and subtypes. Intergroup comparisons were performed using independent t-test, chi-square test or analysis of variance. Univariable regression analysis was done to find a relationship between skeletal risks and OSA characteristics.ResultsThe frequency distribution of skeletal patterns was as follows: sagittally 57.2%, 32.3%, and 10.5% of Class II, Class I, and Cass III; vertically 54.0%, 26.7%, and 19.3% of hyperdivergent, normodivergent, and hypodivergent type, respectively. Polysomnographic, symptomatic, and comorbid variables showed no differences among patients with different skeletal patterns. Conversely, skeletal variables showed no differences according to OSA severity. The prevalence of highly risky skeletal pattern of hyperdivergent Class II was more likely to be females (OR 4.52, P < .01) and less obese (OR 3.21, P < .01), irrelevant to OSA and sleep characteristics.ConclusionCharacteristic frequency distributions of skeletal patterns and subtypes were observed in adult OSA patients however, no statistical association was found between the skeletal patterns and OSA characteristics due to the large interindividual variation.

Background and objective Lipid metabolism dysregulation has been implicated in the pathogenesis of IPF; however, the roles of most lipid metabolites in lung fibrosis remain unexplored. Therefore, we aimed to identify changes in lipid metabolites in the lung tissues of IPF patients and determine their roles in pulmonary fibrosis. Methods Free fatty acids in the lung tissues of IPF patients and controls were quantified using a metabolomic approach. The roles of free fatty acids in fibroblasts or epithelial cells treated with TGF-β1 were evaluated using fibrotic markers. The antifibrotic role of stearic acid was also assessed in a bleomycin-induced lung fibrosis mouse model. Protein levels in cell lysates or tissues were measured by western blotting. Results The levels of stearic acid were lower in IPF lung tissues than in control lung tissues. Stearic acid significantly reduced TGF-β1-induced α-SMA and collagen type 1 expression in MRC-5 cells. Furthermore, stearic acid decreased the levels of p-Smad2/3 and ROS in MRC-5 cells treated with TGF-β1 and disrupted TGF-β1-induced EMT in Beas-2B cells. Stearic acid reduced the levels of bleomycin-induced hydroxyproline in a mouse model. Conclusion Changes in the free fatty acid profile, including low levels of stearic acid, were observed in IPF patients. Stearic acid may exert antifibrotic activity by regulating profibrotic signalling.

The proviral integration site for Moloney murine leukemia virus (PIM) family of serine/threonine-specific kinases consist of three isoforms, that regulate proliferation, apoptosis, metabolism, invasion, and metastasis of cancer cells. Among these, abnormally elevated kinase activity of PIM-1 contributes to the progression of gastric cancer and predicts poor prognosis and a low survival rate in gastric cancer patients. In the present study, we found that resveratrol, one of the representative chemopreventive and anticarcinogenic phytochemicals, directly binds to PIM-1 and thereby inhibits its catalytic activity in human gastric cancer SNU-601 cells. This resulted in suppression of phosphorylation of the proapoptotic Bad, a known substrate of PIM-1. Resveratrol, by inactivating PIM-1, also inhibited anchorage-independent growth and proliferation of SNU-601 cells. To understand the molecular interaction between resveratrol and PIM-1, we conducted docking simulation and found that resveratrol directly binds to the PIM-1 at the ATP-binding pocket. In conclusion, the proapototic and anti-proliferative effects of resveratrol in gastric cancer cells are likely to be mediated through suppression of PIM-1 kinase activity, which may represent a novel mechanism underlying its chemopreventive and anticarcinogenic actions.

Background Obesity associated with various complications has increased worldwide. Body weight gain alters lipid metabolites (especially sphingolipids) contributing to obesity-induced inflammation. However, the significance of the metabolites in the development of obese asthma is not yet clear. Methods The serum levels of sphingolipids were measured using liquid chromatography-tandem mass spectrometry in obese controls (n = 7) and patients with asthma: the obese group (BMI > 25 kg/m2 , n = 13) vs the nonobese (n = 28) group. To examine the relationship between metabolic changes in sphingolipids and macrophage polarization, public microarray data were analyzed. In addition, the alteration in sphingolipid metabolism was investigated in wild-type BALB/c mice fed a high-fat diet. Results The obese asthma had higher levels of serum C18:0 and C20:0 ceramides than the nonobese asthma group (P = .028 and P = .040, respectively). The value of the serum C18:0 ceramide (184.3 ng/mL) for discriminating the obese asthma from the nonobese asthma group showed 53.9% sensitivity and 85.7% specificity (AUC = 0.721, P = .024). The microarray data showed significantly increased ceramide synthesis and metabolic shift to ceramide accumulation during M1 macrophage polarization in humans. Increased airway hyperresponsiveness, M1 macrophage polarization, and C18:0 ceramide levels were noted in obese mice, but not in nonobese mice. Increased expression of ceramide synthase (CerS) 1 and CerS6 (not CerS2) was noted in lung tissues of obese mice. Conclusion Alteration in sphingolipid metabolism favoring ceramide accumulation (especially long-chain ceramides) may contribute to developing obese asthma.

Matrine is a natural compound extracted from the herb Sophora flavescens Ait which is widely used in traditional Chinese medicine for treating various diseases. Recently, matrine was reported to have antitumor effects against a variety of cancers without any obvious side effects; however, the molecular mechanisms of its antiproliferative effects on cancer are unclear. Here, we report that matrine inhibits autophagy-mediated energy metabolism, which is necessary for pancreatic cancer growth. We found that matrine significantly reduces pancreatic cancer growth in vitro and in vivo by insufficiently maintaining mitochondrial metabolic function and energy level. We also found that either pyruvate or α-ketoglutarate supplementation markedly rescues pancreatic cancer cell growth following matrine treatment. Inhibition of mitochondrial energy production results from matrine-mediated autophagy inhibition by impairing the function of lysosomal protease. Matrine-mediated autophagy inhibition requires stat3 downregulation. Furthermore, we found that the antitumor effect of matrine on pancreatic cancer growth depends on the mutation of the KRAS oncogene. Together, our data suggest that matrine can suppress the growth of KRAS-mutant pancreatic cancer by inhibiting autophagy-mediated energy metabolism.

15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the terminal products of cyclooxygenase-2-catalized arachidonic acid metabolism, has been shown to stimulate breast cancer cell proliferation and migration through Akt activation, but the underlying mechanisms remain poorly understood. In the present study, we investigated the effects of 15d-PGJ2 on the activity of PTEN, the inhibitor of the phosphoinositide 3-kinase (PI3K)-Akt axis, in human breast cancer (MCF-7) cells. Since the α,β-unsaturated carbonyl moiety in the cyclopentenone ring of 15d-PGJ2 is electrophilic, we hypothesized that 15d-PGJ2-induced Akt phosphorylation might result from the covalent modification and subsequent inactivation of PTEN that has several critical cysteine residues. When treated to MCF-7 cells, 15d-PGJ2 bound to PTEN, and this was abolished in the presence of the thiol-reducing agent dithiothreitol. A mass spectrometric analysis by using recombinant and endogenous PTEN protein revealed that the cysteine 136 residue (Cys136) of PTEN is covalently modified upon treatment with 15d-PGJ2. Notably, the ability of 15d-PGJ2 to covalently bind to PTEN as well as to induce Akt phosphorylation was abolished in the cells expressing a mutant form of PTEN in which Cys136 was replaced by serine (C136S-PTEN). The present study demonstrates for the first time that electrophilic 15d-PGJ2 directly binds to cysteine 136 of PTEN and provides new insight into PTEN loss in cancer progression associated with chronic inflammation. These observations suggest that 15d-PGJ2 can undergo nucleophilic addition to PTEN, presumably at Cys136, thereby inactivating this tumor suppressor protein with concomitant Akt activation.

Background Curcumin, a yellow ingredient of turmeric (Curcuma longa Linn, Zingiberaceae), has long been used in traditional folk medicine in the management of inflammatory disorders. Although curcumin has been reported to inhibit experimentally-induced colitis and carcinogenesis, the underlying molecular mechanisms remain largely unresolved. Methods Murine colitis was induced by dextran sulfate sodium (DSS) which mimics inflammatory bowel disease. Curcumin or tetrahydrocurcumin was given orally (0.1 or 0.25 mmol/kg body weight daily) for 7 days before and together with DSS administration (3% in tap water). Collected colon tissue was used for histologic and biochemical analyses. Results Administration of curcumin significantly attenuated the severity of DSS-induced colitis and the activation of NF-κB and STAT3 as well as expression of COX-2 and inducible nitric oxide synthase. In contrast to curcumin, its non-electrophilic analogue, tetrahydrocurcumin has much weaker inhibitory effects. Conclusions Intragastric administration of curcumin inhibited the experimentally induced murine colitis, which was associated with inhibition of pro-inflammatory signaling mediated by NF-κB and STAT3.

Objective The aim of this study was to determine cephalometric factors that help predict favorable soft-tissue profile outcomes following treatment with the Class II Twin-block appliance. Methods Pre- and post-treatment lateral cephalograms of 45 patients treated with the Class II Twin-block appliance were retrospectively analyzed. Profile silhouettes were drawn from the cephalograms and evaluated by three orthodontists in order to determine the extent of improvement. Samples were divided into a favorable group (upper 30% of visual analogue scale [VAS] scores, n = 14) and an unfavorable group (lower 30% of VAS scores, n = 14). Skeletal and soft-tissue measurements were performed on the cephalograms and an intergroup comparison was conducted. Results An independent t-test revealed that the following pre-treatment values were lower in the favorable group compared to the unfavorable group: lower incisor to mandibular plane angle, lower incisor to pogonion distance, point A-nasion-point B angle, sella-nasion line (SN) to maxillary plane angle, SN to mandibular plane angle, gonial angle, and symphysis inclination. The favorable group had a larger incisor inclination to occlusal plane. Moreover, the favorable group showed larger post-treatment changes in gonial angle, B point projection, and pogonion projection than did the unfavorable group. Conclusions Class II malocclusion patients with a low divergent skeletal pattern and reduced lower incisor protrusions are likely to show more improvement in soft-tissue profile outcomes following Class II Twin-block treatment.

Objective Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH. Design Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase C¿ (PKC¿), or the NLR family CARD domain-containing protein 4 (NLRC4). Results HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKC¿ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis. Conclusion SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKC¿- NLRC4 axis and holds promise as a therapeutic target for NASH., This study was supported by grants from the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology, Korea (2017R1E1A1A01073206: KUL, 2017R1E1A1A01074207: EHK) and Asan Institute for Life Sciences, Korea (2018IP0557-1). We acknowledge the support from NIH grants R01 DK113592, R01 AA024206 to AEF; grants SAF2017- 85877R and PID2019-1116691RB from Plan Nacional de I+D, Spain and by the CIBEREHD, Instituto de Salud Carlos III, Spain; the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/ NIH; support from AGAUR of the Generalitat de Catalunya SGR-2017–1112 and the ’ER stress-mitochondrial cholesterol axis in obesity-associated insulin resistance and comorbidities’-Ayudas Fundación BBVA (35_2018) a Equipos de Investigación Científica 2017, the Red Nacional 2018–1 02 799 T ’Enfermedades metabólicas y cáncer’ and the Fundació Marató TV3 201916-30-31.

Acanthamoeba keratitis (AK) is a rare disease but its prevalence throughout the globe continues to grow, primarily due to increased contact lens usage. Since early-stage symptoms associated with AK closely resemble those from other corneal infections, accurate diagnosis is difficult and this often results in delayed treatment and exacerbation of the disease, which can lead to permanent visual impairment. Accordingly, developing a rapid Acanthamoeba-specific diagnostic method is highly desired. In the present study, a rapid and differential method for AK diagnosis was developed using the secretory proteins derived from the pathogenic Acanthamoeba. Among the vast quantities of proteins secreted by the pathogenic Acanthamoeba, an open reading frame of the inosine-uridine preferring nucleoside hydrolase (IPNH) gene was obtained. After expressing and purifying the IPNH protein using the pGEX 4T-3 vector system, mice were immunized with the purified proteins for polyclonal antibody generation. Western blot was performed using protein lysates of the human corneal cell, non-pathogenic amoeba, pathogenic amoeba, and clinical amoeba isolate along with lysates from other causes of keratitis such as Staphylococcus aureus, Pseudomonas aeruginosa, and Fusarium solani to confirm Acanthamoeba-specificity. Western blot using the polyclonal IPNH antibody revealed that IPNH was Acanthamoeba-specific since these proteins were only observed in lysates of Acanthamoeba origin or its culture media. Our findings indicate that the IPNH antibody of Acanthamoeba may serve as a potential agent for rapid and differential AK diagnosis.

BACKGROUND Asthma is associated with inflammatory dysregulation, but the underlying metabolic signatures are unclear. This study aimed to classify asthma inflammatory phenotypes based on cellular and metabolic features. METHODS To determine cellular and metabolic profiles, we assessed inflammatory cell markers using flow cytometry, sphingolipid (SL) metabolites using LC-MS/MS, and serum cytokines using ELISA. Targeted gene polymorphisms were determined to identify genetic predispositions related to the asthma inflammatory phenotype. RESULTS In total, 137 patients with asthma and 20 healthy controls (HCs) were enrolled. Distinct cellular and metabolic profiles were found between them; patients with asthma showed increased expressions of inflammatory cell markers and higher levels of SL metabolites compared to HCs (P

Previous studies focusing on phenotyping obstructive sleep apnea (OSA) have outlined its heterogeneity in clinical symptoms, comorbidities, and polysomnographic features. However, the role of anatomical or pathophysiological causality including craniofacial skeletal deformity has not been studied. We aimed to identify and characterize phenotypes of OSA based on multi-perspective clustering by incorporating craniofacial risks with obesity, apnea severity, arousability, symptom, and comorbidity. A total of 421 Korean patients with OSA (apnea-hypopnea index, AHI ≥ 5; age ≥ 20 years old) were recruited. A K-means cluster analysis was performed following principal component analysis with sagittal and vertical skeletal variables (ANB and mandibular plane angle), AHI, body mass index, and Epworth sleepiness scale. Inter-cluster comparison was conducted using demographic, cephalometric, and polysomnographic variables in addition to presence of diabetes and hypertension. Risk factors contributing to OSA severity were evaluated in each cluster using multivariable regression analysis with adjustment for age and gender. Three phenotypic clusters were identified and characterized as follows: Cluster-1 (noncraniofacial phenotype, 39%), non-obese moderate-to-severe OSA with no skeletal discrepancy representing low arousal threshold (ArTh), little sleepiness, and low comorbidity; Cluster-2 (craniofacial skeletal phenotype, 33%), non-obese moderate OSA with definite skeletal discrepancy showing low ArTh, mild sleepiness, and low comorbidity; and Cluster-3 (complicated phenotype, 28%), obese severe OSA with skeletal discrepancy exhibiting high ArTh, excessive daytime sleepiness, and high incidence of hypertension. The three OSA phenotypes from multi-perspective clustering may provide a basis for precise therapeutic decision-making including craniofacial skeletal intervention beyond usual characterization of OSA subgroups.

Objectives To identify and characterize the phenotypes of adult obstructive sleep apnoea (OSA) patients based on clustering using OSA severity, obesity, and craniofacial pattern. Material and methods The samples consisted of 89 adult OSA patients whose polysomnography and lateral cephalogram were available. With cluster analysis using apneahypopnea index (AHI, events/hour), body mass index (BMI, kg/m2), ANB (degree), and mandibular plane angle (MPA, degree), three clusters were identified. Cephalometric variables including craniofacial, soft palate, hyoid bone, and pharyngeal space compartments were compared among clusters by one-way analysis of variance or Kruskal-Wallis test. Multivariable linear regression analysis was performed to find contributing factors to OSA severity within each cluster. Results Cluster-1 (obesity type; 49.4 per cent) exhibited moderate OSA, obesity, and normal sagittal and vertical skeletal pattern (AHI, 22.4; BMI, 25.5; ANB, 3.2 degrees; MPA, 26.3 degrees) without significant upper airway abnormality. Cluster-2 (skeletal type; 33.7 per cent) was characterized by moderate OSA, severe skeletal Class II hyperdivergent pattern with narrow pharyngeal airway spaces, without obesity (AHI, 27.9; BMI, 23.5; ANB, 7.5 degrees; MPA, 36.6 degrees). Cluster-3 (complex type; 16.8 per cent) included severe OSA, obesity, skeletal Class II hyperdivergent pattern (AHI, 52.8; BMI, 28.0; ANB, 4.5 degrees; MPA, 32.2 degrees), with posteriorly displaced hyoid and retroclined soft palate. The main contributing factors to AHI were obesity in Cluster-1; hyperdivergent vertical pattern with narrow pharyngeal space in Cluster-2; and hyperdivergent pattern, obesity, displaced hyoid, and soft palate in Cluster-3. Conclusion Three OSA phenotypes resulted from this study provide a clinical guideline for differential diagnosis and orthodontic intervention in the interdisciplinary treatment for OSA patients.

SIRT1 is a mammalian NAD+-dependent deacetylase, which is known to be involved in various physiological events, such as adaptive response to environmental stresses including caloric restriction, as well as in aging and cellular senescence. However, recent studies have revealed overexpression of SIRT1 in many different types of human malignancies, particularly colon cancer. Interleukin-1β (IL-1β) is a proinflammatory cytokine that plays a major role in invasiveness, stemness and progression of colon cancer. However, the interaction between IL-1β and SIRT1 in the tumor development and progression remains elusive. In this study, we found that IL-1β induces SIRT1 protein expression in human colon cancer HCT-116 cells. IL-1β-induced SIRT1 upregulation led to enhanced expression of mRNA transcripts of pro-inflammatory cytokines, IL-6 and IL-8 as well as that of IL-1β. Knockdown of SIRT1 prevented IL-1β-induced phosphorylation and nuclear accumulation of c-Jun. Furthermore, pharmacologic inhibition of SIRT1 abrogated clonogenicity and migrative capability of human colon cancer cells stimulated with IL-1β. In summary, IL-1β-induced SIRT1 upregulation stimulates production of proinflammatory cytokines via a nuclear accumulation of c-Jun, leadng to colon cancer growth and progression.

Taurine chloramine (TauCl) is an endogenous anti-inflammatory substance which is derived from taurine, a semi-essential sulfur-containing β-amino acid found in some foods including meat, fish, eggs and milk. In general, TauCl as well as its parent compound taurine downregulates production of tissue-damaging proinflammatory mediators, such as chemokines and cytokines in many different types of cells. In the present study, we investigated the protective effects of TauCl on experimentally induced colon inflammation. Oral administration of TauCl protected against mouse colitis caused by 2,4,6-trinitrobenzene sulfonic acid (TNBS). TauCl administration attenuated apoptosis in the colonic mucosa of TNBS-treated mice. This was accompanied by reduced expression of an oxidative stress marker, 4-hydroxy-2-nonenal and proinflammatory molecules including tumor necrosis factor-α, interleukin-6 and cyclooxygenase-2 in mouse colon. TauCl also inhibited activation of NFκB and STAT3, two key transcription factors mediating proinflammatory signaling. Notably, the protective effect of TauCl on oxidative stress and inflammation in the colon of TNBS-treated mice was associated with elevated activation of Nrf2 and upregulation of its target genes encoding heme oxygenase-1, NAD(P)H:quinone oxidoreductase, glutamate cysteine ligase catalytic subunit, and glutathione S-transferase. Taken together, these results suggest that TauCl exerts the protective effect against colitis through upregulation of Nrf2-dependent cytoprotective gene expression while blocking the proinflammatory signaling mediated by NFκB and STAT3.

Maxillomandibular advancement (MMA) surgery, which is the most effective treatment modality for patients with moderate-to-severe obstructive sleep apnea with apparent skeletal discrepancies, has been modified in conjunction with segmental osteotomies, counterclockwise rotation of maxillomandibular complex, and other adjunctive procedures. However, any single type of MMA could not treat or cure all the patients with obstructive sleep apnea showing different dentofacial and pharyngeal patterns. We aimed to suggest critical decision factors for the selective application of MMA subtypes, categorized as straight MMA with genioplasty, rotational MMA, segmental MMA, and segmental-rotational MMA, in the surgical treatment objective process: anteroposterior position of maxilla, upper lip projection, overjet, lower incisor inclination as sagittal factors, and upper incisor exposure and occlusal plane angle as vertical factors. This case series deserves a clinical basis on the way of case-by-case application of the optimal MMA subtype based on the successful treatment outcomes with short-term stability.

Aberrant activation of H-Ras is often associated with tumor aggressiveness in breast cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is a unique enzyme that interacts with phosphorylated serine or threonine of a target protein and isomerizes the adjacent proline residue. Pin1 is prevalently overexpressed in human cancers, and its overexpression correlates with poor prognosis. Nuclear factor E2-related factor 2 (Nrf2) is a master regulator of cellular redox homeostasis. The sustained activation/accumulation of Nrf2 has been observed in many different types of human malignancies, conferring an advantage for growth and survival of cancer cells. The activated form of H-Ras (GTP-H-Ras) is highly overexpressed in human breast cancer tissues. In our present study, silencing of H-Ras decreased the invasiveness of MDA-MB-231 human breast cancer cells and abrogated the interaction between Pin1 and Nrf2 in these cells. Pin1 knockdown blocked the accumulation of Nrf2, thereby suppressing proliferation and clonogenicity of MCF10A-Ras human mammary epithelial cells. We found that Pin1 binds to Nrf2 which stabilizes this transcription factor by hampering proteasomal degradation. In conclusion, H-Ras activation in cooperation with the Pin1-Nrf2 complex represents a novel mechanism underlying breast cancer progression and constitutive activation of Nrf2 and can be exploited as a therapeutic target.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that mutation of the gene encoding this transcription factor causes its overactivation in various types of human malignancies. The aberrant activation of NRF2 is considered to accelerate the proliferation and progression of cancer cells. However, the exact function of NRF2 in the stage of pre-malignancy remains still largely unresolved. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. In the present study, a well-known NRF2 activating chemopreventive phytochemical, sulforaphane (SFN), was daily injected intraperitonally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The relative fold changes of liver weight, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than that in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1 (NQO1), and the cell proliferation marker proliferating cell nuclear antigen (PCNA) and the DNA damage marker gamma-histone 2A family member X (γH2AX) was markedly elevated in SFN-treated mice compared with that in vehicle-treated mice as assessed by the Western blot assay. Immunohistochemistry and Immunofluorescence staining data further verified higher expression of NRF2 and PCNA in SFN-treated mice. These results suggest that once HCC is initiated, SFN stimulates the progression of DEN-induced HCC via activation of NRF2, rather than exerting a cancer chemopreventive effect. RNA sequencing analysis with liver tumors from DEN-treated mice revealed the B-raf V637E mutation (4/7). We speculate that mutation of B-raf proto-oncogene may contribute, at least in part, to activation of oncogenic NRF2 in DEN-induced murine carcinogenesis. The effects of SFN on DEN-induced mutation spectrum is under investigation. This study was supported by the Global Core Research Center (GCRC) Grant (No. 2011-003-0001) from the National Research Foundation (NRF) of Republic of Korea. Citation Format: Jie Zheng, Do-Hee Kim, Xi Zhu Fang, Seong Hoon Kim, Soma Saeidi, Su-Jung Kim, Young-Joon Surh. Tumor promoting effects of sulforaphane on diethylnitrosamine-induced murine hepatocarcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3828.