Dichloroacetate improves systemic energy balance and feeding behavior during sepsis.

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to an infection. The metabolic aberrations associated with sepsis underly an acute and organism-wide hyperinflammatory response and multiple organ dysfunction; however, crosstalk between systemic metabolomic alterations and metabolic reprogramming at organ levels remains unknown. We analyzed substrate utilization by the respiratory exchange ratio, energy expenditure, metabolomic screening, and transcriptional profiling in a cecal ligation and puncture model to show that sepsis increases circulating free fatty acids and acylcarnitines but decreases levels of amino acids and carbohydrates, leading to a drastic shift in systemic fuel preference. Comparative analysis of previously published metabolomics from septic liver indicated a positive correlation with hepatic and plasma metabolites during sepsis. In particular, glycine deficiency was a common abnormality of the plasma and liver during sepsis. Interrogation of the hepatic transcriptome in septic mice suggested that the septic liver may contribute to systemic glycine deficiency by downregulating genes involved in glycine synthesis. Interestingly, intraperitoneal injection of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate reversed sepsis-induced anorexia, energy imbalance, inflammation, dyslipidemia, hypoglycemia, and glycine deficiency. Collectively, our data indicated that PDK inhibition rescued systemic energy imbalance and metabolic dysfunction in sepsis partly through restoration of hepatic fuel metabolism.

Dynamic calibration of process-wide partial-nitritation modeling with airlift granular for nitrogen removal in a full-scale wastewater treatment plant.

A main challenge in rapid nitrogen removal from rejected water in wastewater treatment plants (WWTPs) is growth of biomass by nitrite-oxidizing bacteria (NOB) and ammonia-oxidizing bacteria (AOB). In this study, partial nitritation (PN) coupled with air-lift granular unit (AGU) technology was applied to enhance nitrogen-removal efficiency in WWTPs. For successful PN process at high-nitrogen-influent conditions, a pH of 7.5-8 for high free-ammonia concentrations and AOB for growth of total bacterial populations are required. The PN process in a sequential batch reactor (SBR) with AGU was modeled as an activated sludge model (ASM), and dynamic calibration using full-scale plant data was performed to enhance aeration in the reactor and improve the nitrite-to-ammonia ratio in the PN effluent. In steady-state and dynamic calibrations, the measured and modeled values of the output were in close agreement. Sensitivity analysis revealed that the kinetic and stoichiometric parameters are associated with growth and decay of heterotrophs, AOB, and NOB microorganisms. Overall, 80% of the calibrated data fit the measured data. Stage 1 of the dynamic calibration showed NO2 and NO3 values close to 240 mg/L and 100 mg/L, respectively. Stage 2 showed NH4 values of 200 mg/L at day 30 with the calibrated effluent NO2 and NO3 value of 250 mg/L. In stage 3, effluent NH4 concentration was 200 mg/L at day 60.

Itaconate and Its Derivatives Repress Early Myogenesis In Vitro and In Vivo.

A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of in vitro myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopie the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with in vitro myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. We also show 4-octyl itaconate suppresses injury-induced MYOG expression in vivo. More importantly, our findings suggest the therapeutic potential of itaconate, and its derivatives could be limited due to deleterious effects on myogenesis.

Bandgap characteristics of phononic crystals in steady and unsteady flows.

Over the past 30 years, most phononic crystal research has been done for a stationary medium. As reported in a recent experimental study, phononic crystals cannot preserve their bandgaps in the presence of flow. In this study, the bandgap characteristics of a two-dimensional phononic crystal in steady and unsteady flows are investigated theoretically. To identify the effect of the flow on sound insulation in the bandgap frequency ranges, the acoustic reflectance spectra of phononic crystals for different types of background flows, including a uniform flow, a compressible potential flow, and a turbulent flow were calculated. For the steady flows, which include uniform and compressible potential flows, the reflectance spectra are shifted to a lower frequency by the factor 1-M2 due to convection when the flow is in the same direction as the incident wave. Moreover, the reflectance spectra of a phononic crystal in a turbulent flow were evaluated for various combinations of inflow speeds and geometric parameters, such as the filling ratio and the number of layers. Due to the aerodynamic noise and fluid convection, a phononic crystal cannot work as an acoustic barrier, rather it becomes an aeroacoustic source in a turbulent flow.

Quality properties of various dietary fibers as isolated soy protein (ISP) replacements in pork emulsion systems.

This study aimed to investigate the possibility of replacing the isolated soy protein (ISP) as a binding agent for wheat, oat, and bamboo shoot dietary fibers. Dietary fibers and ISP were added to manufacturing process of pork emulsion, respectively, for investigate quality properties. Moisture contents of pork emulsion added wheat fiber-treated group was significantly higher than ISP-treated group (p < 0.05), and protein contents of dietary fiber-treated group were significantly lower than ISP-treated group (p < 0.05). Raw pork emulsion CIE a* value of oat, bamboo shoot fiber-treated group were significantly lower than ISP-treated group (p < 0.05). After cooking pork emulsion CIE L* value of dietary fiber-treated group were significantly higher than ISP-treated group (p < 0.05). Raw pork emulsion water holding capacity (WHC) of wheat, oat fiber-treated group were significantly higher than ISP-treated group (p < 0.05), and cooked pork emulsion WHC of wheat, bamboo shoot fiber-treated group were higher than ISP-treated group (p < 0.05). Cooking loss of ISP-treated group was significantly higher than dietary fiber-treated group (p < 0.05), and viscosity of ISP-treated group was lower than dietary fiber-treated group. Hardness of ISP-treated group was significantly lower than dietary fiber-treated group (p < 0.05); however, cohesiveness of ISP-treated group was significantly higher than dietary fiber-treated group (p < 0.05). In conclusion, dietary fiber added as binding agent to manufacturing process of pork emulsion was suitable to replacing ISP.

Palmitate-induced autophagy liberates monounsaturated fatty acids and increases Agrp expression in hypothalamic cells.

Fatty acids regulate food intake, although the exact mechanism remains unknown. Emerging evidence suggests that intracellular free fatty acids generated by starvation-induced autophagy regulate food intake. Starvation for 6 h elevated fatty acids such as palmitate, oleate, arachidonate, eicosatrienoate, and docosahexaenoate in the mouse serum. Among them, palmitate induced lipophagy, an autophagic degradation of cellular lipid droplets, in agouti-related peptide (Agrp)-expressing hypothalamic cells. Palmitate-induced lipophagy increased both Agrp expression and the contents of monounsaturated fatty acids such as palmitoleate, oleate, and (E)-9-octadecanoate, whereas these effects were blunted by autophagy deficiency. These findings support the role of free fatty acids in hypothalamic autophagy that regulates the appetite by changing the expression of orexigenic neuropeptides.

ANTI-VIRAL EFFECT OF HERBAL MEDICINE KOREAN TRADITIONAL CYNANCHUM PANICULATUM (BGE.) KITAG EXTRACTS.

BACKGROUND: Pestiviruses in general, and Bovine Viral Diarrhea (BVD) in particular, present several potential targets for directed antiviral therapy. MATERIAL AND METHODS: The antiviral effect of Cynanchum paniculatum (Bge.) Kitag (Dog strangling vine: DS) extract on the bovine viral diarrhea (BVD) virus was tested. First, a cytotoxicity test in MDBK (Madin-Darby bovine kidney) cells was done with all organic extract concentrations. RESULTS: The cytotoxic concentration CC50 for the ethyl acetate (EA) extracts was 18.2 ug/ml. In the tissue culture, infectious dose (TCID50) assay, the BVD virus decreased when treated with 18.2 ug/ml of the ethyl acetate extracts. CONCLUSION: Ethyl acetate extracts and fractions of the DS extract could be used as a potential antiviral for BVD.

Hypothalamic AMP-activated Protein Kinase as a Regulator of Food Intake and Energy Balance.

The maintenance of appetite at proper levels, depending on the energy status, is important; otherwise abnormal appetite may cause a series of disorders, such as anorexia, hyperphagia, obesity, and its complications (diabetes mellitus, hypertension, cardiovascular disease, and fatty liver disease). Hypothalamic AMPactivated protein kinase (AMPK) integrates diverse hormonal and nutritional signals to regulate food intake and energy metabolism. Recent evidence suggests that different hormones, nutrients and synthetic chemicals can modulate AMPK activity in the hypothalamus, thereby regulating food intake and body weight, through neuropeptide expressions. In order to elucidate the mechanisms that control hypothalamic AMPK activity, a variety of studies have focused on finding upstream and downstream modulators of hypothalamic AMPK for the regulation of food intake and energy balance. This review highlights the current evidence for understanding how hypothalamic AMPK regulates food intake and energy balance, and will help in the development of effective interventions for the treatment of food intake-related disorders. In the future, it is hoped that new pharmaceutical developments targeting hypothalamic AMPK, in combination with careful clinical trials, will lead to improved and effective therapeutic strategies for complications caused by abnormal appetite and energy balance.

Hypothalamic AMPK-induced autophagy increases food intake by regulating NPY and POMC expression.

Hypothalamic AMP-activated protein kinase (AMPK) plays important roles in the regulation of food intake by altering the expression of orexigenic or anorexigenic neuropeptides. However, little is known about the mechanisms of this regulation. Here, we report that hypothalamic AMPK modulates the expression of NPY (neuropeptide Y), an orexigenic neuropeptide, and POMC (pro-opiomelanocortin-α), an anorexigenic neuropeptide, by regulating autophagic activity in vitro and in vivo. In hypothalamic cell lines subjected to low glucose availability such as 2-deoxy-d-glucose (2DG)-induced glucoprivation or glucose deprivation, autophagy was induced via the activation of AMPK, which regulates ULK1 and MTOR complex 1 followed by increased Npy and decreased Pomc expression. Pharmacological or genetic inhibition of autophagy diminished the effect of AMPK on neuropeptide expression in hypothalamic cell lines. Moreover, AMPK knockdown in the arcuate nucleus of the hypothalamus decreased autophagic activity and changed Npy and Pomc expression, leading to a reduction in food intake and body weight. AMPK knockdown abolished the orexigenic effects of intraperitoneal 2DG injection by decreasing autophagy and changing Npy and Pomc expression in mice fed a high-fat diet. We suggest that the induction of autophagy is a possible mechanism of AMPK-mediated regulation of neuropeptide expression and control of feeding in response to low glucose availability.

Antifungal Action of Ginkgo biloba Outer Seedcoat on Rice Sheath blight.

From study of antifungal actions on the rice sheath blight by using the extract of Ginkgo biloba outer seedcoats, we found that the extracts of Ginkgo biloba outer seedcoats of all treatment concentrations had inhibited the rice sheath blight. Among them, the most effective concentration was 250 mg/l at which the growth of microbe was 26 mm and even at the packaging test, when sprayed the G. biloba outer seedcoats at the level of 250 mg/l, the damage rate of the rice sheath blight was identified as 13%. As a result investigating the antifungal activity by separating polysaccharides from G. biloba outer seedcoats, it showed that the clear zone of 14 mm or more was formed at the concentration of 250 mg/l or higher. Based on these results, we concluded that the G. biloba outer seedcoat is a natural substance with the antifungal activity on the rice sheath blight.

Saikosaponin D isolated from Bupleurum falcatum inhibits selectin-mediated cell adhesion.

Three saikosaponins were isolated from the MeOH extract of the roots of Bupleurum falcatum L.: saikosaponins B3 (1); B4 (2); and D (3). Of the three, compound 3 inhibited the interaction of selectins (E, L, and P) and THP-1 cells with IC50 values of 1.8, 3.0 and 4.3 µM, respectively. Also, the aglycone structure 4 of compound 3 showed moderate inhibitory activity on L-selectin-mediated cell adhesion. From these results, we suspect that compound 3 isolated from Bupleurum falcatum roots would be a good candidate for therapeutic strategies to treat inflammation.

Long-term observation of the mineral trioxide aggregate extrusion into the periapical lesion: a case series.

One-step apexification using mineral trioxide aggregate (MTA) has been reported as an alternative treatment modality with more benefits than the use of long-term calcium hydroxide for teeth with open apex. However, orthograde placement of MTA is a challenging procedure in terms of length control. This case series describes the sequence of events following apical extrusion of MTA into the periapical area during a one-step apexification procedure for maxillary central incisor with an infected immature apex. Detailed long-term observation revealed complete resolution of the periapical radiolucent lesion around the extruded MTA. These cases revealed that direct contact with MTA had no negative effects on healing of the periapical tissues. However, intentional MTA overfilling into the periapical lesion is not to be recommended.

Gender-dependent protein expression in white adipose tissues of lean and obese rats fed a high fat diet.

BACKGROUND: Proper understanding of molecular mechanisms underlying gender dimorphism in obesity for better nutritional recommendation is still in early stages. As white adipose tissues (WAT) is most important tissue in obesity metabolism, comparative proteomic analysis of all three WAT deposits at the same time to yield immensely important protein markers was the primary goal of this study. METHODS: We performed differential expression analysis of protein profiles of three different WAT viz. subcutaneous, inguinal, and abdominal fat deposits of both genders in lean and obese rats fed a high fat diet (HFD) using a combination of 2-DE and MALDI-TOF-MS. RESULTS: The proteomics analysis enabled us to detect 25, 29, and 46 proteins showing gender differences in three WAT deposits, respectively, to gain insight into cause of higher body weight gain in male in response to HFD. CONCLUSION: The gender dimorphism found in this proteomic study implies that female rats have a lower tendency to undergo metabolic syndrome manifestation, which is associated with lower reliance on lipid as an energy fuel, lower lipogenesis, as well as increased mitochondrial oxidative capacity. In conclusion, most of the candidate proteins identified herein by differential proteomics were previously unrecognized in gender dimorphism of adipose tissue.

DNA microarray analysis reveals differential gene expression in the soleus muscle between male and female rats exposed to a high fat diet.

It is well recognized that diet-induced dysfunctions in skeletal muscle are closely related with many metabolic diseases, such as obesity and diabetes. In the present study, we identified global changes in gender-dependent gene expressions in the soleus muscle of lean and obese rats fed a high fat diet (HFD), using DNA microarray analysis. Prior to microarray analysis, the body weight gains were found to be higher in male HFD rats than the female HFD rats. To better understand the detailed phenotypic differences in response to HFD feeding, we identified differential gene expression in soleus muscle between the genders. To this end, we extracted and summarized the genes that were up- or down-regulated more than 1.5-fold between the genders in the microarray data. As expected, a greater number of genes encoding myofibrillar proteins and glycolytic proteins were expressed higher in males than females when exposed to HFD, reflecting greater muscular activity and higher capacity for utilizing glucose as an energy fuel. However, a series of genes involved in oxidative metabolism and cellular defenses were more up-regulated in females than males. These results allowed us to conclude that compared to males, females have greater fat clearing capacity in skeletal muscle through the activation of genes encoding enzymes for fat oxidation. In conclusion, our microarray data provide a better understanding of the molecular events underlying gender dimorphism in soleus muscle, and will provide valuable information in improving gender awareness in the health care system.

Quantitative method for measuring therapeutic efficacy of the 308 nm excimer laser for vitiligo.

BACKGROUND: There are several available treatments for vitiligo, but measurement of their therapeutic efficacy is not standardized and is somewhat arbitrary based largely on the global impression of the overall response. The purpose of this study was to develop a quantitative method for evaluating the treatment response of vitiligo measuring changes in area using digital image analysis. We applied this parametric model to the evaluation of efficacy of the 308 nm excimer laser. METHODS: This study was a retrospective study, designed as a before and after trial with a single arm. A total of 18 patients were enrolled who had been treated with a 308 nm excimer laser as monotherapy twice a week for 20 sessions. The repigmentation percentage was calculated by measuring changes in area before and after treatment using digital image analysis and graded on a five-point ordinal scale [global assessment scale (GAS)]. GAS was also measured by physician and patient for comparison with our estimates. Additional GASs were also measured by four different evaluators for inter-rater variability. RESULTS: The mean repigmentation percentage after treatment was 45.3% (range, 0.7-100%). The changes in area after treatment were statistically significant (P < 0.05). A substantial agreement of outcomes was observed between physicians and digital image analysis (κ(w) = 0.78), but lower agreement was observed between patients and digital image analysis (κ(w) = 0.49). The inter-rater variability for GAS was substantially low (Krippendorff's α = 79.3%). CONCLUSION: Measurement of changes in area using digital image analysis could be used as a quantitative method in evaluating efficacy of treatment for vitiligo. Because vitiligo lesions can occur in any location with various shapes and sizes, digital image analysis would be a more objective method for measuring treatment response than a GAS.

Comparative hepatic proteome analysis between lean and obese rats fed a high-fat diet reveals the existence of gender differences.

Gender differences in obesity stem from metabolic and hormonal differences between sexes and contribute to differences between women and men in health risks attributable to obesity. We hypothesized that liver may be an ideal target for the evaluation of gender differences in obesity development in response to a high-fat diet (HFD). Therefore, to test this hypothesis, we performed a global proteome analysis in the liver of lean and obese rats of both genders who were fed an HFD through 2-DE combined with MALDI-TOF-MS. When rats were exposed to HFD, male rats gained more body weight with increased values of plasma biochemical parameters than female rats. Image analysis and further statistical analysis of a 2-DE protein map allowed for the detection and identification of 34 proteins that were significantly modulated in a gender-dependent manner. We found 19 proteins showing identical gender-different regulation in both normal diet (ND) and HFD. Five proteins also showed clear gender differences in both ND and HFD; however, their regulation modes in HFD were opposite to those in ND. Of particular interest, 10 proteins showed gender differences only in either ND or HFD rats. Present proteomic insight into gender-dimorphic protein modulation in liver would aid in the improvement of gender awareness in the health-care system and in implementation of evidence-based gender-specific clinical recommendations.

Profiling of gender-specific rat plasma proteins associated with susceptibility or resistance to diet-induced obesity.

Obesity-prone (OP) and obesity-resistant (OR) rats with different responses to development of obesity in spite of the same genetic background are useful animal models for searching for markers during the development of obesity. Here, we investigated whether plasma proteins of OP and OR rats may behave in a different way in males and females. We performed a comparative proteomic analysis using 2-DE combined with MALDI-TOF/MS on proteins from OP and OR male and female rats to discover gender-specific rat plasma proteins associated with susceptibility or resistance to diet-induced obesity. A total of 29 proteins showing differential expression between the groups were identified by MALDI-TOF/MS and database searches. These proteins were classified into 4 groups according to their regulation patterns in response to diet and gender. 22 proteins showed significant differences between OP and OR rats in males and/or females (Group I, II, and III) and 7 proteins exhibited only a high fat diet (HFD)-responsive difference in male or female rats (Group IV). In conclusion, the proteins negatively (ITIH3, FGG, TUBB5, and ZAG) or positively (Hp, ITIH4, and RBP) correlated with obesity found in this study could be used for selection of new targets for gender specific-medical treatment of obesity.

Gender difference in proteome of brown adipose tissues between male and female rats exposed to a high fat diet.

BACKGROUND: Although the importance of gender as a key determinant in health and illness has been recognized for a long time, systematic studies of gender differences in medicine are still lacking. We hypothesized that interscapular brown adipocyte tissue (BAT), is not only a key tissue contributing to energy expenditure, but also regulates diet-induced thermogenesis, and may be an ideal target for studying gender differences in obesity development in response to a high fat diet (HFD). METHODS: We therefore performed differential proteome analysis of BAT from lean and obese rats of both genders fed a HFD using 2-DE combined with MALDI-TOF-MS. RESULTS: When exposed to a HFD, male rats gained more body weight with increased values of plasma biochemical parameters than did female rats. Among 595 matched spots, 48 differentially expressed identified spots showed significant gender differences, whereas 7 proteins showed no gender differences, but did show a HFD response. CONCLUSIONS: Proteomic investigations into gender-dimorphic protein modulation in BAT may provide conclusive results showing higher expression of numerous proteins involved in thermogenesis and fat oxidation as well as lower expression of proteins contributing to fat synthesis in female rats than in male rats.

Gender dimorphism in skeletal muscle proteome between lean and diet-induced obese rats.

BACKGROUND: Although it has been believed for a long time that gender differences in physiology and metabolism were not relevant beyond the reproductive system, new research has indicated that sexual dimorphism may be more prevalent than previously believed. Therefore, the goal of this study was to develop a global view of the changes in gender-dependent protein abundance in two different types of skeletal muscles (soleus and gastrocnemius) of lean and high fat diet (HFD)-induced obese rats. METHODS: To examine differential expression of proteins between gender and diet, we performed differential proteome analysis of skeletal muscle from lean and obese rats of both genders fed a HFD using 2-DE combined with MALDI-TOF-MS. RESULTS: Our gender-specific proteome comparison showed that male and female rats displayed different patterns of proteome regulation including proteins involved in muscle contraction, carbohydrate and lipid metabolism, oxidative phosphorylation, as well as detoxification and antioxidant defenses. CONCLUSIONS: most of the candidate proteins identified herein by differential proteomics were previously unrecognized in gender dimorphism of skeletal muscle. Our data can serve as the basis for specific evidence-based interventions allowing for the prevention and treatment of obesity by matching the different needs of women and men such as the development of gender-based medicine.

Birt-hogg-dubé syndrome, a rare case in Korea confirmed by genetic analysis.

Simple benign tumors can present as part of a syndrome with substantial mortality. Fibrofolliculomas are benign skin tumors most often associated with the Birt-Hogg-Dubé syndrome (BHDS). The most life-threatening complication of this syndrome is renal cancer and other major features include multiple lung cysts and spontaneous pneumothorax. We present the case of a 54 year-old man with multiple flesh-colored papules on his face confirmed histologically as fibrofolliculomas. He had a history of recurrent pneumothorax and chest computed tomography showed multiple lung cysts. To confirm the diagnosis of BHDS, we conducted gene analysis that revealed a single nucleotide duplication in the folliculin (FLCN) gene (Exon 11, C.1285dupC). BHDS confirmed by the FLCN gene mutation is rarely reported in Korea. Appropriate investigation is recommended whenever a patient with benign skin tumors is encountered.