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BACKGROUND & AIMS: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histological and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in two distinct human pancreatitis cohorts. RESULTS: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss-of-ERRγ in primary acini abrogates mRNA expression and protein levels of mitochondrial oxidative phosphorylation (OXPHOS) complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, ER stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared to normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants (SNVs) for ERRγ that associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

Background The present study was investigated to confirm the antiobesity effect of kimchi in high-fat diet-induced obese C57BL/6 mice. Methods Mice in the high-fat diet (HFD) group, standardized kimchi (S-Kimchi) group, and Korean commercial kimchi (D-Kimchi) group, but not in the normal-diet group, were fed a high-fat diet (HFD) for the first 4 weeks to induce obesity. From the 5 th to 8 th weeks, the S- and D-Kimchi groups were fed an HFD containing 10% of S-Kimchi or D-Kimchi, respectively. After 8 weeks, mice were sacrificed and obesity-related factors were determined. Results Body and adipose tissue weights were significantly lower in the kimchi -treated groups than in the HFD group. In particular, in the D-Kimchi group, serum levels of triglyceride, total cholesterol, low-density lipoprotein-cholesterol, insulin, and leptin were significantly lower, and serum levels of high-density lipoprotein-cholesterol and adiponectin were markedly higher than those in the HFD group. Moreover, hepatic mRNA expression of adipogenesis-related genes (CCAAT/enhance-binding protein-α, peroxisome proliferator-activated receptor-γ, sterol regulatory element-binding protein-1c, and fatty acid synthase) in the kimchi -treated groups were lower than those in the HFD group, but fatty acid oxidation-related carnitine palmitoyltransferase-1 expressions were higher. In addition, kimchi decreased the mRNA levels of the inflammation-related monocyte chemotactic protein-1 and interleukin-6 in epididymal fat tissue. Conclusion Administration of kimchi , especially of D-Kimchi, which contained Leuconostoc mesenteroides DRC 0211 starter and other subingredients, exhibited antiobesity activity by reducing body weight gains and adipose tissue weights; modulating serum lipid profiles and hepatic lipogenesis; regulating serum insulin, leptin, and adiponectin levels; and reducing adipocyte size and inflammatory response in epididymal fat tissues.

Bamboo salt (BS) is a specially processed salt according to the traditional recipe using sun-dried salt (SDS) and bamboo in Korea. The present study investigated the effects and mechanism of BS, SDS, NaCl, or mineral mixture (containing zinc, magnesium, and potassium) on ovalbumin (OVA)-induced allergic rhinitis (AR) animal model. The increased number of rubs was inhibited by the oral administration of BS, SDS, NaCl, mineral mixture, or nose inhalation of BS. The increased levels of IgE, histamine, and interleukin (IL)-1β in serum were reduced by BS. The level of interferon-γ was increased, whereas the level of IL-4 was reduced on the spleen tissue of BS-treated mice. In the BS-treated mice, the number of eosinophils and mast cells infiltration increased by OVA-sensitization were also decreased. Protein levels of inflammatory cytokines were reduced by BS or NaCl administration in the nasal mucosa of the AR mice. In addition, BS inhibited caspase-1 activity in the nasal mucosa tissue. In activated human mast cells, BS significantly inhibited the production of IL-1β and thymic stromal lymphopoietin and activation of caspase-1. Our data indicate that BS has anti-allergic and anti-inflammatory effects by regulating of caspase-1 activation in AR mice and in vitro models.

Zingerone, a major component found in ginger root, has been known as anti-mutagenic and anti-carcinogenic activities that are often associated with its anti-oxidative and anti-inflammatory activities. In recent studies, we examined molecular mechanism of zingerone treatment on pro-inflammatory NF-kappaB activation via the redox-related NIK/IKK and MAPK pathways. Action mechanism of zingerone on NF-kappaB signaling was investigated in aged rat kidney and endothelial cells. The results showed that zingerone had not only the antioxidant effect by constitutive suppression of ROS, but also anti-inflammatory effects by suppression of nuclear factor (NF)-kappaB activation in aged rat. In addition, zingerone treatment suppressed gene activation of pro-inflammatory enzymes, COX-2 and iNOS, which were upregulated with aging through NF-kappaB activation and IKK/MAPK signaling pathway. These experiments strongly indicate that zingerone treatment exerts a beneficial efficacy by suppressing both oxidative stress and age-related inflammation through the modulation of several key pro-inflammatory genes and transcription factors. Thus, the significance of our findings is that the zingerone treatment may provide some preventive measure against chronic inflammatory conditions that underlie many age-related inflammatory diseases, such as metabolic syndrome, cardiovascular disease, dementia, arthritis, diabetes, osteoprosis, and cancers.

Objective Fermented soy foods, such as doenjang , are important components of the Korean diet. Doenjang has been shown to have greater antimutagenic and anticancer activities than other fermented soybean foods such as chungkukjang (Korean-style natto ) and miso and non-fermented soybeans. This study investigated the effects of fermentation time of doenjang on its inhibitory activity against solid tumor formation and lung metastasis. Methods Effects of methanol extracts from doenjang prepared with long-term fermentation on tumor formation, natural killer cell activity in spleen, and glutathione S -transferase activity in liver were investigated in sarcoma-180 cell–transplanted mice. Inhibitory effects of these samples on lung metastasis of colon 26-M3.1 cells were also evaluated in Balb/c mice. To determine the effect of aging on functionality, doenjang fermented for 3, 6, and 24 mo were evaluated. Results Doenjang fermented for 24 mo exhibited a two- to three-fold increase in antitumor effects on sarcoma-180–injected mice and antimetastatic effects in colon 26-M 3.1 cells in mice compared with the 3- or 6-mo fermented doenjang . The 24-mo fermentation was the most effective in preventing cancer by decreasing tumor formation and increasing natural killer cell activity in spleens and glutathione S -transferase activity in livers of mice. Conclusions Prolonging the fermentation period when making doenjang increases its antitumor and antimetastatic effects in vivo.

Pretreatment of the methanolic extract of the heartwood of Rhus verniciflua (Anacardiaceae) to rats prevented the activation of hepatic microsomal cytochrome P450 enzymes, inhibition of hepatic glutathione S-transferase by bromobenzene treatment, respectively, and therefore significantly decreased malondialdehyde content in the rat. The Ames test showed that the addition of 1.0 mg/plate of the methanolic extract or the EtOAc fraction of the Rhus verniciflua heartwood extract potentially inhibited the mutagenicity by aflatoxin B1. Column chromatography of the EtOAc fraction yielded four flavonoids, garbanzol (1), sulfuretin (2), fisetin (3), fustin (4), mollisacasidin (5). When these components were subjected to the Ames test, it was found that sulfuretin might effectively prevent the metabolic activation or scavenge electrophilic intermediates capable of causing mutation. In contrast, fustin showed a dose-independent antimutagenic activity and it has mutagenic/antimutagenic activity. However, a mixture of sulfuretin and fustin (1:1) exhibited dose-dependent antimutagenicity indicating that sulfuretin inhibited the mutagenicity of fustin. These results suggest that the extract of Rhus verniciflua heartwood containing flavonoid complex could be a potent anticarcinogen.

Doenjang (Korean fermented soypaste) is one of the important fermented foods of Korea. Doenjang has been traditionally manufactured from meju, which is fermented rectangular shape molded from crushed cooked soybeans. The main microorganisms involved for meju fermentation are Bacillus subtilis and molds such as Rizopus sp., Mucor sp., and Aspergillus sp. We have already reported that doenjang is safe from mycotoxin, especially, aflatoxin contamination due to the manufacturing process of the doenjang. We have demonstrated that the doenjang extracts showed strong antimutagenic activities against various carcinogens/mutagens including aflatoxin B1. The traditionally fermented soypaste, doenjang showed higher antimutagenic activity than the raw soybeans, cooked soybeans, meju and other fermented soybeans in the Ames test. The active compounds that were identified are genistein, linoleic acid, β-sitosterol glucoside, soyasaponin, etc. The active compounds exhibited strong antimutagenic activities in the Ames test, SOS chromotest and Drosophila wing spot test. More genistein was formed during the doenjang fermentation from genistin in the soybeans. Genistein and linoleic acid were the most effective active compounds found in doenjang.

Aflatoxin (AF) production and its stability on meju (crushed Korean soybean cake) by a pure culture of Aspergillus parasiticus and a mixed culture of A. parasiticus . A. oryzae and Bacillus subtilis (fermentation 1) during the manufacture by traditional methods of Korean soy paste (doenjang) and soy sauce (kanjang) were studied. There was a difference in the amount of aflatoxin production on different varieties of soybeans, but the pattern of toxin production was similar. During fermentation, more total aflatoxins were produced under the mixed culture condition. Aflatoxin G1 (AFG1) production was highly stimulated though it degraded quickly, whereas aflatoxin B1 (AFB1) synthesis was low. The exposure of the meju to sunlight during fermentation had no effect in reducing aflatoxin synthesis. When the meju fermented under natural conditions (fermentation 2) with a contamination by A. parasiticus , high levels of aflatoxins were still produced. After a month of ripening of the fermented meju with charcoal in brine, more AFG1 than AFB1 was degraded in both the pure and mixed culture samples (degradation %; B1:2-69%, G1:31-84%). When the meju was ripened in water, most of the aflatoxins were degraded (B1:95-99%, G1:100%) in a month, accompanied by a significant increase in pH (p

Synthesis of type I and III collagens has been examined in MG-63 human osteosarcoma cells after treatment with the steroid hormone, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). Analysis of total [3H]proline-labeled proteins and pepsin-derived collagens revealed that 1,25-(OH)2D3 selectively stimulated synthesis of alpha 1I and alpha 2I components of type I collagen after 6-12 h. Consistent with previous reports (Franceschi, R. T., Linson, C. J., Peter, T. C., and Romano, P. R. (1987) J. Biol. Chem. 262, 4165-4171), parallel increases in fibronectin synthesis were also observed. Hormonal effects were maximal (2- to 2.5-fold versus controls) after 24 h and persisted for at least 48 h. In contrast, synthesis of the alpha 1III component of type III collagen was not appreciably affected by hormone treatment. Of several vitamin D metabolites (1,25-(OH)2D3, 25-dihydroxyvitamin D3, and 24R,25-dihydroxyvitamin D3) tested for activity in stimulating type I collagen synthesis, 1,25-(OH)2D3 was found to be the most active. Analysis of collagen mRNA abundance by Northern blot hybridization indicated that both types I and III procollagen mRNAs were increased 4-fold after a 24-h exposure to 1,25-(OH)2D3. Pro alpha 1I mRNA remained elevated through the 48-h time point while pro alpha 2I and pro alpha 1III mRNAs returned to control values. These results indicate that the regulation of collagen synthesis by 1,25-(OH)2D3 is complex and may involve changes in translational efficiency as well as mRNA abundance. 1,25-(OH)2D3 also caused at least a 20-fold increase in levels of the bone-specific calcium-binding protein, osteocalcin. These results are consistent with the hypothesis that 1,25-(OH)2D3 is stimulating partial differentiation to the osteoblast phenotype in MG-63 cells.

The effects of substrates (synthetic and semisynthetic broths and several foods) on aflatoxin production by Aspergillus parasiticus and Aspergillus flavus were studied at different temperatures. The addition of calcium lactate as a carbon source to synthetic and semisynthetic broth media was evaluated for its effect on mycelial growth and aflatoxin production. At temperatures of 15 and 25°C, lactate did not support either mycelial growth or aflatoxin production in a basal salts broth, but did support mycelial growth, though not aflatoxin production, by both molds in a semisynthetic (YEL) broth. No growth of either mold or aflatoxin production was observed at 5°C on any of the liquid media employed. Little or no aflatoxin was detected on high protein/low carbohydrate foods such as Cheddar cheese, cottage cheese, yogurt and summer sausage inoculated with A. parasiticus and held at 15°C, but substantial quantities of aflatoxins were produced on yogurt and summer sausage by A. flavus at 15°C. Cheddar and cottage cheeses were poor substrates for aflatoxin production by A. flavus at 15°C. Cheddar cheese was a favorable substrate for aflatoxin production by both molds at 25°C. Cottage cheese was a poor substrate for aflatoxin production by both organisms at 25°C. Yogurt and summer sausage were poor substrates for A. parasiticus , but favorable substrates for A. flavus for aflatoxin production at 15 and 25°C. Trace levels of aflatoxins were produced on whole soybeans by A. parasiticus , whereas high levels of aflatoxins were produced by A. flavus on soybeans at 15 and 25°C. No growth or aflatoxin production occurred on soybean blocks (Meju) at 15°C, but high levels of aflatoxins were produced at 25°C by both molds. Aflatoxins did not diffuse into the second 1-cm layer of process cheese at 15°C; however, diffusion occurred at 25°C. Process cheese appeared to be a poor substrate for aflatoxin production by both molds at 15 and 25°C. Trace levels of aflatoxins (10 to 60 ppb of aflatoxin B1) were detected on some samples of yogurt and summer sausage at 5°C, although no growth of either mold was observed.