ZW800-PEG: A Renal Clearable Zwitterionic Near-Infrared Fluorophore for Potential Clinical Translation.

Near-infrared (NIR) fluorescence imaging has advanced medical imaging and image-guided interventions during the past three decades. Despite tremendous advances in imaging devices, surprisingly only a few dyes are currently available in the clinic. Previous fluorophores, ZW800-1A and ZW800-1C, significantly improved the poor performance of the FDA-approved indocyanine green. However, ZW800-1A is not stable in serum and ZW800-1C induces severe stacking in aqueous media. To solve such dilemmas, ZW800-PEG was designed by introducing a flexible yet stable thiol PEG linker. ZW800-PEG shows high solubility in both aqueous and organic solvents, thus improving renal clearance with minimal binding to serum proteins during systemic circulation. The sulfide group on the meso position of the heptamethine core improves serum stability and physicochemical properties including the maximum emission wavelength shift to 800 nm, enabling the use of ZW800-PEG for image-guided interventions and augmenting photothermal therapy.

Associations between metabolic syndrome and urinary Na-to-K ratio and glomerular filtration rate in middle-aged adults regardless of Na and K intakes.

BACKGROUND: Intake of Na-to-K ratio (I-Na/K), urinary Na-to-K ratio (U-Na/K), and estimated glomerular filtration rate (GFR) have been reported to be risk factors of metabolic syndrome (MetS), but results are inconsistent. We examined the hypothesis that U-Na/K, GFR, and a preference for salty foods are associated with MetS risk and the hypothesis in 8540 adults aged over 40 years without chronic kidney disease. METHODS: Participants were categorized using a U-Na/K of < 2.1 (low-U-Na/k) and a GFR of < 60 mL/min (low-GFR). A GFR of 60-90 mL/min was considered as a normal level, since it is a normal or marginal disease state. Correlations and associations were determined using Pearson's correlation coefficients and logistic regression analysis after adjusting for covariates related to MetS. RESULTS: U-Na/K, but not I-Na/K, was positively correlated with blood pressure (r2 = 0.20, P < 0.0001). The GFR was negatively correlated with age, gender, HOMA-B, and MetS (r2 = - 0.14 to - 0.595, P < 0.0001), and positively correlated with education, current smoking, and alcohol intake (r2 = 0.21 to 0.40, P < 0.0001). MetS risk had a positive association with the following combinations with low-U-Na/K + low-GFR, high-U-Na/K + high-GFR, and high-U-Na/K +low-GFR by 1.830-, 3.182-, and 3.696-fold, respectively, as compared with low-U-Na/K + high-GFR. Risks of the MetS components (abdominal obesity, hypertriglyceridemia, hypo-HDL-cholesterolemia, hypertension, and hyperglycemia) were similarly associated with U-Na/K and GFR, though hypertension had the strongest association. Hypertension risk had positive associations with low-U-Na/K + low-GFR, high-U-Na/K + high-GFR, and high-U-Na/K + low-GFR by 1.526-, 14.06-, and 7.079-fold, respectively, as compared with low-U-Na/K + high-GFR. CONCLUSION: MetS risk was found to be associated with U-Na/K and GFR regardless of I-Na/K. Women need to maintain a high GFR to reduce the MetS risk, especially the risk of hypertension.

Carbohydrate and sodium intake and physical activity interact with genetic risk scores of four genetic variants mainly related to lipid metabolism to modulate metabolic syndrome risk in Korean middle-aged adults.

Metabolic syndrome (MetS) risk is influenced by genetic and environmental factors. The present study explored genetic risk scores (GRS) of genetic variants that influence the MetS and the effect of interactions between GRS and nutrient intake on MetS risk. The genetic variants that influence MetS risk were selected by genome-wide association study after adjusting for age, sex, area of residence and BMI in 8840 middle-aged adults. GRS were calculated by summing the risk alleles of the selected SNP and divided into low (0-1), medium (2-3) and high (4-7) risk groups, and the relationships between the MetS and GRS were determined by logistic regression after adjusting covariates involved in MetS risk. We also analysed the interaction between GRS and lifestyles. Four genetic variants (APOA5_rs651821, EFCAB4B_rs4766165, ZNF259_rs2160669 and APOBEC1_rs10845640) were selected because they increased MetS risk after adjusting for covariates. Individuals with medium-GRS and high-GRS alleles had a higher MetS risk by 1·48- and 2·23-fold, respectively, compared with those with low-GRS after adjusting for covariates. The increase in MetS risk was mainly related to serum TAG and HDL-cholesterol concentrations. The GRS had an interaction with carbohydrate (CHO) and Na intakes and daily physical activities for MetS risk. In conclusion, Asian middle-aged adults with high-GRS alleles were at increased MetS risk mainly due to dyslipidaemia. High daily physical activity (≥1 h moderate activity per d) reduced the MetS risk but a low-CHO diet (<65 % of total energy intake) increased the risk in carriers with high-GRS alleles. Low Na intake (<1·6 g Na intake/4 MJ) did not decrease its risk.

Total ionization cross section of cyclic organic molecules.

Two independent methods, namely, Binary-encounter Bethe (BEB) and complex scattering potential-ionization contribution (CSP-ic) methods, are employed to calculate the total ionization cross section (Qion) for cyclic organic molecules from ionization threshold to 5 keV for which there is a paucity of data in the literature. The Qion calculated with the (BEB/ωB97X) combination is found to give good agreement with the experimental results, the CSP-ic method, and the Qion calculated from Irikura orbital energies. The Qion for most of the targets are calculated for the first time over such a wide energy range. Hence, to check the consistency and reliability of the present data, we have also computed the static polarizability for all the targets and the variation of maximum ionization cross section (Qion,max) with polarizability is studied. A linear relationship is observed between these quantities indicating the consistency and reliability of the present Qion data. The targets studied are important for industrial applications, radiation biology, and astrophysics.

The Effect of Temporary Cement Cleaning Methods on the Retention of Crowns.

PURPOSE: To evaluate the effect of temporary cement cleaning methods on the retention of cemented crowns using zinc phosphate cement and resin-modified glass ionomer cement. MATERIALS AND METHODS: Forty titanium specimens were fabricated to simulate prepared molars with minimally retentive taper. The Ni-Cr cast crowns were fabricated, temporarily cemented, and separated. The specimens were divided into four groups according to the temporary cement cleaning method (n = 10) as follows: control group (no temporary cementation), orange solvent group, ultrasonic cleaning group, and air-abrasion group. After the cleaning procedures, the specimens were cemented with definitive cements (zinc phosphate cement and resin-modified glass ionomer, RMGI, cement) and subjected to thermocycling (5000 cycles, 5-55°C, dwell time, 10 seconds). The tensile bond strength of each specimen was measured using a universal testing machine, and the results were analyzed using the Kruskal-Wallis and Mann-Whitney U test (α = 0.05). RESULTS: When cemented with zinc phosphate cement, the statistical analysis showed that the value of the air-abrasion group was significantly higher than those of the other groups (p < 0.01). There was no statistically significant difference among the other groups. When cemented with RMGI cement, the air-abrasion group showed the lowest value, and the control group showed the highest value (p < 0.01). The difference between the ultrasonic cleaning group and the orange solvent group was not statistically significant. CONCLUSION: The use of temporary cement did not have a significant influence on retention of permanently cemented crowns when zinc phosphate cement was used for permanent cementation. Airborne-particle abrasion after provisional cementation improved retention of crowns cemented with zinc phosphate cement; however, the use of temporary cement significantly decreased retention of permanently cemented crowns when RMGI cement was used regardless of the temporary cement cleaning method.

The Root of Atractylodes macrocephala Koidzumi Prevents Obesity and Glucose Intolerance and Increases Energy Metabolism in Mice.

Targeting energy expenditure offers a strategy for treating obesity more effectively and safely. In previous studies, we found that the root of Atractylodes macrocephala Koidzumi (Atractylodis Rhizoma Alba, ARA) increased energy metabolism in C2C12 cells. Here, we investigated the effects of ARA on obesity and glucose intolerance by examining energy metabolism in skeletal muscle and brown fat in high-fat diet (HFD) induced obese mice. ARA decreased body weight gain, hepatic lipid levels and serum total cholesterol levels, but did not modify food intake. Fasting serum glucose, serum insulin levels and glucose intolerance were all improved in ARA treated mice. Furthermore, ARA increased peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) expression, and the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle tissues, and also prevented skeletal muscle atrophy. In addition, the numbers of brown adipocytes and the expressions of PGC1α and uncoupling protein 1 (UCP1) were elevated in the brown adipose tissues of ARA treated mice. Our results show that ARA can prevent diet-induced obesity and glucose intolerance in C5BL/6 mice and suggests that the mechanism responsible is related to the promotion of energy metabolism in skeletal muscle and brown adipose tissues.

Atractylenolide III Enhances Energy Metabolism by Increasing the SIRT-1 and PGC1α Expression with AMPK Phosphorylation in C2C12 Mouse Skeletal Muscle Cells.

Targeting energy expenditure provides a potential alternative strategy for achieving energy balance to combat obesity and the development of type 2 diabetes mellitus (T2DM). In the present study, we investigated whether atractylenolide III (AIII) regulates energy metabolism in skeletal muscle cells. Differentiated C2C12 myotubes were treated with AIII (10, 20, or 50 µM) or metformin (2.5 mM) for indicated times. The levels of glucose uptake, the expressions of key mitochondrial biogenesis-related factors and their target genes were measured in C2C12 myotubes. AIII significantly increased the glucose uptake levels, and significantly increased the expressions of peroxisome proliferator-activated receptor coactivator-1α (PGC1α) and mitochondrial biogenesis-related markers, such as, nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM) and mitochondrial mass and total ATP contents. In addition, AIII significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of sirtuin1 (SIRT1). These results suggest that AIII may have beneficial effects on obesity and T2DM by improving energy metabolism in skeletal muscle.

Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17A production from programmed cell death 1-high T cells.

BACKGROUND: Psoriasis is one of the most common chronic inflammatory diseases of the skin. Recently, IL-17-producing T cells have been shown to play a critical role in psoriatic inflammation. Programmed cell death 1 (PD-1) is a coinhibitory receptor expressed on T cells in various chronic inflammatory diseases; however, the expression and function of PD-1 during psoriatic inflammation have not previously been characterized. OBJECTIVE: We examined PD-1 expression on IL-17A-producing T cells from imiquimod-treated mice and patients with psoriasis. Additionally, we investigated the therapeutic effect of recombinant programmed cell death ligand 1 (PD-L1) protein on imiquimod-induced psoriatic inflammation. METHODS: PD-1 expression on IL-17A-producing γδ T cells from imiquimod-treated mice was examined by means of multicolor flow cytometric analysis. In the psoriatic skin of patients, PD-1 and IL-17A expression was analyzed by using immunofluorescence. The therapeutic effect of PD-L1-Fc fusion protein (PD-L1-Fc) was assessed in imiquimod-treated mice ex vivo and in vivo. RESULTS: During imiquimod-induced psoriatic inflammation, PD-1 is overexpressed on CD27(-)Vγ1(-) γδ T cells. Furthermore, PD-1 expression on IL-17A(+) T cells was confirmed in psoriatic skin tissues from patients and imiquimod-treated mice. In the CD27(-)Vγ1(-) γδ T-cell population, Vγ4(-) γδ T cells with Vγ6 mRNA expression showed a high level of PD-1 expression. Furthermore, these PD-1(hi)Vγ4(-) (Vγ6(+)) γδ T cells were specialized for anti-CD3-induced IL-17A production, which was inhibited by PD-L1-Fc treatment. In imiquimod-treated mice PD-L1-Fc reduced psoriatic inflammation when given alone and enhanced the therapeutic effect of anti-p40 when given in combination. CONCLUSION: PD-1 is overexpressed in IL-17A-producing T cells in both imiquimod-treated mice and patients with psoriasis. Moreover, recombinant PD-L1-Fc alleviates psoriatic inflammation in imiquimod-treated mice.

Protective effects of Fc-fused PD-L1 on two different animal models of colitis.

OBJECTIVE: Programmed death-ligand 1 (PD-L1) has been shown to negatively regulate immune responses via its interaction with PD-1 receptor. In this study, we investigated the effects of PD-L1-Fc treatment on intestinal inflammation using two murine models of inflammatory colitis induced by dextran sulfate sodium (DSS) and T-cell transfer. DESIGN: The anti-colitis effect of adenovirus expressing Fc-conjugated PD-L1 (Ad/PD-L1-Fc) and recombinant PD-L1-Fc protein was evaluated in DSS-treated wild-type and Rag-1 knockout (KO) mice. We examined differentiation of T-helper cells, frequency of innate immune cells, and cytokine production by dendritic cells (DCs) in the colon from DSS-treated mice after PD-L1-Fc administration. In Rag-1 KO mice reconstituted with CD4 CD45RB(high) T cells, we assessed the treatment effect of PD-L1-Fc protein on the development of colitis. RESULTS: Administration of Ad/PD-L1-Fc significantly ameliorated DSS-induced colitis, which was accompanied by diminished frequency of interleukin (IL)-17A-producing CD4 T cells and increased interferon-γ-producing CD4 T cells in the colon of DSS-fed mice. The anti-colitic effect of PD-L1-Fc treatment was also observed in DSS-treated Rag-1 KO mice, indicating lymphoid cell independency. PD-L1-Fc modulated cytokine production by colonic DCs and the effect was dependent on PD-1 expression. Furthermore, PD-L1-Fc protein could significantly reduce the severity of colitis in CD4 CD45RB(high) T-cell-transferred Rag-1 KO mice. CONCLUSIONS: Based on the protective effect of PD-L1-Fc against DSS-induced and T-cell-induced colitis, our results suggest that PD-1-mediated inhibitory signals have a crucial role in limiting the development of colonic inflammation. This implicates that PD-L1-Fc may provide a novel therapeutic approach to treat inflammatory bowel disease.

The NLRP3 inflammasome is dispensable for ER stress-induced pancreatic ß-cell damage in Akita mice.

Uncontrolled endoplasmic reticulum (ER) stress activates members of the NOD-like receptor family, which are involved in the pyrin domain containing 3 (NLRP3) inflammasome pathway. This pathway has been proposed to contribute to ß-cell dysfunction and death. However, the connection between ER stress and NLRP3 inflammasome activation remains controversial. Here we generated Akita/KO (Ins2(+/C96Y); NLRP3(-/-)) mice by crossing Akita (Ins2(+/C96Y); NLRP3(+/+)) mice with NLRP3 KO (Ins2(+/+); NLRP3(-/-)) mice. We then compared the metabolic phenotypes of the different strains. Knockout of the NLRP3 inflammasome did not affect the onset or the severity of diabetes in Akita/KO mice at any point of the study. Histological observations of pancreatic islets supported these findings. Tunicamycin-exposed islets from NLRP3 KO mice exhibited similar levels of ER stress and apoptosis induction as islets from WT (Ins2(+/+); NLRP3(+/+)) mice. Furthermore, NLRP3 deletion did not prevent tunicamycin-mediated reduction of glucose-stimulated insulin secretion. In conclusion, deletion of the NLRP3 inflammasome did not protect against ER stress-induced diabetes development or ß-cell damage, indicating that ß cell death in Akita mice is not mediated via activation of the NLRP3 inflammasome.

Design, synthesis, and biological evaluation of a series of alkoxy-3-indolylacetic acids as peroxisome proliferator-activated receptor γ/δ agonists.

A series of alkoxy-3-indolylacetic acid analogs has been discovered as peroxisome proliferator-activated receptor (PPAR) agonists. Structure-activity relationship study indicated that PPARα/γ/δ activities were dependent on the nature of the hydrophobic group, the attachment position of the alkoxy linker to the indole ring, and N-alkylation of indole nitrogen. Some compounds presented significant PPARγ/δ activity and molecular modeling suggested their putative binding modes in the ligand binding domain of PPARγ. Of these, compound 51 was selected for in vivo study via an evaluation of microsomal stability in mouse and human liver. Compound 51 lowered the levels of fasting blood glucose, insulin, and HbA1c without gain in body weight in db/db mice. When compound 51 was treated, hepatic triglycerides level and the size of adipocytes in white adipose tissue of db/db mice were also reduced as opposed to treatment with rosiglitazone. Taken together, compound 51 shows high potential warranting further studies in models for diabetes and related metabolic disorders and may be in use as a chemical tool for the understanding of PPAR biology.

Delivery of IL-12p40 ameliorates DSS-induced colitis by suppressing IL-17A expression and inflammation in the intestinal mucosa.

IL-12p40 homodimer is a natural antagonist of IL-12 and IL-23, which are potent pro-inflammatory cytokines required for Th1 and Th17 immune responses, respectively. It has been reported that Th17 response is involved in inflammatory bowel disease (IBD), a chronic disorder of the digestive system with steadily increasing incidence. Here, we investigated the effects of IL-12p40 delivered via recombinant adenovirus (rAd/IL-12p40) or mesenchymal stem cells (MSC/IL-12p40) in a dextran sulfate sodium salt (DSS)-induced colitis model. Injection of rAd/IL-12p40 or MSC/IL-12p40 efficiently attenuated colitis symptoms and tissue damage, leading to an increased survival rate. Moreover, IL-12p40 delivery suppressed IL-17A, but enhanced IFN-γ production from mesenteric lymph node cells, supporting the preferential suppression of IL-23 by IL-12p40 homodimer in vitro and the suppression of Th17 responses in vivo. Our results demonstrate that IL-12p40 delivery ameliorates DSS-induced colitis by suppressing IL-17A production and inflammation in the intestinal mucosa, providing an effective new therapeutic strategy for IBDs.

Limonium tetragonum Promotes Running Endurance in Mice through Mitochondrial Biogenesis and Oxidative Fiber Formation.

The purpose of this study was to examine whether Limonium tetragonum, cultivated in a smart-farming system with LED lamps, could increase exercise capacity in mice. C57BL/6 male mice were orally administered vehicle or Limonium tetragonum water extract (LTE), either 30 or 100 mg/kg, and were subjected to moderate intensity treadmill exercise for 4 weeks. Running distance markedly increased in the LTE group (100 mg/kg) by 80 ± 4% compared to the vehicle group, which was accompanied by a higher proportion of oxidative fibers (6 ± 6% vs. 10 ± 4%). Mitochondrial DNA content and gene expressions related to mitochondrial biogenesis were significantly increased in LTE-supplemented gastrocnemius muscles. At the molecular level, the expression of PGC-1α, a master regulator of fast-to-slow fiber-type transition, was increased downstream of the PKA/CREB signaling pathway. LTE induction of the PKA/CREB signaling pathway was also observed in C2C12 cells, which was effectively suppressed by PKA inhibitors H89 and Rp-cAMP. Altogether, these findings indicate that LTE treatment enhanced endurance exercise capacity via an improvement in mitochondrial biosynthesis and the increases in the formation of oxidative slow-twitch fibers. Future study is warranted to validate the exercise-enhancing effect of LTE in the human.

Sirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression.

Expanding the exercise capacity of skeletal muscle is an emerging strategy to combat obesity-related metabolic diseases and this can be achieved by shifting skeletal muscle fibers toward slow-twitch oxidative type. Here, we report that Sirt6, an anti-aging histone deacetylase, is critical in regulating myofiber configuration toward oxidative type and that Sirt6 activator can be an exercise mimetic. Genetic inactivation of Sirt6 in skeletal muscle reduced while its transgenic overexpression increased mitochondrial oxidative capacity and exercise performance in mice. Mechanistically, we show that Sirt6 downregulated Sox6, a key repressor of slow fiber specific gene, by increasing the transcription of CREB. Sirt6 expression is elevated in chronically exercised humans, and mice treated with an activator of Sirt6 showed an increase in exercise endurance as compared to exercise-trained controls. Thus, the current study identifies Sirt6 as a molecular target for reprogramming myofiber composition toward the oxidative type and for improving muscle performance.

Inflammation promotes synucleinopathy propagation.

The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. The current understanding of the mechanism of proteinopathy spread is far from complete. Here, we propose that inflammation is fundamental to proteinopathy spread. A sequence variant of α-synuclein (V40G) was much less capable of fibril formation than wild-type α-synuclein (WT-syn) and, when mixed with WT-syn, interfered with its fibrillation. However, when V40G was injected intracerebrally into mice, it induced aggregate spreading even more effectively than WT-syn. Aggregate spreading was preceded by sustained microgliosis and inflammatory responses, which were more robust with V40G than with WT-syn. Oral administration of an anti-inflammatory agent suppressed aggregate spreading, inflammation, and behavioral deficits in mice. Furthermore, exposure of cells to inflammatory cytokines increased the cell-to-cell propagation of α-synuclein. These results suggest that the inflammatory microenvironment is the major driver of the spread of synucleinopathy in the brain.

Marked enhancement of antigen-specific T-cell responses by IL-7-fused nonlytic, but not lytic, Fc as a genetic adjuvant.

IL-7 plays a crucial role in the homeostatic proliferation, differentiation and survival of T cells, as well as in the survival and proliferation of precursor B cells. Here, we demonstrated that utilizing nonlytic Fc-fused IL-7 (IL-7-Fc(m)) as a genetic adjuvant significantly enhanced not only CD4(+) but also CD8(+) T-cell responses by E7 DNA immunization, in addition to improving protection against TC-1-induced tumors in comparison to IL-7 alone. Similar results were obtained in OT-1 adoptive transfer experiments with OVA DNA injection, suggesting independence from antigenic nature and experimental conditions. In particular, the increased frequency of CD8(+) T cells was mainly due to enhanced T-cell proliferation in T-cell priming, and not to decreased cellular apoptosis. Interestingly, the enhanced adjuvant effect was not seen in the co-delivery of lytic Fc-fused IL-7 (IL-7-Fc) which increases T-cell apoptosis as well as T-cell proliferation, suggesting that the T-cell proliferative effect may be neutralized by T-cell apoptosis. Thus, our findings suggest that nonlytic Fc, in contrast to lytic Fc, fusion to cytokines may provide an insight in designing a potent genetic adjuvant for inducing CD4(+) and CD8(+) T-cell responses.

Ontology for medicinal materials based on traditional Korean medicine.

UNLABELLED: We are constructing an ontology for traditional Korean medicine, and we started with medicinal materials to express the relationships between patients' symptoms, diseases and treatments. Biological materials and mineral resources have been used traditionally for patient treatments. The ontology includes various data related to these materials, such as their scientific names, parts of materials used, effectiveness and related oriental organ of the human body. AVAILABILITY: http://tkm.kiom.re.kr/ontology/TraditionalKoreanMedicine.rdf-xml.owl (10-20 s using Internet Explorer.)

A prenylated flavan from Broussonetia kazinoki prevents cytokine-induced ß-cell death through suppression of nuclear factor-κB activity.

The generation of nitric oxide (NO) via inducible NO synthase (iNOS) and reactive oxygen species plays a key role in cytokine-mediated pancreatic ß-cell damage. Oxidative stress due to reactive oxygen species activates the nuclear factor-κB (NF-κB) transcription factor, which regulates iNOS expression. In this regard, suppression of the NF-κB pathway is a novel strategy for protecting ß-cells from damage. This study was performed to explore the effects of kazinol U, a prenylated flavan from Broussonetia kazinoki, on the NF-κB activation pathway in interleukin-1ß (IL-1ß)- and interferon-γ (IFN-γ)-treated ß-cells. The cytotoxic effects of cytokines were completely abolished when RINm5F cells or islets were pretreated with kazinol U. Kazinol U inhibited the nuclear translocation and DNA binding of NF-κB subunits, which correlated with the inhibitory effects on IκB kinase (IKK) phosphorylation and IκBα degradation. In addition, kazinol U suppressed NO and hydrogen peroxide production and apoptotic cell death by cytokines in RINm5F cells. The protective effects of kazinol U were further demonstrated by normal insulin secretion of cytokine-treated islets in response to glucose. Taken together, these results suggest that using kazinol U to block the NF-κB pathway in pancreatic ß-cells reduces cell damage. Therefore, kazinol U may have therapeutic value in delaying pancreatic ß-cell destruction in type 1 diabetes.

Butein from Rhus verniciflua protects pancreatic ß cells against cytokine-induced toxicity mediated by inhibition of nitric oxide formation.

Butein (3,4,2',4'-tetrahydroxychalcone), a plant polyphenol, is a major component in isolate of Rhus verniciflua STOKES (Anacardiaceae). It is shown to exert various potent effects such as antioxidant, antiinflammatory induction of apoptosis among many properties. In this study, we investigated the effect of butein on cytokine-induced ß-cell damage. Pre-treatment with butein is shown to increase the viability of cytokine-treated INS-1 cells at concentrations of 15-30 µM. Butein prevented cytokine-mediated cell death, as well as nitric oxide (NO) production, and these effects correlated well with reduced levels of protein expression of the inducible nitric oxide synthase (iNOS). Furthermore, the molecular mechanisms by which butein inhibits iNOS gene expression appeared to be through the inhibition of nuclear factor-κB (NF-κB) translocation. In a second set of experiments, rat islets were used to demonstrate the protective effects of butein and the results were essentially the same as those observed in Beutin pretreated INS-1 cells. Butein prevented cytokine-induced NO production, iNOS expression, and NF-κB translocation and inhibition of glucose-stimulated insulin secretion (GSIS). In conclusion, these results suggest that butein can be used for the prevention of functional ß-cell damage and preventing the progression of Type 1 diabetes mellitus (T1DM).

Association of Polygenetic Risk Scores Related to Immunity and Inflammation with Hyperthyroidism Risk and Interactions between the Polygenetic Scores and Dietary Factors in a Large Cohort.

Graves's disease and thyroiditis induce hyperthyroidism, the causes of which remain unclear, although they are involved with genetic and environmental factors. We aimed to evaluate polygenetic variants for hyperthyroidism risk and their interaction with metabolic parameters and nutritional intakes in an urban hospital-based cohort. A genome-wide association study (GWAS) of participants with (cases; n = 842) and without (controls, n = 38,799) hyperthyroidism was used to identify and select genetic variants. In clinical and lifestyle interaction with PRS, 312 participants cured of hyperthyroidism were excluded. Single nucleotide polymorphisms (SNPs) associated with gene-gene interactions were selected by hyperthyroidism generalized multifactor dimensionality reduction. Polygenic risk scores (PRSs) were generated by summing the numbers of selected SNP risk alleles. The best gene-gene interaction model included tumor-necrosis factor (TNF)_rs1800610, mucin 22 (MUC22)_rs1304322089, tribbles pseudokinase 2 (TRIB2)_rs1881145, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)_rs231775, lipoma-preferred partner (LPP)_rs6780858, and human leukocyte antigen (HLA)-J_ rs767861647. The PRS of the best model was positively associated with hyperthyroidism risk by 1.939-fold (1.317-2.854) after adjusting for covariates. PRSs interacted with age, metabolic syndrome, and dietary inflammatory index (DII), while hyperthyroidism risk interacted with energy, calcium, seaweed, milk, and coffee intake (P < 0.05). The PRS impact on hyperthyroidism risk was observed in younger (<55 years) participants and adults without metabolic syndrome. PRSs were positively associated with hyperthyroidism risk in participants with low dietary intakes of energy (OR = 2.74), calcium (OR = 2.84), seaweed (OR = 3.43), milk (OR = 2.91), coffee (OR = 2.44), and DII (OR = 3.45). In conclusion, adults with high PRS involved in inflammation and immunity had a high hyperthyroidism risk exacerbated under low intakes of energy, calcium, seaweed, milk, or coffee. These results can be applied to personalized nutrition in a clinical setting.