Gene Expression and Metabolome Analysis Reveals Anti-Inflammatory Impacts of 11,17diHDoPE on PM10-Induced Mouse Lung Inflammation.

Oxylipins, the metabolites of polyunsaturated fatty acids, are vital in regulating cell proliferation and inflammation. Among these oxylipins, specialized pro-resolving mediators notably contribute to inflammation resolution. Previously, we showed that the specialized pro-resolving mediators isomer 11,17dihydroxy docosapentaenoic acid (11,17diHDoPE) can be synthesized in bacterial cells and exhibits anti-inflammatory effects in mammalian cells. This study investigates the in vivo impact of 11,17diHDoPE in mice exposed to particulate matter 10 (PM10). Our results indicate that 11,17diHDoPE significantly mitigates PM10-induced lung inflammation in mice, as evidenced by reduced pro-inflammatory cytokines and pulmonary inflammation-related gene expression. Metabolomic analysis reveals that 11,17diHDoPE modulates inflammation-related metabolites such as threonine, 2-keto gluconic acid, butanoic acid, and methyl oleate in lung tissues. In addition, 11,17diHDoPE upregulates the LA-derived oxylipin pathway and downregulates arachidonic acid- and docosahexaenoic acid-derived oxylipin pathways in serum. Correlation analyses between gene expression and metabolite changes suggest that 11,17diHDoPE alleviates inflammation by interfering with macrophage differentiation. These findings underscore the in vivo role of 11,17diHDoPE in reducing pulmonary inflammation, highlighting its potential as a therapeutic agent for respiratory diseases.

Adverse Events Following COVID-19 Vaccination in Adolescents: Insights From Pharmacovigilance Study of VigiBase.

BACKGROUND: During coronavirus disease 2019 (COVID-19) pandemic, several COVID-19 vaccines were licensed with fast-track procedures. Although these vaccines have demonstrated high immunogenicity, there has been concerns on the serious adverse events (AEs) following COVID-19 vaccination among adolescents. We aimed to analyze comparative safety of COVID-19 vaccination in adolescents. METHODS: In this pharmacovigilance study, we performed a disproportionality analysis using VigiBase, the World Health Organization's global individual case safety report (ICSR) database. To compare serious AEs reported following COVID-19 vaccines vs. all other vaccines in adolescents aged 12-17 years, ICSRs following any vaccines on adolescents aged 12-17 years were included, defining cases as reports with the AEs of interest, with all other AEs as non-cases. The AEs of interest were myocarditis/pericarditis, multisystem inflammatory syndrome/Kawasaki disease (MIS/KD), anaphylaxis, Guillain-Barré syndrome (GBS), and immune thrombocytopenia (ITP). We conducted a disproportionality analysis to estimate reporting odds ratio (ROR) with 95% confidence interval (CI) for each AE of interest, adjusted for sex by using logistic regression. RESULTS: Of 99,735 AE reports after vaccination in adolescents, 80,018 reports were from COVID-19 vaccinated adolescents (52.9% females; 56.3% America). The AEs of interest were predominantly reported as serious AE (76.1%) with mRNA vaccines (99.4%). Generally, higher reporting odds for the AEs were identified following COVID-19 vaccination in adolescents; myocarditis/pericarditis (2,829 reports for the COVID-19 vaccine vs. 35 for all other vaccines, adjusted ROR [aROR], 19.61; 95% CI, 14.05-27.39), and MIS/KD (104 vs. 6, aROR, 4.33; 95% CI, 1.89-9.88). The reporting odds for anaphylaxis (515 vs. 165, aROR, 0.86; 95% CI, 0.72-1.02), GBS (94 vs. 40, aROR, 0.64; 95% CI, 0.44-0.92) and ITP (52 vs. 12, aROR, 1.12; 95% CI, 0.59-2.09) were not significantly higher following COVID-19 vaccination. CONCLUSION: In this study, there were disproportionate reporting of immune-related AEs following COVID-19 vaccination. While awaiting definitive evidence, there is a need to closely monitor for any signs of immune-related AEs following COVID-19 vaccination among adolescents.

The effect of goal-directed hemodynamic therapy on clinical outcomes in patients undergoing radical cystectomy: a randomized controlled trial.

BACKGROUND: This study investigated the effects of intraoperative goal-directed hemodynamic therapy (GDHT) on postoperative outcomes in patients undergoing open radical cystectomy. METHODS: This prospective, single-center, randomized controlled trial included 82 patients scheduled for open radical cystectomy between September 2018 and November 2021. The GDHT group (n = 39) received the stroke volume index- and cardiac index-based hemodynamic management using advanced hemodynamic monitoring, while the control group (n = 36) received the standard care under the discretion of attending anesthesiologists during surgery. The primary outcome was the incidence of a composite of in-hospital postoperative complications during hospital stays. RESULTS: A total of 75 patients were included in the final analysis. There was no significant difference in the incidence of in-hospital postoperative complications (28/39 [71.8%] vs. 30/36 [83.3%], risk difference [95% CI], -0.12 [-0.30 to 0.07], P = 0.359) between the groups. The amounts of intraoperative fluid administered were similar between the groups (2700 [2175-3250] vs. 2900 [1950-3700] ml, median difference [95% CI] -200 [-875 to 825], P = 0.714). The secondary outcomes, including the incidence of seven major postoperative complications, duration of hospital stay, duration of intensive care unit stay, and grade of complications, were comparable between the two groups. Trends in postoperative estimated glomerular filtration rate, serum creatinine, and C-reactive protein did not differ significantly between the two groups. CONCLUSIONS: Intraoperative GDHT did not reduce the incidence of postoperative in-hospital complications during the hospital stay in patients who underwent open radical cystectomy. TRIAL REGISTRATION: This study was registered at http://www. CLINICALTRIALS: gov (Registration number: NCT03505112; date of registration: 23/04/2018).

Novel Activity of ODZ10117, a STAT3 Inhibitor, for Regulation of NLRP3 Inflammasome Activation.

The NLRP3 inflammasome serves as a host defense mechanism against various pathogens, but there is growing evidence linking its activation in sterile condition to diverse inflammatory diseases. Therefore, the identification of specific inhibitors that target NLRP3 inflammasome activation is meaningful and important for novel therapies for NLRP3 inflammasome-associated diseases. In this study, we identified a chemical compound, namely ODZ10117 (ODZ), that showed NLRP3 inflammasome-targeting anti-inflammatory effects during the screening of a chemical library for anti-inflammatory activity. Although ODZ was initially discovered as a STAT3 inhibitor, here we found it also has inhibitory activity on NLRP3 inflammasome activation. ODZ inhibited the cleavage of caspase-1 and IL-1ß-induced canonical NLRP3 inflammasome triggers, but had no effect on those induced by AIM2 or NLRC4 triggers. Mechanistically, ODZ impairs NLRP3 inflammasome activation through the inhibition of NLRP3-NEK7 interaction that is required for inflammasome formation. Moreover, the results obtained from the in silico docking experiment suggested that ODZ targets NLRP3 protein, which provides evidence for the specificity of ODZ to the NLRP3 inflammasome. Furthermore, ODZ administration significantly reduced MSU-induced IL-1ß release and the mortality rate of mice with LPS-induced sepsis. Collectively, these results demonstrate a novel effect of ODZ10117 in regulating NLRP3 inflammasome activation both in vitro and in vivo, making it a promising candidate for the treatment of NLRP3-inflammasome-associated immune disorders and cancer.

10-mer and 9-mer WALK Peptides with Both Antibacterial and Anti-Inflammatory Activities.

Natural antimicrobial peptides (AMPs) are multifunctional host defense peptides (HDPs) that are valuable for various therapeutic applications. In particular, natural and artificial AMPs with dual antibacterial immunomodulatory functions emerged as promising candidates for the development of therapeutic agents to treat infectious inflammation. In an effort to develop useful AMP variants with short lengths and simple amino acid composition, we devised a de novo design strategy to generate a series of model peptide isomer sequences, named WALK peptides, i.e., tryptophan (W)-containing amphipathic-helical (A) leucine (L)/lysine (K) peptides. Here, we generated two groups of WALK peptide isomers: W2L4K4 (WALK244.01~WALK244.10) and W2L4K3 (WALK243.01~WALK243.09). Most showed apparent antibacterial activities against both Gram-positive and Gram-negative bacteria at a concentration of approximately 4 µg/mL along with varied hemolytic activities against human red blood cells. In addition, some exhibited significant anti-inflammatory activities without any significant cytotoxicity in macrophages. Collectively, these results suggest that the two selected peptides, WALK244.04 and WALK243.04, showed promise for the development of antibacterial and anti-inflammatory agents.

Amino acid digestibility in diets containing copra meal with ß-mannanase fed to growing pigs.

OBJECTIVE: The objective of this study was to estimate standardized ileal digestibility (SID) of amino acids (AA) in growing pigs fed diets containing increasing levels of copra meal (CM) with ß-mannanase supplementation. METHODS: Twenty barrows (initial body weight: 34.43±0.11 kg) surgically fitted with T-cannulas at the distal ileum were individually housed in metabolism crates. Pigs were allotted to 5 dietary treatments in a completely randomized design with 4 replicates per treatment. The dietary treatments were: i) NC, negative control, corn-soybean meal (SBM) based diet, ii) PC, positive control, basal diet + 0.10% ß-mannanase supplementation (800 IU/kg), iii) CM6, PC diet with 6% CM supplementation, iv) CM12, PC diet with 12% CM supplementation, and v) CM18, PC diet with 18% CM supplementation. A nitrogen-free diet was used to estimate basal endogenous losses of AA for SID calculation. All experimental diets contained 0.5% chromic oxide as an indigestible marker. Each period consisted of a 4-d diet adaptation period and a 3-d ileal digesta collection period. RESULTS: There were no differences in apparent ileal digestibility (AID) and SID of all AA between the NC and PC treatments except that the PC treatment had lower AID and SID of glycine than the NC treatment (p<0.05). There were linear decreases in AID and SID of lysine (p<0.05) and aspartic acid (p = 0.06; tendency) with increasing levels of CM in the diets with ß-mannanase. CONCLUSION: The ß-mannanase supplementation had no effect on AA digestibility in pigs fed the corn-SBM based diet but increasing levels of CM reduced SID of lysine and aspartic acid.

Effects of Copra Meal Inclusion Level in Growing-Finishing Pig Diets Containing ß-Mannanase on Growth Performance, Apparent Total Tract Digestibility, Blood Urea Nitrogen Concentrations and Pork Quality.

This experiment was conducted to evaluate the effects of copra meal (CM) inclusion level on the growth performance, apparent total tract digestibility (ATTD), blood urea nitrogen (BUN) concentrations, and pork quality of growing-finishing pigs fed diets containing ß-mannanase. Eighty crossbred pigs with average body weight (BW) of 27.22 ± 0.09 kg were allotted to five dietary treatments with four pigs per pen and four replicates per treatment based on sex and BW. The dietary treatments were: (1) NC: negative control, corn-soybean meal (SBM) based basal diet, (2) PC: positive control, basal diet + 0.10% ß-mannanase (800 IU/ kg diet), (3) CM6: PC diet with 6% CM inclusion, (4) CM12: PC diet with 12% CM inclusion, and (5) CM18: PC diet with 18% CM inclusion in a three-phase feeding program (growing: 0-6 weeks, finishing I: 7-9 weeks, and finishing II: 10-12 weeks). The quadratic responses were observed in the BW at six weeks (p < 0.05), ADG in the growing phase (0-6 weeks; p < 0.05), and ADFI in the finishing phase with a tendency (7-12 weeks; p = 0.06) as the inclusion level of CM increased. However, the BW at 12 weeks (linear, p < 0.05 and quadratic, p = 0.06), the overall ADG (0-12 weeks; linear and quadratic, p < 0.05), and the G:F ratio in the finishing (7-12 weeks; linear, p < 0.05) and overall (0-12 weeks; linear, p < 0.05) phases decreased with increasing levels of CM in the diets. The ATTD of crude protein (linear, p < 0.05), crude fiber (linear, p < 0.05), and ash (linear, p < 0.05) decreased linearly as the inclusion level of CM increased. The BUN concentrations increased linearly with increasing levels of CM in the diets at 12 weeks of the experiment (p < 0.05). As the inclusion level of CM increased, TBARS value at d 3 post-mortem (linear, p = 0.07) tended to increase, whereas initial loin pH at 1 h post-mortem decreased (linear and quadratic, p < 0.05) with no difference in ultimate loin pH at 24 h post-mortem. These results indicated that CM inclusion up to 12% in the growing-finishing pig diets with ß-mannanase did not affect growth performance, nutrient utilization, and pork quality whereas 18% CM inclusion to the diets could negatively impact nutrient digestibility, BUN concentrations, and thereby growth performance.

Surface Enrichment of Mg and Ca in Cu-Mg Alloy Containing a Trace Amount of Ca and Its Effects on Oxidation Resistance.

In this study, the surface segregation of Mg and Ca in Cu-Mg alloys containing a trace amount of Ca under an oxidative atmosphere and its effects on oxidation resistance were examined. The use of a Mg+Mg2Ca master alloy as an alloying element for Mg rendered significant surface protection during melting and casting. During solid-state oxidation, the oxidation resistance was increased by the addition of Mg. Ca containing alloys with the same Mg exhibited a relatively higher oxidation resistance. From the phase diagram with the oxygen partial pressure as a function of the Mg content, the Ca containing alloy led to the formation of CaO as the primary oxide. The improved oxidation resistance of Ca containing alloys can be attributed to a mixed surface layer of CaO and MgO.

Effect of Ca on Phase Stability and Oxidation Resistance of Al3Mg2 at Elevated Temperature.

In this study, effect of Ca on phase stability and oxidation of Al3Mg2 at elevated temperature was investigated. From thermogravimetric analysis (TGA) at 420 °C, rapid weight gains in the initial stage and incubation were observed for Al3Mg2 and Ca-added Al3Mg2. After incubation for some time, Al3Mg2 sample exhibited the second weight growth, while Ca added sample exhibited continuous incubation during the testing time. The phase diagrams calculated by Factsage 7.1 revealed that Ca exists as Laves_C36 in Al3Mg2 and also forms Ca3MgAl4O10, following formation of MgO and MgAl2O4-spinel as primary and secondary oxides, respectively, on the surface during oxidation at 420 °C.

Effects of different creep feed types on pre-weaning and post-weaning performance and gut development.

OBJECTIVE: This experiment was carried out to determine the effects of different creep feed types on suckling performance and further adjustments to solid feed after weaning. METHODS: A total of 24 multiparous sows and their litters were allotted to one of three treatment groups: i) provided highly digestible creep feed (Creep), ii) provided a pig weaning diet (Weaner), and iii) provided sow feed (Sow) as creep feed until weaning. After weaning, a total of 96 piglets were selected for evaluation of post-weaning performance. RESULTS: For pre-weaning performance, the Creep treatment led to a significantly higher feed intake from 14 to 28 d (p<0.05) and higher body weight gain from 21 to 28 d than piglets that were provided other diets. However, after weaning, the Weaner treatment yielded a significantly higher feed intake and average daily gain than other treatments from 0 to 14 d after weaning (p<0.05); Creep treatment tended to generate lower villus heights in the duodenum than the other treatments (p = 0.07). CONCLUSION: Highly digestible creep feed improved pre-weaning performance, but feed familiarity and grain-based creep feed improved post-weaning performance.

Visible-Light-Driven Silver-Catalyzed One-Pot Approach: A Selective Synthesis of Diaryl Sulfoxides and Diaryl Sulfones.

An efficient one-pot approach for the synthesis of diaryl sulfoxides and diaryl sulfones using aryl thiols and aryl diazonium salts was developed. The use of a visible-light-driven silver catalysis and the subsequent singlet-oxygen-induced oxidation enabled selective synthesis of sulfoxides and sulfones in the absence of a photocatalyst. The reactions were carried out under mild reaction conditions; the desired products were obtained under air atmosphere at room temperature.

Recent omics technologies and their emerging applications for personalised medicine.

A major objective of 'omics' technologies is to understand genetic causality of complex traits of human diseases. High-throughput omics technologies and their application to medicine open up remarkable opportunities for realising optimised medical treatment for individuals. Because many major breakthrough and discoveries in this field have been driven by the development of new omics technologies, in this review, the authors aim to provide an in-depth description of their underlying principles as a foundation of developing another new omics technology, and to introduce their emerging applications for personalised medicine. The systems biology approach is then introduced as a future direction towards actionable personalised medicine.

Effect of different soybean meal type on ileal digestibility of amino acid in weaning pigs.

An experiment was conducted to evaluate apparent (AID) and standardized (SID) ileal digestibilities of crude protein (CP) and amino acids (AA) with 6 soybean products in weaning pigs. A total of 14 weaning barrows with an initial body weight of 6.54 ± 0.34 kg were fitted with T-cannula at the distal ileum and allotted to 7 diets containing various soybean products. The soybean products used in the experiment were conventional soybean meal (CSBM), SBM fermented by Aspergillus oryzae GB-107 (FSBMA), SBM fermented by Bacillus subtilis PP6 (FSBMB), UV sterilized SBM fermented by Bacillus subtilis PP6 (UVFSBMB), SBM containing Bacillus subtilis PP6 (PSBM), and soy protein concentrate (SPC). Six corn-based diets were used and each of soybean products was added. All diets contained 5.0 g/kg of chromic oxide as an indigestible indicator and an N-free diet was used to measure basal endogenous losses of CP and AAs. Ileal CP digestibility did not differ by different soybean products. However, SIDs of Ile, Phe and Val were improved in pigs fed the FSBMB, UVFSBMB and SPC diets and the pigs fed the FSBMA diet showed higher SIDs of Phe and Val compared with those fed the CSBM diet (P < 0.05). The FSBMB diet had higher SIDs in most AAs compared with the FSBMA diet (P < 0.05), and higher SIDs of Lys, Ala, Pro, Ser, and Tyr compared with PSBM diet (P < 0.05). However, there was no response of UV-sterilization on the FSBMB in the SIDs of AAs. These results suggest that SIDs of AAs could be improved by the supplementation of fermented soybean products in the diet for weaning pigs but fermentation with Bacillus subtilis is more efficient in improving ileal AA digestibility than that with Aspergillus oryzae. Furthermore, probiotics supplementation in the CSBM and UV-sterilization of the FSBMB had no effects on chemical composition and ileal AA digestibility.

Non-alcoholic fatty liver disease, metabolic syndrome and subclinical cardiovascular changes in the general population.

OBJECTIVE: The effect of non-alcoholic fatty liver disease (NAFLD) on cardiovascular system remains controversial. We investigated the independent contribution of NAFLD to cardiovascular structure and function in the general population. METHODS: A total of 1886 participants without known cardiovascular disease were enrolled from the Korean Genome Epidemiology Study. The participants were divided into four groups, based on the presence of NAFLD, metabolic syndrome (MetS), neither or both. NAFLD was diagnosed by CT. Changes in cardiovascular structure and function were assessed by tissue Doppler imaging (TDI) echocardiography, carotid ultrasound and brachial-ankle pulse wave velocity (baPWV). RESULTS: In multivariate analyses, subjects with both NAFLD and MetS had a higher E/Ea ratio and baPWV, as well as a lower TDI Ea velocity (all p<0.001) than those with neither NAFLD nor MetS. Subjects with either NAFLD or MetS also showed significant differences in TDI Ea velocity and baPWV (all p<0.05). However, no significant differences of carotid intima-media thickness (CIMT) values were seen among the four groups. Multivariate linear regression revealed that both NAFLD and MetS were independent predictors of TDI Ea velocity and baPWV (all p<0.001). Both MetS and NAFLD were not a determinant of CIMT. CONCLUSIONS: NAFLD was associated with early alterations of cardiovascular system, independent of established cardiovascular risk factors and MetS.

Direct interaction and functional coupling between human 5-HT6 receptor and the light chain 1 subunit of the microtubule-associated protein 1B (MAP1B-LC1).

Serotonin (5-HT) receptors of type 6 (5-HT6R) play important roles in mood, psychosis, and eating disorders. Recently, a growing number of studies support the use of 5-HT6R-targeting compounds as promising drug candidates for treating cognitive dysfunction associated with Alzheimer's disease. However, the mechanistic linkage between 5-HT6R and such functions remains poorly understood. By using yeast two-hybrid, GST pull-down, and co-immunoprecipitation assays, here we show that human 5-HT6R interacts with the light chain 1 (LC1) subunit of MAP1B protein (MAP1B-LC1), a classical microtubule-associated protein highly expressed in the brain. Functionally, we have found that expression of MAP1B-LC1 regulates serotonin signaling in a receptor subtype-specific manner, specifically controlling the activities of 5-HT6R, but not those of 5-HT4R and 5-HT7R. In addition, we have demonstrated that MAP1B-LC1 increases the surface expression of 5-HT6R and decreases its endocytosis, suggesting that MAP1B-LC1 is involved in the desensitization and trafficking of 5-HT6R via a direct interaction. Together, we suggest that signal transduction pathways downstream of 5-HT6R are regulated by MAP1B, which might play a role in 5-HT6R-mediated signaling in the brain.

Localized surface plasmon enhanced cathodoluminescence from Eu3+-doped phosphor near the nanoscaled silver particles.

We elucidate that the luminescence from Eu3+-doped phosphor excited by the electron collision can be modified on location near the metallic nanoparticles. The Eu3+-doped phosphor was fabricated on the nanoscaled Ag particles ranging of 5 nm to 30 nm diameter. As a result of the cathodoluminescence measurements, the phosphor films on the Ag particles showed up to twofold more than that of an isolated phosphor film. Enhanced cathodoluminescence originated from the resonant coupling between the localized surface plasmon of Ag nanoparticles and radiating energy of the phosphor. Cathodoluminescent phosphor for high luminous display devices can be addressed by locating phosphor near the surface of metallic nanoparticles.

Stilbene derivatives as human 5-HT(6) receptor antagonists from the root of Caragana sinica.

The 5-HT6 receptor (5-HT6R) is a member of the class of recently discovered 5-hydroxytryptamine (5-HT) receptors. Due to the lack of selective 5-HT6R ligands, the cellular signaling mechanisms of the 5-HT6R are poorly understood. We previously developed a cell-based high-throughput screening (HTS) method for the 5-HT6R and screened synthetic chemical compounds. In the present study, we expanded our screening into natural products to find novel 5-HT6R ligands. We found that the ethyl acetate fraction from the root of Caragana sinica (537-18BE) produced the most potent antagonistic activity. After further isolation of 537-18BE, we found that three stilbene derivatives, (+)-α-viniferin, miyabenol C and pallidol, are active constituents of 537-18BE inhibiting the 5-HT6R. Among them, (+)-α-viniferin showed the most potent inhibition, and miyabenol C also produced a considerable inhibition. When examined effects on other neurotransmitters for selectivity, 537-18BE and three stilbene derivatives did not produce any notable effects on 5-HT4, 5-HT7, or muscarinic acetylcholine M1 (M(1)) receptors. Furthermore, 5-HT6R antagonistic effects of (+)-α-viniferin, miyabenol C and pallidol were confirmed on extracellular signal-regulated kinase 1 and 2 (ERK1/2) which exerts effects in downstream pathways of 5-HT6R activation.

Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer.

microRNAs (miRNAs) play integral roles in diverse processes including tumorigenesis. miRNA gene loci are often found in close conjunction, and such clustered miRNA genes are transcribed from a common promoter to generate polycistronic primary transcript. The primary transcript (pri-miRNA) is then processed by two RNase III proteins to release the mature miRNAs. Although it has been speculated that the miRNAs in the same cluster may play related biological functions, this has not been experimentally addressed. Here we report that the miRNAs in two clusters (miR-106b approximately 93 approximately 25 and miR-222 approximately 221) suppress the Cip/Kip family members of Cdk inhibitors (p57(Kip2), p21(Cip1) and p27(Kip1)). We show that miR-25 targets p57 through the 3'-UTR. Furthermore, miR-106b and miR-93 control p21 while miR-222 and miR-221 regulate both p27 and p57. Ectopic expression of these miRNAs results in activation of Cdk2 and facilitation of G1/S phase transition. Consistent with these results, both clusters are abnormally upregulated in gastric cancer tissues compared to the corresponding normal tissues. Ectopic expression of miR-222 cluster enhanced tumor growth in the mouse xenograft model. Our study demonstrates the functional associations between clustered miRNAs and further implicates that effective cancer treatment may require a combinatorial approach to target multiple oncogenic miRNA clusters.