Altered CD226/TIGIT expressions were associated with NK phenotypes in primary antiphospholipid syndrome and affected by IL-4/JAK pathway.

Natural killer (NK) cells were reported to be involved in the pathogenesis of primary antiphospholipid syndrome (pAPS). Immunosuppressive receptor T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and activating receptor cluster of differentiation 226 (CD226) are specifically expressed on NK cells with competitive functions. This study aims to investigate the expression diversities of CD226/TIGIT on NK subsets and their associations with NK subsets activation phenotypes and potential clinical significance, furthermore, to explore potential cause for CD226/TIGIT expression diversities in pAPS. We comparatively assessed the changes of CD56brightNK, CD56dimNK, and NK-like cells in 70 pAPS patients compared with control groups, including systemic lupus erythematosus, asymptomatic antiphospholipid antibodies carriers (asymp-aPLs carriers), and healthy controls and their expression diversities of CD226/TIGIT by flow cytometry. CD25, CD69, CD107α expression, and interferon gamma (IFN-γ) secretion levels of NK subsets were detected to determine the potential association of CD226/TIGIT expression with NK subsets phenotypes. CD226/TIGIT expression levels were compared among different subgroups divided by aPLs status. Moreover, in vitro cultures were conducted to explore the potential mechanisms of CD226/TIGIT expression imbalance. CD56brightNK and CD3+CD56+NK-like cells were significantly increased while CD56dimNK cells were obviously decreased in pAPS, and CD56brightNK and NK-like cells exhibited significantly higher CD226 but lower TIGIT expressions. CD226+CD56brightNK and TIGIT-CD56brightNK cells show higher CD69 expression and IFN-γ secretion capacity, and CD226+NK-like and TIGIT-NK-like cells showed higher expressions of CD25 and CD69 but lower apoptosis rate than CD226- and TIGIT+CD56brightNK/NK-like cells, respectively. The imbalanced CD226/TIGIT expressions were most significant in aPLs triple-positive group. Imbalanced expressions of CD226/TIGIT on CD56brightNK and NK-like cells were aggravated after interleukin-4 (IL-4) stimulation and recovered after tofacitinib blocking. Our data revealed significant imbalanced CD226/TIGIT expressions on NK subsets in pAPS, which closely associated with NK subsets phenotypes and more complicated autoantibody status. CD226/TIGIT imbalanced may be affected by IL-4/Janus Kinase (JAK) pathway activation.

Analysis of PANoptosis-related ceRNA network reveals lncRNA MIR17HG involved in osteogenic differentiation inhibition impaired by tumor necrosis factor-α.

BACKGROUND: Inflammatory cytokines such as Interleukin 1ß(IL1ß), IL6,Tumor Necrosis Factor-α (TNF-α) can inhibit osteoblast differentiation and induce osteoblast apoptosis. PANoptosis, a newly identified type of programmed cell death (PCD), may be influenced by long noncoding RNA (lncRNAs) which play important roles in regulating inflammation. However, the potential role of lncRNAs in inflammation and PANoptosis during osteogenic differentiation remains unclear. This study aimed to investigate the regulatory functions of lncRNAs in inflammation and apoptosis during osteogenic differentiation. METHODS AND RESULTS: High-throughput sequencing was used to identify differentially expressed genes involved in osteoblast differentiation under inflammatory conditions. Two lncRNAs associated with inflammation and PANoptosis during osteogenic differentiation were identified from sequencing data and Gene Expression Omnibus (GEO) databases. Their functionalities were analyzed using diverse bioinformatics methodologies, resulting in the construction of the lncRNA-miRNA-mRNA network. Among these, lncRNA (MIR17HG) showed a high correlation with PANoptosis. Bibliometric methods were employed to collect literature data on PANoptosis, and its components were inferred. PCR and Western Blotting experiments confirmed that lncRNA MIR17HG is related to PANoptosis in osteoblasts during inflammation. CONCLUSIONS: Our data suggest that TNF-α-induced inhibition of osteogenic differentiation and PANoptosis in MC3T3-E1 osteoblasts is associated with MIR17HG. These findings highlight the critical role of MIR17HG in the interplay between inflammation, PANoptosis, and osteogenic differentiation, suggesting potential therapeutic targets for conditions involving impaired bone formation and inflammatory responses.

Diabetes and osteoporosis: a two-sample mendelian randomization study.

BACKGROUND: The effects on bone mineral density (BMD)/fracture between type 1 (T1D) and type 2 (T2D) diabetes are unknown. Therefore, we aimed to investigate the causal relationship between the two types of diabetes and BMD/fracture using a Mendelian randomization (MR) design. METHODS: A two-sample MR study was conducted to examine the causal relationship between diabetes and BMD/fracture, with three phenotypes (T1D, T2D, and glycosylated hemoglobin [HbA1c]) of diabetes as exposures and five phenotypes (femoral neck BMD [FN-BMD], lumbar spine BMD [LS-BMD], heel-BMD, total body BMD [TB-BMD], and fracture) as outcomes, combining MR-Egger, weighted median, simple mode, and inverse variance weighted (IVW) sensitivity assessments. Additionally, horizontal pleiotropy was evaluated and corrected using the residual sum and outlier approaches. RESULTS: The IVW method showed that genetically predicted T1D was negatively associated with TB-BMD (ß = -0.018, 95% CI: -0.030, -0.006), while T2D was positively associated with FN-BMD (ß = 0.033, 95% CI: 0.003, 0.062), heel-BMD (ß = 0.018, 95% CI: 0.006, 0.031), and TB-BMD (ß = 0.050, 95% CI: 0.022, 0.079). Further, HbA1c was not associated with the five outcomes (ß ranged from - 0.012 to 0.075). CONCLUSIONS: Our results showed that T1D and T2D have different effects on BMD at the genetic level. BMD decreased in patients with T1D and increased in those with T2D. These findings highlight the complex interplay between diabetes and bone health, suggesting potential age-specific effects and genetic influences. To better understand the mechanisms of bone metabolism in patients with diabetes, further longitudinal studies are required to explain BMD changes in different types of diabetes.

[Risk factors for bronchopulmonary dysplasia in twin preterm infants: a multicenter study]. / åŒèƒŽæ—©äº§å„¿æ”¯æ°”ç®¡è‚ºå‘è‚²ä¸è‰¯å±é™©å› ç´ åˆ†æžï¼šä¸€é¡¹å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To investigate the risk factors for bronchopulmonary dysplasia (BPD) in twin preterm infants with a gestational age of <34 weeks, and to provide a basis for early identification of BPD in twin preterm infants in clinical practice. METHODS: A retrospective analysis was performed for the twin preterm infants with a gestational age of <34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020. According to their conditions, they were divided into group A (both twins had BPD), group B (only one twin had BPD), and group C (neither twin had BPD). The risk factors for BPD in twin preterm infants were analyzed. Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins. RESULTS: A total of 904 pairs of twins with a gestational age of <34 weeks were included in this study. The multivariate logistic regression analysis showed that compared with group C, birth weight discordance of >25% between the twins was an independent risk factor for BPD in one of the twins (OR=3.370, 95%CI: 1.500-7.568, P<0.05), and high gestational age at birth was a protective factor against BPD (P<0.05). The conditional logistic regression analysis of group B showed that small-for-gestational-age (SGA) birth was an independent risk factor for BPD in individual twins (OR=5.017, 95%CI: 1.040-24.190, P<0.05). CONCLUSIONS: The development of BPD in twin preterm infants is associated with gestational age, birth weight discordance between the twins, and SGA birth.

Cost-effectiveness of the screen-and-treat strategies using HPV test linked to thermal ablation for cervical cancer prevention in China: a modeling study.

BACKGROUND: Self-sampling HPV test and thermal ablation are effective tools to increase screening coverage and treatment compliance for accelerating cervical cancer elimination. We assessed the cost-effectiveness of their combined strategies to inform accessible, affordable, and acceptable cervical cancer prevention strategies. METHODS: We developed a hybrid model to evaluate costs, health outcomes, and incremental cost-effectiveness ratios (ICER) of six screen-and-treat strategies combining HPV testing (self-sampling or physician-sampling), triage modalities (HPV genotyping, colposcopy or none) and thermal ablation, from a societal perspective. A designated initial cohort of 100,000 females born in 2015 was considered. Strategies with an ICER less than the Chinese gross domestic product (GDP) per capita ($10,350) were considered highly cost-effective. RESULTS: Compared with current strategies in China (physician-HPV with genotype or cytology triage), all screen-and-treat strategies are cost-effective and self-HPV without triage is optimal with the most incremental quality-adjusted life-years (QALYs) gained (220 to 440) in rural and urban China. Each screen-and-treat strategy based on self-collected samples is cost-saving compared with current strategies (-$818,430 to -$3540) whereas more costs are incurred using physician-collected samples compared with current physician-HPV with genotype triage (+$20,840 to +$182,840). For screen-and-treat strategies without triage, more costs (+$9404 to +$380,217) would be invested in the screening and treatment of precancerous lesions rather than the cancer treatment compared with the current screening strategies. Notably, however, more than 81.6% of HPV-positive women would be overtreated. If triaged with HPV 7 types or HPV16/18 genotypes, 79.1% or 67.2% (respectively) of HPV-positive women would be overtreated with fewer cancer cases avoided (19 cases or 69 cases). CONCLUSIONS: Screen-and-treat strategy using self-sampling HPV test linked to thermal ablation could be the most cost-effective for cervical cancer prevention in China. Additional triage with quality-assured performance could reduce overtreatment and remains highly cost-effective compared with current strategies.

Plasmonic Hot-Electron-Painted Au@Pt Nanoparticles as Efficient Electrocatalysts for Detection of H2O2.

Plasmon-driven catalysis of metal nanostructures has garnered wide interest. Here, a photogenerated plasmonic hot-electron painting strategy was reported to form Au@Pt composite nanoparticles (Au@Pt NPs) with high catalytic reactivity without using reducing agents. Au nanoparticles, including Au nanospheres (Au NSs), Au nanorods (Au NRs), and Au nanobipyramids (Au NBPs), generated hot electrons under localized surface plasmon resonance (LSPR) excitation, which made the platinum precursor reduced as a consequence that Pt(0) atoms were painted on the surface of Au NPs to form an asymmetric Pt shell outside the plasmonic Au core. Compared with bare Au NPs, Au@Pt NPs exhibited significantly enhanced electrocatalytic activity toward reduction of H2O2 due to the bimetallic synergistic effect and great dispersion of Au@Pt NP-modified indium tin oxide (Au@Pt NPs/ITO). It exhibited a linear detection of H2O2 in a wide concentration range from 0.5 to 1000 µM with a low detection limit of 0.11 µM (S/N = 3). Therefore, the plasmonic hot-electron-painted Au@Pt NPs represent a novel and simple method for the design of advanced noble asymmetric metal nanomaterials.

Enzyme mediated transformation of CO2 into calcium carbonate using purified microbial carbonic anhydrase.

In this study, a bacterial carbonic anhydrase (CA) was purified from Corynebacterium flavescens for the CO2 conversion into CaCO3. The synthesized CaCO3 can be utilized in the papermaking industry as filler material, construction material and in steel industry. Herein, the CA was purified by using a Sephadex G-100 column chromatography having 29.00 kDa molecular mass in SDS-PAGE analysis. The purified CA showed an optimal temperature of 35 °C and pH 7.5. In addition, a kinetic study of CA using p-NPA as substrate showed Vmax (166.66 µmoL/mL/min), Km (5.12 mM), and Kcat (80.56 sec-1) using Lineweaver Burk plot. The major inhibitors of CA activity were Na2+, K+, Mn2+, and Al3+, whereas Zn2+ and Fe2+ slightly enhanced it. The purified CA showed a good efficacy to convert the CO2 into CaCO3 with a total conversion rate of 65.05 mg CaCO3/mg of protein. In silico analysis suggested that the purified CA has conserved Zn2+ coordinating residues such as His 111, His 113, and His 130 in the active site center. Further analysis of the CO2 binding site showed conserved residues such as Val 132, Val 142, Leu 196, Thr 197, and Val 205. However, a substitution has been observed where Trp 208 of its closest structural homolog T. ammonificans CA is replaced with Arg 207 of C. flavescens. The presence of a hydrophilic mutation in the CO2 binding hydrophobic region is a further subject of investigation.

Effects of mitochondrial dysfunction on bone metabolism and related diseases: a scientometric study from 2003 to 2022.

BACKGROUND: In recent years, mitochondrial dysfunction has been extensively studied and published, but research on the effects of mitochondrial dysfunction on bone metabolism and related diseases is only just beginning. Furthermore, no studies have been carried out to systematically illustrate this area from a scientometric point of view. The goal of this research is to review existing knowledge and identify new trends and possible hotspots in this area. METHODS: All publications related to the relationship between mitochondrial dysfunction and bone metabolism and related diseases from 2003 to 2022 were searched at the Web of Science Core Collection (WoSCC) on May 7, 2022. Four different analytical tools: VOSviewer 1.6.18, CiteSpace V 6.1, HistorCite (12.03.07), and Excel 2021 were used for the scientometric research. RESULTS: The final analysis included 555 valid records in total. Journal of Biological Chemistry (Co-citations = 916) is the most famous journal in this field. China (Percentage = 37%), the United States (Percentage = 24%), and Korea (Percentage = 12%) are the most productive countries. Blanco FJ and Choi EM are the main researchers with significant academic influence. Current research hotspots are basic research on mitochondrial dysfunction and the prevention or treatment of bone metabolism-related diseases. CONCLUSION: The study of the consequences of mitochondrial dysfunction on bone metabolism and associated diseases is advancing rapidly. Several prominent researchers have published extensive literature and are widely cited. Future research in this area will focus on oxidative stress, aging, gene expression, and the pathogenesis of bone metabolism-related diseases.

[Rapid identification of raw and sulfur-fumigated Paeoniae Radix Alba based on Heracles NEO ultra-fast gas phase electronic nose].

Since the current identification method for Paeoniae Radix Alba is complex in operation and long time-consuming with high requirements for technicians, the present study employed Heracles NEO ultra-fast gas phase electronic nose(E-nose) technology to identify raw and sulfur-fumigated Paeoniae Radix Alba decoction pieces in order to establish a rapid identification method for sulfur-fumigated Paeoniae Radix Alba. The odors of raw Paeoniae Radix Alba and its sulfur-fumigated products were analyzed by Heracles NEO ultra-fast gas phase E-nose to obtain the odor chromatographic information. The chemometric model was established, and the data were processed by principal component analysis(PCA), discriminant function analysis(DFA), soft independent modeling of class analogy(SIMCA), and partial least squares discriminant analysis(PLS-DA). The differential compounds of raw and sulfur-fumigated samples were qualitatively analyzed based on the Kovats retention index and Arochembase. As revealed by the comparison of gas chromatograms of raw and sulfur-fumigated Paeoniae Radix Alba, the heights of several peaks in the chromatograms before and after sulfur fumigation changed significantly. The peak(No.8) produced by ethylbenzene disappeared completely due to sulfonation reaction in the process of sulfur fumigation, indicating that ethylbenzene may be the key component in the identification of Paeoniae Radix Alba and its sulfur-fumigated products. In PCA, DFA, SIMCA, and PLS-DA models, the two types of samples were separated into two different regions, indicating that the established models can clearly distinguish between raw and sulfur-fumigated Paeoniae Radix Alba. The results showed that Heracles NEO ultra-fast gas phase E-nose technology could realize the rapid identification of raw and sulfur-fumigated Paeoniae Radix Alba, which provides a new method and idea for the rapid identification of sulfur-fumigated Chinese medicine.

Dendrocrepidamine, a novel octahydroindolizine alkaloid from the roots of Dendrobium crepidatum.

A novel octahydroindolizine alkaloid, named dendrocrepidamine (1) with an unusual 18,19,19'-cyclopropanone-dendrocrepine skeleton, was isolated from the ethanol extract of the roots of Dendrobium crepidatum, along with six known compounds (2-7). The structure of 1 was elucidated through HR-ESIMS, NMR spectroscopic data and computational calculations. All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells with IC50 values in the range of 3.04-54.89 µM. In vivo, crepidatin (6) (80, 40 and 10 mg/kg) showed a significant protective effect against LPS-induced acute lung injury (ALI) in mice.

Comparative performance evaluation of different HPV tests and triaging strategies using self-samples and feasibility assessment of thermal ablation in 'colposcopy and treat' approach: A population-based study in rural China.

Human papillomavirus (HPV) test, self-sampling and thermal ablation for cervical intraepithelial neoplasia (CIN) have been developed separately to increase screening coverage and treatment compliance of cervical cancer screening programmes. A large-scale study in rural China screened 9,526 women with their combinations to explore the optimal cervical cancer-screening cascade in the real-world. Participants received careHPV and polymerase chain reaction (PCR) HPV tests on self-collected samples. Women positive on either HPV test underwent colposcopy, biopsy and thermal ablation in a single visit. Samples positive on either HPV test were retested for genotyping. Absolute and relative performance of HPV tests, triage strategies, 'colposcopy and thermal ablation' approach were statistically evaluated. PCR HPV test detected 33.3% more CIN grade two or worse (CIN2+) at a cost of 28.1% more colposcopies compared to careHPV. Sensitivities of PCR HPV and careHPV tests to detect CIN2+ were 96.7 and 72.5%. Specificities for the same disease outcome were 82.1 and 86.0%. Triaging HPV-positive women with HPV16/18 genotyping considerably improved the positive predictive value for CIN2+ (4.8-5.0 to 18.2-19.2%). Ninety-six women positive on HPV and having abnormal colposcopy were eligible for thermal ablation and all accepted same-day treatment, contributing to 64.6% being treated appropriately (CIN1+ on histopathology), which reached up to 84.8% among women positive on HPV 16/18 triage. No serious side-effects/complications were reported. The combination of PCR HPV test followed by HPV 16/18 triaging on self-collected samples and colposcopy of triage positive women followed by immediate thermal ablation might be the appropriate screening cascade for rural China.

Enzyme Activity Triggered Blocking of Plasmon Resonance Energy Transfer for Highly Selective Detection of Acid Phosphatase.

Plasmon resonance energy transfer (PRET), as a new form of energy transfer first discovered in 2007, has been widely applied for the biomolecular recognition, detection of ions, cellular physiological status monitoring, and energy conversion. It occurs between noble metal nanoparticles (donor) and conjugated molecules or nanoparticles (acceptor). In this study, we used urchin-like gold nanoplasmonics (UGPs) and oxTMB as a new donor-acceptor pair to establish a novel PRET coupling system, avoiding trivial modification. PRET from UGPs to conjugated redox-active oxTMB leads to resonant quenching in the localized surface plasmon resonance (LSPR) spectra. However, when the acid phosphatase (ACP) was introduced, the hydrolyzate ascorbic acid (AA) converted from 2-phospho-l-ascorbic acid trisodium salt (AAP) could be capable of reducing oxTMB into TMB, thereby preventing the occurrence of PRET. The recovery of the scattering spectral intensity of UGPs was linearly related to the concentration of ACP in the range of 0.1 to 5.0 U/L, and the ACP with a detection limit of 0.076 U/L could be measured. In addition, this method also showed good selectivity attributed to the substrate specificity of enzyme.

DNA Nanofirecrackers Assembled through Hybridization Chain Reaction for Ultrasensitive SERS Immunoassay of Prostate Specific Antigen.

Isothermal nucleic acid amplification technology has been widely adopted for analytical chemistry with the purpose of sensitivity improvement. Herein we present an ultrasensitive concatenated hybridization chain reaction (C-HCR) based surface-enhanced Raman scattering (SERS) immunoassay by forming antibody-antigen-aptamer heterosandwich structures with the model analyte of total prostate specific antigens (tPSA). In the C-HCR, two HCRs, one proceeds with two hairpins and the other with four biotin-modified hairpins, are coupled, making the formation of DNA nanofirecrackers with the lengths longer than 200 nm and more than four hundred million binding sites of streptavidin modified enzymes. These types of DNA nanofirecrackers through the aptamer encoded linker strand to form heterosandwich structures could provide a general signal application platform such as enzyme catalysis with high amplification efficiency. As a proof of concept, the Au@Ag core-shell nanostructure based SERS immunoassay with excellent signal amplification has been developed by employing the streptavidin modified alkaline phosphatase (SA-ALP) through its catalysis of 2-phospho-l-ascorbic acid trisodium salt (AAP) to form Au@Ag core-shell nanostructures via the formation of ascorbic acid (AA) to reduce AgNO3 and deposition of silver element on gold nanorods (AuNRs). The newly developed method has a detection limit as low as 0.94 fg/mL and has successfully achieved the detection of serum samples from clinical patients, which was consistent with the clinical test results, showing that this C-HCR strategy to form DNA nanofirecrackers has great potential in clinical applications.

The intention to undertake physical activity in pregnant women using the theory of planned behaviour.

AIM: To identify the intention of Chinese pregnant women to undertake physical activity (PA) using the theory of planned behaviour. DESIGN: A cross-sectional survey. METHODS: From April - October 2017, a cross-sectional questionnaire was completed by 746 pregnant women from the Health Birth Cohort in Wuhan, China. The theory of planned behaviour variables as well as sociodemographic characteristics was recorded, and the Pregnancy PA Questionnaire was together used to assess their PA during pregnancy. RESULTS: Only 11.3% of the women met the international guideline. The intention to undertake PA was found it to be positive in 63.9% of pregnant women. Structural equation modelling analysis revealed that behavioural attitudes, subjective norms, and perceived behavioural control (PBC) influenced PA by directly influencing the behaviour intention. Both behavioural attitude and subjective norms influenced PA by indirectly affecting the behaviour. Overall, the model described 60% variance of the behavioural intention to undertake PA during pregnancy. CONCLUSION: PBC was confirmed to be a prominent factor in determining behavioural intention to undertake PA during pregnancy. Pregnant women should be helped and appropriately guided by health providers to overcome barriers to PA. EFFECT: This study investigates the effect of perceived behavioural control (PBC) on the intention to undertake physical activity (PA). The findings suggest that nurses' and midwives' attention should be focused on how to promote the improvement of perceived behavioural control ability of pregnant women to improve pregnant women's PA intention. The attitude of pregnant women on taking up PA and their ability to control behaviours can be improved with support from family or healthcare providers.

[Fingerprint analysis and Q-marker prediction of processed liquorice products].

Licorice has long been regarded as one of the most popular herbs, with a very wide clinical application range. Whether being used alone or as an ingredient in prescription, it has an important role which cannot be ignored. However, the efficacy and chemical constituents of licorice will change after honey-processing. Therefore, it is necessary to find quality markers before and after honey-processing to lay the foundation for a comprehensive evaluation of the differences between raw and processed licorice pieces. HPLC-DAD was employed to establish fingerprints of raw and processed licorice. Multivariate statistical analysis methods including principal component analysis(PCA) and orthogonal partial least squares discrimination analysis(OPLS-DA) were applied to screen out the differential components before and after processing of licorice. Based on network pharmacology, the targets and pathways corresponding to the differential components were analyzed with databases such as Swiss Target Prediction and Metascape, and the "component-target-pathway" diagram was constructed with Cytoscape 3.6.0 software to predict the potential quality markers. A total of 17 common peaks were successfully identified in the established fingerprint, and seven differential components were selected as potential quality markers(licoricesaponin G2, glycyrrhizic acid, liquiritigenin, liquiritin, isoliquiritin, liquiritin apioside and isoliquiritigenin). The HPLC fingerprint method proposed in this study was efficient and feasible. The above seven differential chemical components screened out as potential quality markers of licorice can help to improve and promote the overall quality. These researches offer more sufficient theoretical basis for scientific application of licorice and its corresponding products.

MRP14 enhances the ability of macrophage to recruit T cells and promotes obesity-induced insulin resistance.

OBJECTIVE: Myeloid-related protein-14 (MRP14) and its binding partner MRP8 play an essential role in innate immune function and have been implicated in a variety of inflammatory diseases. However, the role of MRP14 in obesity-induced inflammation and insulin resistance is not well defined. This study investigated the role of MRP14 in macrophage-mediated adipose tissue inflammation and obesity-induced insulin resistance. SUBJECTS AND RESULTS: Wild-type (WT) and Mrp14-/- mice were fed with a high-fat diet or normal chow for 12 weeks. Tissue-resident macrophages in both adipose tissue and liver from obese WT mice expressed higher levels of MRP14 in the visceral adipose fat and liver compared with the lean mice. Mrp14-/- mice demonstrated a significantly improved postprandial insulin sensitivity, as measured by intraperitoneal glucose tolerance test and insulin tolerance testing. Macrophages secreted MRP14 in response to inflammatory stimuli, such as LPS. Extracellular MRP8/14 induced the production of CCL5 and CXCL9. Deficiency of MRP14 did not affect macrophage proliferation, mitochondrial respiration, and glycolytic function, but Mrp14-/- macrophages showed a reduced ability to attract T cells. Depletion of the extracellular MRP14 reduced the T cell attracting ability of WT macrophages to a level similar to Mrp14-/- macrophages. CONCLUSION: Our data indicate that MRP14 deficiency decreases obesity-induced insulin resistance and MRP8/14 regulates T-cell recruitment through the induction of T-cell chemoattractant production from macrophages.

Effect of high glucose on cytokine production by human peripheral blood immune cells and type I interferon signaling in monocytes: Implications for the role of hyperglycemia in the diabetes inflammatory process and host defense against infection.

The major metabolic feature of diabetes is hyperglycemia which has been linked to the diabetes inflammatory processes, and diabetes-related vulnerability to infection. In the present study, we assessed how glucose affected PBMCs in type I interferon (IFN) production and subsequent signaling. We found that the moderately elevated glucose promoted, and high glucose suppressed type I IFN production, respectively. Pre-exposure to high glucose rendered monocytes more sensitive to IFN-α stimulation with heightened signaling, whereas, instantaneous addition of high glucose did not exhibit such effect. Consistent with this finding, the mRNA levels of IFN-α-induced IRF-7 in PBMCs were positively correlated with HbA1c levels of diabetes patients. Additionally, we found that high glucose promoted the production of other proinflammatory cytokines/chemokines. This study suggests that hyperglycemia may affect the inflammatory process in diabetes via promoting proinflammatory cytokines, as well as the host defense against microbial infections through impeding type I IFN production and signaling.

Self-Resistance during Muraymycin Biosynthesis: a Complementary Nucleotidyltransferase and Phosphotransferase with Identical Modification Sites and Distinct Temporal Order.

Muraymycins are antibacterial natural products from Streptomyces spp. that inhibit translocase I (MraY), which is involved in cell wall biosynthesis. Structurally, muraymycins consist of a 5'-C-glycyluridine (GlyU) appended to a 5″-amino-5″-deoxyribose (ADR), forming a disaccharide core that is found in several peptidyl nucleoside inhibitors of MraY. For muraymycins, the GlyU-ADR disaccharide is further modified with an aminopropyl-linked peptide to generate the simplest structures, annotated as the muraymycin D series. Two enzymes encoded in the muraymycin biosynthetic gene cluster, Mur29 and Mur28, were functionally assigned in vitro as a Mg·ATP-dependent nucleotidyltransferase and a Mg·ATP-dependent phosphotransferase, respectively, both modifying the 3″-OH of the disaccharide. Biochemical characterization revealed that both enzymes can utilize several nucleotide donors as cosubstrates and the acceptor substrate muraymycin also behaves as an inhibitor. Single-substrate kinetic analyses revealed that Mur28 preferentially phosphorylates a synthetic GlyU-ADR disaccharide, a hypothetical biosynthetic precursor of muraymycins, while Mur29 preferentially adenylates the D series of muraymycins. The adenylated or phosphorylated products have significantly reduced (170-fold and 51-fold, respectively) MraY inhibitory activities and reduced antibacterial activities, compared with the respective unmodified muraymycins. The results are consistent with Mur29-catalyzed adenylation and Mur28-catalyzed phosphorylation serving as complementary self-resistance mechanisms, with a distinct temporal order during muraymycin biosynthesis.

Effect on absorption and electron transfer by using Cd(ii) or Cu(ii) complexes with phenanthroline as auxiliary electron acceptors (A) in D-A-π-A motif sensitizers for dye-sensitized solar cells.

To broaden the absorption spectrum, improve intramolecular electronic push-pull balance capability, enhance electron transfer and promote the photovoltaic performances of dye sensitizers, four new polymeric metal complex dyes (PBDTT-PhenCd, PBDTT-PhenCu, PPV-PhenCd and PPV-PhenCu) with donor-acceptor-π-bridge-acceptor (D-A-π-A) structure were designed and synthesized. These dyes, for the first time, used the complexes of Cd(ii) or Cu(ii) with phenanthroline as auxiliary electron acceptors (A) instead of organic electron withdrawing groups and adopted thienylbenzo [1,2-b:4,5-b'] dithiophene (BDTT) or hydroquinone (PV) derivatives as electron donors (D) and 8-quinolinol derivatives as π bridge and acceptors (A). The impacts of different auxiliary electron acceptors (A) of metal complexes due to their thermal, optical, electrochemical properties and photovoltaic performance were also investigated. The best power conversion efficiency of 6.68% was achieved in PBDTT-PhenCd DSSC device. In addition, all dyes showed outstanding thermal stability (Td > 300 °C). The results revealed that these novel polymeric metal complex dyes are potential materials for constructing new sensitizers of high performance.

A Novel Vaccine Targeting Glypican-3 as a Treatment for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate worldwide, with limited treatment options. Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored glycoprotein that is overexpressed in most HCC tissues but not in normal tissues. GPC3-targeting antibody therapy shows limited response in a clinical trial due to the lack of a tumor-specific cytotoxic T lymphocyte (CTL) response. Here, in C57/B6 mice, we demonstrated that intravenous infusion of GPC3-coupled lymphocytes (LC/GPC3+) elicited robust GPC3-specific antibody and CTL responses, which effectively restricted proliferation and lysed cultured-HCC cells. Treatment with LC/GPC3+ induced durable tumor regression in HCC-bearing C57/B6 mice. Administration of LC/GPC3+ induced elevated levels of the cytotoxic T cell bioactive factors tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ), granzyme B, and perforin, and substantially increased the number of infiltrating CD8+ T cells in tumor tissues. Moreover, immune responses elicited by LC/GPC3+ selectively suppressed GPC3+ tumors, but didn't affect the GPC3- tumors in BALB/c mice. Our findings provide the first preclinical evidence that intravenous infusion of the LC/GPC3+ complex can induce a strong anti-HCC effect through regulating systemic and local immune responses. These results indicate that the LC/GPC3+ complex could be developed as precision therapeutics for HCC patients in the future.