Body Compositions Correlate With Overt Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt: A Multicentre Cohort Study.

BACKGROUND: The relationship between body composition and the risk of overt hepatic encephalopathy (OHE) following transjugular intrahepatic portosystemic shunt (TIPS) needs to be investigated. METHODS: Overall, 571 patients from 5 medical centers were included. To assess body compositions, we evaluated skeletal muscle indices, adipose tissue indices, sarcopenia, and myosteatosis at the third lumbar vertebral level. Univariate and Multivariate logistic regression analyses were performed to identify independent risk factors for post-TIPS OHE. An integrated score was then constructed using stepwise multiple regression analyses, with a cut-off value selected using the best Youden index. Finally, the Akaike information criterion (AIC) was performed to compare the integrated score and independent risk factors on their ability in predicting post-TIPS OHE. RESULTS: Sarcopenia and all skeletal muscle indices had limited associations with post-TIPS OHE. The index of the subcutaneous adipose tissue (SATI) (P=0.005; OR: 1.034, 95% CI: 1.010-1.058) and myosteatosis (297 cases, 52.01%, 125 with OHE, 42.09%; P=0.003; OR: 1.973; 95% CI: 1.262-3.084) were both ascertained as independent risk factors for post-TIPS OHE. The integrated score (ScoreALL=1.5760 + 0.0107 * SATI + 0.8579 * myosteatosis) was established with a cutoff value of -0.935. The akaike information criterion (AIC) of ScoreALL, SATI, and myosteatosis was 655.28, 691.18, and 686.60, respectively. CONCLUSIONS: SATI and myosteatosis are independent risk factors for post-TIPS OHE. However, the integrated score was more significantly associated with post-TIPS OHE than other skeletal muscle and adipose tissue factors.

α1,3-fucosylation of MEST promotes invasion potential of cytotrophoblast cells by activating translation initiation.

Embryo implantation into the uterus is the gateway for successful pregnancy. Proper migration and invasion of embryonic trophoblast cells are the key for embryo implantation, and dysfunction causes pregnancy failure. Protein glycosylation plays crucial roles in reproduction. However, it remains unclear whether the glycosylation of trophoblasts is involved in trophoblast migration and invasion processes during embryo implantation failure. By Lectin array, we discovered the decreased α1,3-fucosylation, especially difucosylated Lewis Y (LeY) glycan, in the villus tissues of miscarriage patients when compared with normal pregnancy women. Downregulating LeY biosynthesis by silencing the key enzyme fucosyltransferase IV (FUT4) inhibited migration and invasion ability of trophoblast cells. Using proteomics and translatomics, the specific LeY scaffolding glycoprotein of mesoderm-specific transcript (MEST) with glycosylation site at Asn163 was identified, and its expression enhanced migration and invasion ability of trophoblast cells. The results also provided novel evidence showing that decreased LeY modification on MEST hampered the binding of MEST with translation factor eIF4E2, and inhibited implantation-related gene translation initiation, which caused pregnancy failure. The α1,3-fucosylation of MEST by FUT4 may serve as a new biomarker for evaluating the functional state of pregnancy, and a target for infertility treatment.

Analysis of HLA Profiles in 390 Uveitis Cases: Insights into Clinical Presentations.

Objective: This study aimed to explain the associations between different types of uveitis and human leukocyte antigen (HLA)-B27, HLA-DR4, and HLA-DRw53. Methods: A retrospective analysis of 390 uveitis cases was conducted among inpatients and outpatients diagnosed at Weifang Eye Hospital from 2013 to 2016. All 390 patients underwent HLA-B27 examination, and an additional 40 patients underwent examination for HLA-DR4 and HLA-DRw53. Gender, age, corrected visual acuity (CVA), and recurrence frequency were statistically analyzed based on the onset site and etiology classification. Results: Among the 390 enrolled patients, 206 were male, and 183 were female, with ages ranging from 6 to 87 years (mean: 44.2). The disease onset was classified into anterior uveitis (AU), panuveitis (panU), posterior uveitis (PU), and intermediate uveitis in 180, 112, 88, and 10 cases, respectively. HLA-B27 was positive in 94 cases (53 males and 41 females), yielding a positive rate of 24.1%. In AU patients, 80 (44.4%) tested positive for HLA-B27, while 8 (7.1%) panU patients and 6 PU patients (6.8%) were HLA-B27 positive; none of the intermediate uveitis (IU) patients exhibited HLA-B27 positivity. HLA-B27, HLA-DR4, and HLA-DRw53 examinations were performed on 40 patients with binocular uveitis, resulting in 2 HLA-B27 positive cases, 15 HLA-DR4 positive cases, and 20 HLA-DRw53 positive cases, with positive rates of 5%, 37.5%, and 50%, respectively. Among 25 Vogt Koyanagi-Harada (VKH) cases, 1 tested positive for HLA-B27, 22 were positive for HLA-DR4, and 24 were positive for HLA-DRw53, with positive rates of 4%, 88%, and 96%, respectively. No positive HLA-B27, HLA-DR4, or HLA-DRw53 cases were found among the 10 cases of Behcet's disease (BD). Conclusions: Human leukocyte antigens (HLAs) play a significant role in the mechanism of uveitis. HLA-B27 exhibits high diagnostic value in acute AU, while HLA-DR4 and HLA-DRw53 are crucial for diagnosing binocular uveitis, particularly Vogt Koyanagi-Harada (VKH) syndrome. Further investigation is warranted to explore the relationship between HLA-DR4, HLA-DRw53, and uveitis.

Galectin-3 is associated with the functional outcome and mortality in stroke patients: A systematic review and meta-analysis.

Introduction: There is still a lack of sensitive predictive tools for stroke outcomes. High galectin-3 concentration is associated with an increased risk of stroke. This study investigated the relationship between blood galectin-3 levels and stroke prognosis. Methods: The PubMed, EMBASE, and Cochrane Library databases were searched as of May 2021. Data from eligible studies on the relationship between galectin-3 and stroke prognosis were extracted for the meta-analysis. Results: The outcomes included the modified Rankin Scale (mRS), mortality rate, and prognostic accuracy of galectin-3 on mRS after stroke. Odds ratio (OR) and 95% CI were used to assess the association between galectin-3 and the prognostic outcomes. Subgroup analysis based on the study design was performed to evaluate the correlation of galectin-3 with mRS and mortality. A random-effects model was adopted for this meta-analysis. A total of 5 studies involving 3607 stroke patients were included. Higher serum galectin-3 level was associated with mRS (OR [95% CI]: 2.02 [1.08, 3.77]) and mortality (OR [95% CI]: 2.17 [1.17, 4.02]) after stroke. Subgroup analysis revealed a similar relationship between galectin-3 and mRS for both prospective and retrospective studies. There were no associations between galectin-3 level and mortality rate in prospective studies. Galectin-3 had a good predictive ability on mRS after stroke (AUC: 0.88, 95% CI:0.85, 0.91). Conclusion: Elevated blood galectin-3 levels were associated with prognostic outcomes after stroke, including functional outcome mRS and mortality rate. Moreover, galectin-3 had a good predictive ability for the prognosis of stroke.

Maximizing the Performance of Similarity-Based Virtual Screening Methods by Generating Synergy from the Integration of 2D and 3D Approaches.

Methods for the pairwise comparison of 2D and 3D molecular structures are established approaches in virtual screening. In this work, we explored three strategies for maximizing the virtual screening performance of these methods: (i) the merging of hit lists obtained from multi-compound screening using a single screening method, (ii) the merging of the hit lists obtained from 2D and 3D screening by parallel selection, and (iii) the combination of both of these strategies in an integrated approach. We found that any of these strategies led to a boost in virtual screening performance, with the clearest advantages observed for the integrated approach. On test sets for virtual screening, covering 50 pharmaceutically relevant proteins, the integrated approach, using sets of five query molecules, yielded, on average, an area under the receiver operating characteristic curve (AUC) of 0.84, an early enrichment among the top 1% of ranked compounds (EF1%) of 53.82 and a scaffold recovery rate among the top 1% of ranked compounds (SRR1%) of 0.50. In comparison, the 2D and 3D methods on their own (when using a single query molecule) yielded AUC values of 0.68 and 0.54, EF1% values of 19.96 and 17.52, and SRR1% values of 0.20 and 0.17, respectively. In conclusion, based on these results, the integration of 2D and 3D methods, via a (balanced) parallel selection strategy, is recommended, and, in particular, when combined with multi-query screening.

Nav1.6 promotes the progression of human follicular thyroid carcinoma cells via JAK-STAT signaling pathway.

Follicular thyroid carcinoma (FTC) is one of the most common malignant tumors of the endocrine system. Recent studies have shown that voltage-gated sodium channels (VGSCs) affect the proliferation, migration, and invasion of tumor cells. However, the expression and functions of VGSCs, and the molecular pathways activated by VGSCs in FTC cells remain unclear. Our studies revealed that the expression of Nav1.6, encoded by SCN8A, was the predominantly upregulated subtype of VGSCs in FTC tissues. Knockdown of Nav1.6 significantly inhibited the proliferation, epithelial-mesenchymal transition and invasiveness of FTC cells. Using gene set enrichment analysis and Kyoto Encyclopedia of Genes and Genomics, SCN8A was predicted to be related to the JAK-STAT signaling pathway. Hence, we targeted the JAK-STAT pathway and demonstrated that Nav1.6 enhanced FTC cell proliferation, epithelial-mesenchymal transition, and invasion by phosphorylating JAK2 to activate STAT3. Furthermore, downregulating the expression of Nav1.6 improve the susceptibility of FTC cells to ubenimex in vitro. These results suggest Nav1.6 accelerates FTC progression through JAK/STAT signaling and may be a potential target for FTC therapy.

Clinical significance and role of CXCL16 in anti-neutrophil cytoplasmic autoantibody-associated vasculitis.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a group of potentially life-threatening autoimmune diseases. The kidney and lung are the most common and most severely affected organs. Previous studies have shown that the chemokine ligand CXCL16 and its receptor CXCR6 play an important role in kidney disease. However, whether CXCL16/CXCR6 is involved in the pathogenesis of AAV remains elusive. In this study, the levels of CXCL16 and its specific receptor CXCR6 were investigated. According to kidney outcome, patients were divided into two groups, specifically one with high CXCL16 levels and one with low CXCL16 levels, by cut-off values using receiver operating characteristic (ROC) curves. The clinical parameters and histological features were further compared between the two groups. The ability of CXCL16 to induce neutrophil chemotaxis was analysed using a Transwell migration assay in a coculture system of conditional immortalized human glomerular endothelial cells (ciGEnCs) and neutrophils. We observed that the levels of CXCL16 were significantly increased in the circulation, along with the expression in renal tissue of AAV patients compared to healthy controls (HCs). CXCR6 expression on neutrophils was significantly higher in patients with AAV than in HCs. There were positive correlations between the levels of CXCL16 and serum creatinine, IL-6, CRP, and TNF-α and negative correlations with eGFR. The serum levels of CXCL16 could act as a predictive biomarker of renal outcome in AAV. CXCL16 secretion was upregulated in ciGEnCs treated with AAV serum. CXCL16 released from ciGEnCs contributed to neutrophil migration. Furthermore, neutrophil migration was attenuated by silencing CXCL16 expression via transfection with short hairpin RNA (shRNA) sequences and lentivirus. Taken together, these data suggest that the inhibition of the CXCL16/CXCR6 axis may provide new therapeutic strategies targeting AAV.

Increased Circulating PD-1 hi CXCR5 - Peripheral T Helper Cells are Associated with Disease Activity of ANCA-Associated Vasculitis.

Newly identified PD-1 hiCXCR5 -CD4 + T cells, termed as peripheral helper T cells (Tph), have been found elevated and playing pathogenic role in some autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatic arthritis (RA). However, the potential role of Tph cells in Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) remains unclear. Here, we explored the potential clinical significance of circulating Tph cells in the pathogenesis of AAV. Comparing 32 active AAV patients and 18 age- and sex-matched healthy controls (HCs), we found that the frequency of circulating Tph cells was significantly expanded in active AAV patients. Besides, programmed death 1 (PD-1) expression on the surface of Tph cells was significantly up-regulated in active AAV patients. Importantly, the frequency of circulating Tph cells was greatly decreased in AAV patients after receiving treatment. Tph cells frequency was positively correlated with the Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil lymphocyte ratio (NLR) and cellular crescent in active AAV patients, but negatively correlated with fibrosus crescent. Tph cells frequency was also positively correlated with naïve B cells, serum concentration of MPO-ANCAs, serum tumor necrosis factor-α (TNF-α), IL-4, IL-21 and IL-12. However, serum IL-10 exhibited negative correlation with circulating Tph cells in active AAV patients. These results demonstrated that circulating Tph cells are greatly expanded in active AAV patients and are positively associated with serum MPO-ANCAs and disease activity, thus contributing to the pathogenesis of AAV.

ALADDIN: Docking Approach Augmented by Machine Learning for Protein Structure Selection Yields Superior Virtual Screening Performance.

Protein flexibility and solvation pose major challenges to docking algorithms and scoring functions. One established strategy for addressing these challenges is to use multiple protein conformations for docking (all-against-all ensemble docking). Recent studies have shown that the performance of ensemble docking can be improved by selecting the most relevant protein structures for docking. In search for a robust approach to protein structure selection, we have come up with an integrated mAchine Learning AnD DockINg approach (ALADDIN). ALADDIN employs a battery of random forest classifiers to select, individually for each compound of interest, from an ensemble of protein structures, the single most suitable protein structure for docking. ALADDIN outperformed the best single-structure docking runs, ensemble docking and a similarity-based docking approach on three out of four investigated targets, with up to 0.15, 0.11 and 0.16 higher area under the receiver operating characteristic curve (AUC) values, respectively. Only in the case of cytochrome P450 3A4, ALADDIN, like any of the other tested approaches, failed to obtain decent performance. ALADDIN can be particularly useful for structure-based virtual screening of malleable proteins, including kinases, some viral enzymes and anti-targets.

Docking field-based QSAR and pharmacophore studies on the substituted pyrimidine derivatives targeting HIV-1 reverse transcriptase.

HIV-1 reverse transcriptase (RT) is one of the most important enzymes required for viral replication, thus acting as an attractive target for antiretroviral therapy. Pyrimidine analogues reportedly have selective inhibition on HIV-1 RT with favorable antiviral activities in our previous study. To further explore the relationship between inhibitory activity and pharmacophoric characteristics, field-based QSAR models were generated and validated using Schrodinger Suite (correlation coefficient of .8078, cross-validated value of 0.5397 for training set and Q2 of 0.4669, Pearson's r of .7357 for test set). Docking, pocket surfaces, and pharmacophore study were also investigated to define the binding pattern and pharmacophoric features, including (i) π-π interaction with residue Tyr181, Tyr188, and Trp229 and p-π interaction with His235 and (ii) hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The pharmacophore features of six-point hypothesis AADRRR.184, AAADRR.38, and AADRRR.26 further complimented to the docking and QSAR results. We also found that the protein-ligand complex exhibited high relative binding free energy. These observations could be potentially utilized to guide the rational design and optimization of novel HIV-1 RT inhibitors.

Design, synthesis and biological evaluation of (E)-3,4-dihydroxystyryl 4-acylaminophenethyl sulfone, sulfoxide derivatives as dual inhibitors of HIV-1 CCR5 and integrase.

Aiming at the limited effectiveness of current clinical therapeutic effect of AIDS, novel series of compounds bearing (E)-3,4-dihydroxystyryl sulfone (or sulfoxide) and anilide fragments were designed and synthesized as dual inhibitors of HIV-1 CCR5/IN. The biological results indicated that several target compounds showed inhibitory activity against HIV-1 Bal (R5) infection in TZM-bl cells. Besides targeting the chemokine receptor on the host cell surface, they also displayed binding affinities with HIV-1 integrase using the surface plasmon resonance (SPR) binding assays. Molecular docking studies have inferred the possible binding mode of target compounds against integrase. These data demonstrate that the structure of (E)-3,4-dihydroxystyryl sulfone and sulfoxide derivatives have the potential to derive potent dual inhibitors of HIV-1 Integrase and CCR5.

Study on 2-arylthio-5-iodo pyrimidine derivatives as novel nonnucleoside inhibitors against hepatitis B virus DNA replication.

BACKGROUND: Novel nonnucleoside hepatitis B virus inhibitors have been recently developed for the reason of drug-resistant mutations and adverse effects of nucleoside analogs. In this study, two series of 2-arylthio-5-iodo pyrimidine analogs were firstly reported as potential anti-HBV agents. METHODOLOGY: Target compounds were prepared according to two high-yielded synthetic routes, and their anti-HBV activities were evaluated on Hep2.2.15 and HepAD38 cell lines, respectively. To probe the mechanism of active agents, a cell-based (Huh-7) study of biochemical markers (e.g., HBeAg, HBsAg, intracellular HBV DNA and pgRNA) was performed. Furthermore, the pharmacophore models were constructed for future optimization of lead compounds. CONCLUSION: 2-Arylthio-5-iodo pyrimidine derivatives firstly proved to be effective against HBV, which paves the way for future development of nonnucleoside anti-HBV agents.

A stereo configuration-activity study of 3-iodo-4-(2-methylcyclohexyloxy)-6-phenethylpyridin-2(2H)-ones as potency inhibitors of HIV-1 variants.

3-Iodo-4-(2'-methylcyclohexyloxy)-6-phenethylpyridin-2(1H)-ones, as effective non-nucleoside reverse transcriptase inhibitors, were synthesized and resolved with different configurations. Biological results revealed that the trans-racemate 2b exhibited more potent activity than the cis-isomers. Noticeably, the trans-(S,S)-enantiomer 2e turned out to be significantly more potent than its counterpart enantiomer 2d against wild-type and double-mutant strains with high selectivity indexes.

A novel chemical, STF-083010, reverses tamoxifen-related drug resistance in breast cancer by inhibiting IRE1/XBP1.

Recent studies show that the unfolded protein response (UPR) within the endoplasmic reticulum is correlated with breast cancer drug resistance. In particular, human X-box binding protein-1(XBP1), a transcription factor which participates in UPR stress signaling, is reported to correlate with poor clinical responsiveness to tamoxifen. In this study, we develop a tamoxifen-resistant MCF-7 cell line by treating the cell line with low concentration of tamoxifen, and we find that XBP1 is indeed up-regulated at both the mRNA and protein levels compared to normal MCF-7 cells. STF-083010, a novel inhibitor which specifically blocks the XBP1 splicing, reestablishes tamoxifen sensitivity to resistant MCF-7 cells. Moreover, co-treatment with STF-083010 and tamoxifen can significantly delay breast cancer progression in a xenograft mammary tumor model. We next investigate the expression of XBP1s in over 170 breast cancer patients' samples and the results demonstrate that XBP1s expression level is highly correlated with overall survival in the ER+ subgroup, but not in the ER- subgroup, suggesting a potential therapeutic application of XBP1 inhibitors in ER+breast cancer treatment.

Creatine kinase is a bacteriostatic factor with a lectin-like activity.

Creatine kinase (CK), an enzyme catalyzing the conversion of adenosine diphosphate (ADP) to adenosine triphosphate (ATP), has been shown to be an acute phase reactant in the amphioxus Branchiostoma belcheri. However, immune and functional characterization of this protein remains lacking. Here we demonstrate clearly that the expression of B. belcheri gene, BbCK, was inducible by the challenge with LPS, and the recombinant BbCK was capable of binding to the Gram-negative bacterium Escherichia coli and inhibiting the bacterial growth. Moreover, the bacteriostatic activity of the recombinant BbCK against E. coli was able to be suppressed by some sugars including N-acetyl-d-mannosamine, N-acetyl-d-glucosamine, l-fucose, d-mannose, d-fructose and d-glucose. In contrast, BbCK exerted little effect on the growth of the Gram-positive bactterium Staphylococcus aureus. Taken together, these data suggest that CK is a bacteriostatic factor with a lectin-like activity, capable of specifically inhibiting the growth of the Gram-negative bacteria like E. coli. This is the first report exhibiting the integrative role of CK in immunity via its pleiotropic effects on recognizing the Gram-negative bacterium E. coli and inhibiting its growth.

Characterization, expression, and response to stress of p8 gene in amphioxus.

The amphioxus Branchiostoma belcheri tsingtaunese homolog of p8, Bbp8, was identified from the gut cDNA library. The full-length Bbp8 cDNA consists of 1032 bp, which is clearly longer than those of p8 in human, mouse, rat, frog, zebrafish and fruit fly. The genomic DNA sequences of amphioxus p8 contain three exons and two introns, which is similar to the exon/intron organization of p8 homologues in vertebrates such as human, mouse and zebrafish, while it is sharply different to the organization of p8 gene in fruit fly, which has only one exon. Sequence alignment and phylogenetic analysis showed that the basic helix-loop-helix (bHLH) region of p8 is well conserved during the long process of evolution, and Bbp8 is more close to its homologous proteins in the invertebrates than to those in the vertebrates. RT-PCR and In situ hybridization histochemistry demonstrated the expression of Bbp8 in all the tissues assayed, with relatively higher expression in the gut, gill and ovaries. Quantitative real-time PCR assay revealed quick up-regulation of Bbp8 transcripts on lipopolysaccharide (LPS) challenge and starvation, implying a stress-related function for Bbp8.

Synthesis of Monodisperse Nanocrystals via Microreaction: Open-to-Air Synthesis with Oleylamine as a Coligand.

Microreaction provides a controllable tool to synthesize CdSe nanocrystals (NCs) in an accelerated fashion. However, the surface traps created during the fast growth usually result in low photoluminescence (PL) efficiency for the formed products. Herein, the reproducible synthesis of highly luminescent CdSe NCs directly in open air was reported, with a microreactor as the controllable reaction tool. Spectra investigation elucidated that applying OLA both in Se and Cd stock solutions could advantageously promote the diffusion between the two precursors, resulting in narrow full-width-at-half maximum (FWHM) of PL (26 nm). Meanwhile, the addition of OLA in the source solution was demonstrated helpful to improve the reactivity of Cd monomer. In this case, the focus of size distribution was accomplished during the early reaction stage. Furthermore, if the volume percentage (vol.%) of OLA in the precursors exceeded a threshold of 37.5%, the resulted CdSe NCs demonstrated long-term fixing of size distribution up to 300 s. The observed phenomena facilitated the preparation of a size series of monodisperse CdSe NCs merely by the variation of residence time. With the volume percentage of OLA as 37.5% in the source solution, a 78 nm tuning of PL spectra (from 507 to 585) was obtained through the variation of residence time from 2 s to 160 s, while maintaining narrow FMWH of PL (26-31 nm) and high QY of PL (35-55%).