Influence of Lipopolysaccharide-Interacting Peptides Fusion with Endolysin LysECD7 and Fatty Acid Derivatization on the Efficacy against Acinetobacter baumannii Infection In Vitro and In Vivo.

Acinetobacter baumannii has developed multiple drug resistances, posing a significant threat to antibiotic efficacy. LysECD7, an endolysin derived from phages, could be a promising therapeutic agent against multi-drug resistance A. baumannii. In this study, in order to further enhance the antibacterial efficiency of the engineered LysECD7, a few lipopolysaccharide-interacting peptides (Li5, MSI594 and Li5-MSI) were genetically fused with LysECD7. Based on in vitro antibacterial activity, the fusion protein Lys-Li5-MSI was selected for further modifications aimed at extending its half-life. A cysteine residue was introduced into Lys-Li5-MSI through mutation (Lys-Li5-MSIV12C), followed by conjugation with a C16 fatty acid chain via a protonation substitution reaction(V12C-C16). The pharmacokinetic profile of V12C-C16 exhibited a more favorable characteristic in comparison to Lys-Li5-MSI, thereby resulting in enhanced therapeutic efficacy against lethal A. baumannii infection in mice. The study provides valuable insights for the development of novel endolysin therapeutics and proposes an alternative therapeutic strategy for combating A. baumannii infections.

Association between monocyte-to-lymphocyte ratio and prostate cancer in the U.S. population: a population-based study.

Introduction: Monocyte-to-lymphocyte ratio (MLR) is a convenient and noninvasive inflammatory biomarker, and inflammation has been reported to be associated with prostate cancer (PCa). Our objective was to ascertain any possible correlation between PCa and MLR. Methods: We utilized data from the 1999-2020 cycles of the National Health and Nutrition Examination Survey (NHANES) regarding MLR and PCa. The independent associations of MLR and other inflammatory biomarkers (platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), system inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI)) with PCa was investigated using weighted multivariate logistic regression and generalized additive models. Receiver operating characteristic (ROC) curves were conducted to evaluate and contrast their diagnostic capabilities. Results: The analysis we conducted comprised 25,367 persons in total. The mean MLR was 0.31 ± 0.14. The prevalence of PCa was 3.1%. A positive association was found between MLR and PCa (OR = 2.28; 95% CI: 1.44, 3.62). According to the interaction tests, age, body mass index (BMI), hypertension, diabetes, and smoking status did not significantly impact the relationship between MLR and PCa (all p for interaction >0.05). ROC analysis showed that MLR had a stronger discriminative ability and accuracy in predicting PCa than other inflammatory biomarkers (NLR, SII, AISI, PLR, and SIRI). Conclusion: MLR might be better than other inflammatory biomarkers (NLR, SIRI, AISI, PLR, and SII) in predicting PCa. American adults who have elevated levels of MLR, NLR, PLR, SII, and AISI should be aware that they have a greater risk of PCa.

Design and Biological Evaluation of the Long-Acting C5-Inhibited Ornithodoros moubata Complement Inhibitor (OmCI) Modified with Fatty Acid.

Disorder of complement response is a significant pathogenic factor causing some autoimmune and inflammation diseases. The Ornithodoros moubata Complement Inhibitor (OmCI), a small 17 kDa natural protein, was initially extracted from soft tick salivary glands. The protein was found binding to complement C5 specifically, inhibiting the activation of the complement pathway, which is a successful therapeutic basis of complement-mediated diseases. However, a short half-life due to rapid renal clearance is a common limitation of small proteins for clinical application. In this study, we extended the half-life of OmCI by modifying it with fatty acid, which was a method used to improve the pharmacokinetics of native peptides and proteins. Five OmCI mutants were initially designed, and single-site cysteine mutation was introduced to each of them. After purification, four OmCI mutants were obtained that showed similar in vitro biological activities. Three mutants of them were subsequently coupled with different fatty acids by nucleophilic substitution. In total, 15 modified derivatives were screened and tested for anticomplement activity in vitro. The results showed that coupling with fatty acid would not significantly affect their complement-inhibitory activity (CH50 and AH50). OmCIT90C-CM02 and OmCIT90C-CM05 were validated as the applicable OmCI bioconjugates for further pharmacokinetic assessments, and both showed improved plasma half-life in mice compared with unmodified OmCI (15.86, 17.96 vs 2.57 h). In summary, our data demonstrated that OmCI conjugated with fatty acid could be developed as the potential long-acting C5 complement inhibitor in the clinic.

Daphnane-Type Diterpenes from Stelleropsis tianschanica and Their Antitumor Activity.

Four new daphnane-type diterpenes named tianchaterpenes C-F (1-4) and six known ones were isolated from Stelleropsis tianschanica. Their structures were elucidated based on chemical and spectral analyses. The comparisons of calculated and experimental electronic circular dichroism (ECD) methods were used to determine the absolute configurations of new compounds. Additionally, compounds 1-10 were evaluated for their cytotoxic activities against HGC-27 cell lines; the results demonstrate that compound 2 had strong cytotoxic activities with IC50 values of 8.8 µM, for which activity was better than that of cisplatin (13.2 ± 0.67 µM).

Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling.

Adhesion G protein-coupled receptors (aGPCRs) are keys of many physiological events and attractive targets for various diseases. aGPCRs are also known to be capable of self-activation via an autoproteolysis process that removes the inhibitory GAIN domain on the extracellular side of receptor and releases a stalk peptide to bind and activate the transmembrane side of receptor. However, the detailed mechanism of aGPCR activation remains elusive. Here, we report the cryo-electron microscopy structures of GPR110 (ADGRF1), a member of aGPCR, in complex with Gq, Gs, Gi, G12 and G13. The structures reveal distinctive ligand engaging model and activation conformations of GPR110. The structures also unveil the rarely explored GPCR/G12 and GPCR/G13 engagements. A comparison of Gq, Gs, Gi, G12 and G13 engagements with GPR110 reveals details of G-protein engagement, including a dividing point at the far end of the alpha helix 5 (αH5) of Gα subunit that separates Gq/Gs engagements from Gi/G12/G13 engagements. This is also where Gq/Gs bind the receptor through both hydrophobic and polar interaction, while Gi/G12/G13 engage receptor mainly through hydrophobic interaction. We further provide physiological evidence of GPR110 activation via stalk peptide. Taken together, our study fills the missing information of GPCR/G-protein engagement and provides a framework for understanding aGPCR activation and GPR110 signaling.

Exercise-induced calf muscle hyperemia: Rapid mapping of magnetic resonance imaging using deep learning approach.

Exercise-induced hyperemia in calf muscles was recently shown to be quantifiable with high-resolution magnetic resonance imaging (MRI). However, processing of the MRI data to obtain muscle-perfusion maps is time-consuming. This study proposes to substantially accelerate the mapping of muscle perfusion using a deep-learning method called artificial neural network (NN). Forty-eight MRI scans were acquired from 21 healthy subjects and patients with peripheral artery disease (PAD). For optimal training of NN, different training-data sets were compared, investigating the effect of data diversity and reference perfusion accuracy. Reference perfusion was estimated by tracer kinetic model fitting initialized with multiple values (multigrid model fitting). Result: The NN method was much faster than tracer kinetic model fitting. To generate a perfusion map of matrix 128 × 128 on a same computer, multigrid model fitting took about 80 min, single-grid or regular model fitting about 3 min, while the NN method took about 1 s. Compared to the reference values, NN trained with a diverse group gave estimates with mean absolute error (MAE) of 15.9 ml/min/100g and correlation coefficient (R) of 0.949, significantly more accurate than regular model fitting (MAE 22.3 ml/min/100g, R 0.889, p < .001). Conclusion: the NN method enables rapid perfusion mapping, and if properly trained, estimates perfusion with accuracy comparable to multigrid model fitting.

Effects of Sodium Valproate Combined with Lamotrigine on Quality of Life and Serum Inflammatory Factors in Patients with Poststroke Secondary Epilepsy.

BACKGROUND: We sought to explore the effects of sodium valproate combined with lamotrigine on quality of life and serum inflammatory factors in patients with poststroke secondary epilepsy. METHODS: A total of 145 patients with post-stroke secondary epilepsy admitted to our hospital from January 2017 to June 2018 were collected: 76 treated with sodium valproate combined with lamotrigine (study group) and 69 patients treated with sodium valproate alone (control group). The levels of serum high-mobility group protein B1, matrix metalloproteinase 9, and interleukin 6 were detected before and after treatment, and the therapeutic efficacy and adverse reactions were compared between the 2 groups. RESULTS: The total effective rate of the study group was higher than that of the control group. Both groups decreased in epileptiform discharges or in the number of involved leads after treatment, with the results of the study group being lower than those of the control group. The quality of life scores in both groups was increased after treatment, albeit the scores of the study group were higher than those of the control group. In terms of the levels of serum inflammatory factors, the 2 groups were reduced after treatment; the levels of the study group were lower than those of the control group. Regarding the incidence of adverse reactions, no significant difference was seen between the 2 groups. CONCLUSIONS: Sodium valproate combined with lamotrigine has better clinical efficacy and higher safety in the treatment of poststroke secondary epilepsy and is able to reduce the expression levels of serum inflammatory factors.

Transarterial Onyx Embolization of Residual Arteriovenous Malformation After Surgical Resection.

OBJECTIVE: We sought to report transarterial Onyx embolization of residual brain arteriovenous malformation (AVM) after surgical resection. METHODS: From January 2017 to January 2019, 7 patients with residual AVM after surgery were treated by transarterial Onyx embolization. Demographics, angioarchitectural characteristics, complications, and results were retrospectively reviewed. RESULTS: All patients presented initially with a ruptured AVM. Residual AVM was found on control angiograms within 1 month after surgery. All residual AVMs were cured by transarterial Onyx embolization. One patients experienced feeding artery perforation without adding new neurologic deficits. CONCLUSIONS: Complete obliteration of residual AVMs can be obtained by salvage transarterial Onyx embolization.

Activation of peroxydisulfate by nanoscale zero-valent iron for sulfamethoxazole removal in agricultural soil: Effect, mechanism and ecotoxicity.

In this study, peroxydisulfate (PDS) was successfully activated by nanoscale zero-valent iron (nZVI) for the degradation of sulfamethoxazole (SMX, antibiotic frequently detected in the environment) in agricultural soils. The results indicated that the degradation of SMX was affected by the nZVI dose, the ratio of SMX/PDS, the ratio of soil/water and reaction temperature, and in cinnamon soils 87.6% of SMX degradation can be achieved within 4 h at 30 °C when the initial nZVI dose was 0.03 g g-1 soil, the molar ratio of SMX/PDS = 1/75 and the soil/water = 1/1. The results of radical scavenger experiments and electron spin resonance (ESR) tests showed that hydroxyl radical (OH) was the dominant reactive species in this system. The ecotoxicity tests of the soil by germination test, luminescent bacteria experiment and enzyme activity test indicated that the ecotoxicity of soil after treatment was obviously lower than the contaminated soil. In addition, there was almost no effect on plant growth when compared with original soil. Furthermore, this system exhibited a great degradation capacity for SMX in different types of agricultural soils, and the degradation efficiencies of SMX in other four soils were 90.6% (yellow brown earths), 80.8% (brown earths), 86.5% (black soils) and 96.1% (red earths), respectively. This work provides an optional method for agricultural soil pollution control.

Autofocusing optical-resolution photoacoustic endoscopy.

Photoacoustic (PA) endoscopy has the potential to diagnose early diseases in the gastrointestinal tract. For the first time, to our knowledge, we developed an autofocusing PA endoscope (AF-PAE) for the usually irregular gastrointestinal tract imaging to solve the deterioration of transverse resolution caused by the defocus scanning of the probe. The 9-mm-diameter AF-PAE probe integrated a 6-mm aspheric lens and 6-mm liquid lens to automatically adjust the optical focal length, and an unfocused ultrasonic transducer with a center frequency of 15 MHz is coaxially set for detecting PA signals. With this probe, the AF-PAE achieved a focus-shifting range from approximately 2 to 10 mm with high transverse resolution and image contrast in a 360° field of view. Phantom experiment and vasculature distribution of a resected rabbit rectum have been performed to demonstrate the imaging ability of the AF-PAE for potential clinical applications in colorectal vessel imaging and subsequent diagnosis.

MicroRNA-29a: A potential biomarker in the development of intracranial aneurysm.

AIM: To identify serum microRNA-29a (miR-29a) level in patients with intracranial aneurysm and its role in the development of intracranial aneurysm (IA). METHODS: Case group included 165 IA patients hospitalized in the department of neurosurgery between January 2010 and January 2012 while control group enrolled 220 healthy volunteers. Morning fasting blood samples were collected from peripheral vein. RT-PCR was used for miR-29a detection. Receiver Operating Characteristic (ROC) curve was drawn. Survival curves were drawn for survival analysis with Kaplan-Meier method and Long-rank test was conducted. MiR-29a expression Glasgow Prognosis Score (GOS) was used for prognosis scaling. Multivariate Cox proportional hazards regression analysis was performed for prognosis analysis. Results Cases had significantly higher miR-29a expressions than controls (P<0.05). ROC curve analysis indicated that miR-29a expression in IA had high effectiveness in IA diagnosis. Close associations were identified between miR-29a expression and rupture, Hunt-Hess level and surgical timing (all P<0.05). GOS strongly associated with history of hypertension, aneurysm location, rupture, Hunt-Hess level and miR-29a expression. Patients with low miR-29a expression had longer disease-free survival (DFS) and overall survival (OS) than those with high miR-29a expression (both P<0.05). MiR-29a expression, tumor aneurysm, rupture and Hunt-Hess were risk factors to the prognosis of IA (all P<0.05). CONCLUSION: MiR-29a may be closely related to IA development and therefore could be a useful predicator of IA prognosis, providing a new target for IA therapy.

[Inhibitory Effects of Sphingosine-1-phosphate Receptor-2 on Vascular Permeability in Mice].

OBJECTIVES: To determine the effect of sphingosine-1-phosphate receptor 2 (S1PR2) on vascular permeability in mice. METHODS: Acute lung injury models of mice were constructed with intra-tracheal administration of lipopolysaccharide (LPS) and compared with the controls with intra-tracheal administration of saline. The effect of S1PR2 on vascular permeability was observed by detecting leakage of Evans blue into lung tissues, pulmonary vascular leakage of fluorescein isothiocyanate (FITC)-dextran, and the wet/dry mass ratio of lungs. The effect of vascular endothelial growth factor (VEGF) on vascular endothelial permeability was detected by Miles analysis. RESULTS: LPS injections induced significant Evans blue leakage, FITC-dextran pulmonary vascular leakage and pulmonary edema, which appeared to be more serious in S1PR2-deleted mice compared with those in wild-type mice. LPS enhanced Evans blue leakage associated with VEGF in a dose-dependent way in both S1PR2-deleted mice and wild type mice. But the vascular permeability response in subcutaneous tissues induced by VEGF was higher in S1PR2-deleted mice than that in wild-type mice. CONCLUSIONS: S1PR2 is involved in endothelial cell barrier protections, which inhibits vascular permeability.

Inhibition of tumor angiogenesis by TTF1 from extract of herbal medicine.

AIM: To study the inhibition of tumor angiogenesis by 5,2,4´-trihydroxy-6,7,5´-trimethoxyflavone (TTF1) isolated from an extract of herbal medicine Sorbaria sorbifolia. METHODS: Angiogenic activity was assayed using the chick embryo chorioallantoic membrane (CAM) method. Microvessel density (MVD) was determined by staining tissue sections immunohistochemically for CD34 using the Weidner capillary counting method. The mRNA and protein levels of vascular endothelial growth factor (VEGF), vascular endothelialgrowth factor receptor 2 (VEGFR2, Flk-1/KDR), basic fibroblast growth factor (bFGF), cyclo-oxygenase (COX)-2 and hypoxia-inducible factor (HIF)-1α were detected by quantitative real-time polymerase chain reaction and Western blotting analysis. RESULTS: The TTF1 inhibition rates for CAM were 30.8%, 38.2% and 47.5% with treatment concentrations of 25, 50 and 100 µg/embryo × 5 d, respectively. The inhibitory rates for tumor size were 43.8%, 49.4% and 59.6% at TTF1 treatment concentrations of 5, 10, and 20 µmol/kg, respectively. The average MVD was 14.2, 11.2 and 8.5 at treatment concentrations of 5 µmol/kg, 10 µmol/kg and 20 µmol/kg TTF1, respectively. The mRNA and protein levels of VEGF, KDR, bFGF, COX-2 and HIF-1α in mice treated with TTF1 were significantly decreased. CONCLUSION: TTF1 can inhibit tumor angiogenesis, and the mechanism may be associated with the down-regulation of VEGF, KDR, bFGF, HIF-1α and COX-2.