Label-free cell phenotypic profiling of histamine H4R receptor and discovery of non-competitive H4R antagonist from natural products.

Histamine 4 receptor (H4R), the most recently identified subtype of histamine receptor, primarily induces inflammatory reactions upon activation. Several H4R antagonists have been developed for the treatment of inflammatory bowel disease (IBD) and atopic dermatitis (AD), but their use has been limited by adverse side effects, such as a short half-life and toxicity. Natural products, as an important source of anti-inflammatory agents, offer minimal side effects and reduced toxicity. This work aimed to identify novel H4R antagonists from natural products. An H4R target-pathway model deconvoluted downstream Gi and MAPK signaling pathways was established utilizing cellular label-free integrative pharmacology (CLIP), on which 148 natural products were screened. Cryptotanshinone was identified as selective H4R antagonist, with an IC50 value of 11.68 ± 1.30 µM, which was verified with Fluorescence Imaging Plate Reader (FLIPR) and Cellular Thermal Shift (CTS) assays. The kinetic binding profile revealed the noncompetitive antagonistic property of cryptotanshinone. Two allosteric binding sites of H4R were predicted using SiteMap, Fpocket and CavityPlus. Subsequent molecular docking and dynamics simulation indicated that cryptotanshinone interacts with H4R at a pocket formed by the outward interfaces between TM3/4/5, potentially representing a new allosteric binding site for H4R. Overall, this study introduced cryptotanshinone as a novel H4R antagonist, offering promise as a new hit for drug design of H4R antagonist. Additionally, this study provided a novel screening model for the discovery of H4R antagonists.

Oil-water separation property of polymer-contained wastewater from polymer-flooding oilfields in Bohai Bay, China.

In this study, the effects of gravitational settling time, temperature, speed and time of centrifugation, flocculant type and dosage, bubble size and gas amount were investigated. The results show that the simple increase in settling time and temperature is of no use for oil-water separation of the three wastewater samples. As far as oil-water separation efficiency is concerned, increasing centrifugal speed and centrifugal time is highly effective for L sample, and has a certain effect on J sample, but is not valid for S sample. The flocculants are highly effective for S and L samples, and the oil-water separation efficiency increases with an increase in the concentration of inorganic cationic flocculants. There exist critical reagent concentrations for the organic cationic and the nonionic flocculants, wherein a higher or lower concentration of flocculant would cause a decrease in the treatment efficiency. Flotation is an effective approach for oil-water separation of polymer-contained wastewater from the three oilfields. The oil-water separation efficiency can be enhanced by increasing floatation agent concentration, flotation time and gas amount, and by decreasing bubble size.

Identification of microRNAs as novel biomarkers for detecting esophageal squamous cell carcinoma in Asians: a meta-analysis.

Accumulating evidence has suggested that microRNAs (miRNAs) may play potential role as ideal diagnostic indicators of esophageal squamous cell carcinoma (ESCC). However, previous studies have met discrepant results. Thus, we conducted this meta-analysis to assess the potential diagnostic value of miRNAs for ESCC. A systematic literature search was conducted in PubMed and other databases. The pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated to evaluate the overall test performance. The Q statistic and the I(2) test were used to assess between-study heterogeneity. The potential sources of heterogeneity were further analyzed by subgroup analyses and meta-regression. Seventeen studies from eight articles, including 995 ESCC patients and 733 healthy controls, were included in this meta-analysis. The pooled SEN and SPE were 0.81 (95% confidence interval (CI) 0.76-0.85) and 0.83 (95 % CI 0.76-0.88), respectively. The pooled PLR was 4.6 (95% CI 3.3-6.5), NLR was 0.23 (95% CI 0.19-0.29), and DOR was 20 (95% CI 13-31). The pooled AUC was 0.91 (95% CI 0.88-0.93). Subgroup analyses indicated that blood-based miRNA assay displays better diagnostic accuracy than saliva-based miRNA assay. In summary, miRNA analysis may serve as novel noninvasive biomarkers for ESCC with excellent diagnostic characteristic. In addition, subgroup analysis suggested that blood-based assay yields better diagnostic characteristics than saliva-based assay. However, many issues should be managed before these findings can be translated into a clinically useful detection method for ESCC.

Overexpression of Let-7a mitigates diploidization in mouse androgenetic haploid embryonic stem cells.

Mouse androgenetic haploid embryonic stem cells (mAG-haESCs) can be utilized to uncover gene functions, especially those of genes with recessive effects, and to produce semicloned mice when injected into mature oocytes. However, mouse haploid cells undergo rapid diploidization during long-term culture in vitro and subsequently lose the advantages of haploidy, and the factors that drive diploidization are poorly understood. In this study, we compared the small RNAs (sRNAs) of mAG-haESCs, normal embryonic stem cells (ESCs), and mouse round spermatids by high-throughput sequencing and identified distinct sRNA profiles. Several let-7 family members and miR-290-295 cluster microRNAs (miRNAs) were found significantly differentially transcribed. Knockdown and overexpression experiments showed that let-7a and let-7g suppress diploidization while miR-290a facilitates diploidization. Our study revealed the unique sRNA profile of mAG-haESCs and demonstrated that let-7a overexpression can mitigate diploidization in mAG-haESCs. These findings will help us to better understand mAG-haESCs and utilize them as tools in the future.

Antiparasitic efficacy of flavonoids identified from Psoralea corylifolia against Tetrahymena piriformis in guppy (Poecilia reticulate).

Tetrahymena piriformis belongs to the ciliated protists (ciliates), causing severe economic losses in aquaculture. Chemical drugs currently used usually have toxic side effects, and there is no specific drug against Tetrahymena. Therefore, it is an urgent need to identify new antiparasitic lead compounds. In the present study, the in vitro parasiticidal activity of ethyl acetate (EtOAc) extracts and water extracts from 22 selected traditional Chinese medicines (TCMs) were evaluated against T. piriformis. The EtOAc extract of P. corylifolia turned out to be the most active with the minimum parasiticidal concentration of 100 mg/L within 3 h. Thus, it was separated into 12 fractions by the first-dimensional (D1) normal phase liquid chromatography (NPLC), meanwhile combining with in vitro antiparasitic tests for activity tracking. Subsequently, 8 flavonoids were identified in the active fractions by the second-dimensional (D2) reverse phase liquid chromatography (RPLC) tandem high-resolution mass spectrometry. According to the results, 5 flavonoids were selected for in vitro antiparasitic test, of which isobavachalcone showed the minimum parasiticidal concentration of 3.125 mg/L in 2 h. Bathing treatment of infected guppies with isobavachalcone could significantly reduce the burden of T. piriformis, obtaining a 24-h median effective concentration (24-h EC50) value of 1.916 mg/L. And the concentration of isobavachalcone causing guppies to die within 24 h is 39 times than that of 24-h EC50. The results demonstrated that isobavachalcone has the potential to be developed into a novel commercial fish drug against T. piriformis.

Characterization of dynamical changes in vital signs during allogeneic human umbilical cord-derived mesenchymal stem cells infusion.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), a kind of adult stem cell, were studied for clinical applications in regenerative medicine. To date, the safety evaluations of intravenous infusion of allogeneic hUC-MSCs were focused on fever, infection, malignancy, and death. However, the characteristics of dynamical changes in vital signs during hUC-MSCs infusion are largely unknown. In this study, twenty participants with allogeneic hUC-MSCs transplanted (MSC group) and twenty sex- and age-matched individuals with cardiovascular disease who treated with the equal volume of 0.9% normal saline were recruited (NS group). Heart rate, respiratory rate, oxygen saturation, systolic and diastolic blood pressure, and temperature were monitored at intervals of 15 min during infusion. Adverse events were recorded during infusion and within seven days after infusion. No adverse events were observed during and after infusion in both groups. Compared with the baseline, the mean systolic blood pressure (SBP) levels were significantly decreased at 15 min, 30 min, 45 min and 60 min in the MSC group (all P < 0.05) during infusion. In addition, SBP changed significantly from baseline during hUC-MSCs infusion when compared with that of NS group (P < 0.05). Repeated measures analysis of variance confirmed difference over time on the SBP levels (P < 0.05). Our results showed that the process of allogeneic hUC-MSCs intravenous infusion was safe and the vital signs were stable, whereas a slight decrease in SBP was observed.

Triblock Copolymer Compatibilizers for Enhancing the Mechanical Properties of a Renewable Bio-Polymer.

Poly(lactic acid) (PLA) is an emerging plastic that has insufficient properties (e.g., it is too brittle) for widespread commercial use. Previous research results have shown that the strength and toughness of basalt fiber reinforced PLA composites (PLA/BF) still need to be improved. To address this limitation, this study aimed to obtain an effective compatibilizer for PLA/BF. Melt-blending of poly(butylene adipate-co-terephthalate) (PBAT) with PLA in the presence of 4,4'-methylene diphenyl diisocyanate (MDI: 0.5 wt% of the total resin) afforded PLA/PBAT-MDI triblock copolymers. The triblock copolymers were melt-blended to improve the interfacial adhesion of PLA/BF and thus obtain excellent performance of the PLA-ternary polymers. This work presents the first investigation on the effects of PLA/PBAT-MDI triblock copolymers as compatibilizers for PLA/BF blends. The resultant mechanics, the morphology, interface, crystallinity, and thermal stability of the PLA-bio polymers were comprehensively examined via standard characterization techniques. The crystallinity of the PLA-ternary polymers was as high as 43.6%, 1.44× that of PLA/BF, and 163.5% higher than that of pure PLA. The stored energy of the PLA-ternary polymers reached 20,306.2 MPa, 5.5× than that of PLA/BF, and 18.6× of pure PLA. Moreover, the fatigue life of the PLA-ternary polymers was substantially improved, 5.85× than that of PLA/PBAT-MDI triblock copolymers. Thus, the PLA/PBAT-MDI triblock copolymers are compatibilizers that improve the mechanical properties of PLA/BF.

Fractal Characteristics and Significance of Different Pore Types of the Wufeng-Longmaxi Formation, Southern Sichuan Basin, China, Based on N2 Adsorption and Image Analysis.

Shale gas is an important unconventional natural gas resource, and its reservoirs have pores with strong heterogeneity, which have an important effect on the adsorption and migration of shale gas, but the specific mechanism is still unclear. To further clarify the pore structure characteristics of shale gas reservoirs and the mechanism of their influence on CH4 adsorption capacity, marine shale samples from the Wufeng-Longmaxi formation of wells N1, N3, and N10 in Changning block, southern Sichuan Basin, China, were selected for total organic carbon (TOC), X-ray diffraction (XRD), N2 gas adsorption (N2-GA), CH4 gas adsorption (CH4-GA), and field emission scanning electron microscopy (FE-SEM). The Frenkel-Halsey-Hill (FHH) model and Slit Island Analysis (SIA) were used to calculate the fractal dimension of the pore system and different types of pores, and their relationship and influence on CH4 adsorption capacity were also discussed. The results show that the fractal dimension could reflect the complexity and heterogeneity of pores. According to the FHH model, fractal dimensions of the surface and structure of the pore system (D 1 and D 2, D 1 < D 2) were obtained, and the pore structure was more complex than the pore surface. According to SIA, the surface fractal dimensions of four types of reservoir space (D DP, D OP, D IP, and D MF) decrease progressively, and their main body is 2.60-2.80, 2.40-2.65, 2.20-2.40, and 2.05-2.30. Organic pores and intergranular pores are the most abundant, and so D 1 is mainly related to D OP and D IP. In high-TOC samples, D 1 is close to D OP, while in low-TOC samples, D 1 is close to D IP. The complexity of the pore surface, D 1, and specific surface area have a positive correlation, and with the increase of pore surface complexity, methane adsorption capacity could be significantly improved. Therefore, D 1 may be used as a characterization parameter of CH4 adsorption capacity, which could provide some evidence to further clarify the adsorption mechanism of shale gas.

In vitro Apatite Mineralization, Degradability, Cytocompatibility and in vivo New Bone Formation and Vascularization of Bioactive Scaffold of Polybutylene Succinate/Magnesium Phosphate/Wheat Protein Ternary Composite.

PURPOSE: A bioactive and degradable scaffold of ternary composite with good biocompatibility and osteogenesis was developed for bone tissue repair. MATERIALS AND METHODS: Polybutylene succinate (PS:50 wt%), magnesium phosphate (MP:40 wt%) and wheat protein (WP:10 wt%) composite (PMWC) scaffold was fabricated, and the biological performances of PMWC were evaluated both in vitro and vivo in this study. RESULTS: PMWC scaffold possessed not only interconnected macropores (400 µm to 600 µm) but also micropores (10 µm ~20 µm) on the walls of macropores. Incorporation of MP into composite improved the apatite mineralization (bioactivity) of PMWC scaffold in simulated body fluid (SBF), and addition of WP into composite further enhanced the degradability of PMWC in PBS compared with the scaffold of PS (50 wt%)/MP (50 wt%) composite (PMC) and PS alone. In addition, the PMWC scaffold containing MP and WP significantly promoted the proliferation and differentiation of mouse pre-osteoblastic cell line (MC3T3-E1) cells. Moreover, the images from synchrotron radiation microcomputed tomography (SRmCT) and histological sections of the in vivo implantation suggested that the PMWC scaffold containing MP and WP prominently improved the new bone formation and ingrowth compared with PMC and PS. Furthermore, the immunohistochemical analysis further confirmed that the PMWC scaffold obviously promoted osteogenesis and vascularization in vivo compared with PMC and PS. CONCLUSION: This study demonstrated that the biocompatible PMWC scaffold with improved bioactivity and degradability significantly promoted the osteogenesis and vascularization in vivo, which would have a great potential to be applied for bone tissue repair.

The Scale, Collections, and Biospecimen Distribution of Grade A Tertiary Hospital Biobanks in China: A National Survey.

Chinese clinical biobanks were built rapidly in grade A tertiary hospitals. However, the general information of biorepositories in China remained largely unknown. The aim of this study was to investigate the size, collections, biospecimens distribution and other characteristics of Chinese biobanks in grade A tertiary hospitals. In 2018, we launched a national survey among biobank leaders to provide a comprehensive understanding of Chinese grade A tertiary hospital biobanks. A total of 70 biobank managers or directors completed an online questionnaire to collect information about the biorepositories. Nearly 20% of biobanks stored over one million specimens, while almost one-third of biobanks stored 50-200,000 specimens. In general, plasma and serum were the specimens most commonly stored. For the use of collections, biospecimens were most commonly applied by internal clinical departments. Further analyses revealed that the large-scale biobanks were characterized by earlier establishment, more types of specimens in storage and distribution compared with small-scale biobanks. Moreover, specimens in large-scale biobanks were more commonly used for basic research (62.86% vs. 34.29%, P = 0.017) and clinical research (57.14% vs. 28.57%, P = 0.016). Large-scale biobanks also had more opportunities to cooperate with domestic research institutes (34.29% vs. 5.71%, P = 0.003). Our survey revealed diversity in collections, distribution and utilization of biospecimens among Chinese grade A tertiary hospital biobanks. Although the biobanks had relatively large collections, the underutilization of stored biospecimens and lack of sharing could hamper clinical and biological research.

A large-scale measurement of dielectric properties of normal and malignant colorectal tissues obtained from cancer surgeries at Larmor frequencies.

PURPOSE: Knowledge of dielectric properties of malignant human tissues is necessary for the recently developed magnetic resonance (MR) technique called MR electrical property tomography. This technique may be used in early tumor detection based on the obvious differentiation of the dielectric properties between normal and malignant tissues. However, the dielectric properties of malignant human tissues in the scale of the Larmor frequencies are not completely available in the literature. In this study, the authors focused only on the dielectric properties of colorectal tumor tissue. METHODS: The dielectric properties of 504 colorectal malignant samples excised from 85 patients in the scale of the Larmor frequencies were measured using the precision open-ended coaxial probe method. The obtained complex-permittivity data were fitted to the single-pole Cole-Cole model. RESULTS: The median permittivity and conductivity for the malignant tissue sample were 79.3 and 0.881 S/m at 128 MHz, which were 14.6% and 17.0% higher, respectively, than those of normal tissue samples. Significant differences between normal and malignant tissues were found for the dielectric properties (p < 0.05). CONCLUSIONS: Experimental results indicated that the dielectric properties were significantly different between normal and malignant tissues for colorectal tissue. This large-scale clinical measurement provides more subtle base data to validate the technique of MR electrical property tomography.