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Our previous study demonstrated that neuroglobin (Ngb) functions as an independent predictive indicator of the prognosis of patients with glioma and promotes cancer cell growth by suppressing apoptosis. However, the understanding of the mechanisms underlying the survival-enhancing function of Ngb in glioma is limited. In the present study, KEGG PathwayFinder by gene correlation analysis was performed on the R2: Genomics Analysis and Visualization Platform, which revealed a high association between Ngb and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway using glioma data (GSE4290) from the Gene Expression Omnibus database. Furthermore, western blotting experiments were performed in U251 and U87 glioma cells, and Ngb knockdown using short hairpin RNA reduced the protein levels of phosphorylated (p)-AKT, p-mammalian target of rapamycin (mTOR) and antiapoptotic factor Bcl-2, and increased the expression of the proapoptotic protein Bcl-2-associated X, in U251 cells. In addition, Ngb overexpression promoted the activation of the PI3K/AKT pathway in U87 cells. MK2206, a PI3K/AKT signaling inhibitor, reduced the expression of p-AKT and increased the levels of apoptosis-associated proteins, including cleaved poly(ADP-ribose) polymerase 1 and cleaved caspase-3/7/8, in Ngb-overexpressing U87 cells. Furthermore, MK2206 treatment reduced the proliferation and induced the apoptosis of Ngb-overexpressing U87 cells, as indicated by the results of MTT, colony formation and flow cytometry assays. In addition, insulin-like growth factor-1, a PI3K/AKT signaling activator, reversed Ngb knockdown-induced growth arrest and apoptosis in U251 cells. In conclusion, the results of the present study indicate that Ngb may facilitate a malignant phenotype of glioma cells by activating the PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

In this work, the effect of annealing on microstructure and tensile properties of polypropylene (PP) cast film was investigated by differential scanning calorimetry (DSC), wide-angle X-ray diffraction (XRD), small-angle X-ray scattering (SAXS), SEM, etc. The SAXS data showed that the elevating annealing temperature led to the increase of thickness of lamellae phase and amorphous phase. The orientation of lamellae along MD direction after annealing was proved with the SAXS data. Moreover, these annealed samples had an extra low-temperature melting peak in the DSC curves and it moved to a higher temperature obviously with increasing the annealing temperature. More importantly, the relationship between the yield strength and the lamellar thickness was built through testing the tensile properties and calculating the Thomson-Gibbs equation, respectively. It revealed that the yield strength first increased rapidly and grew slowly when the lamellar thickness increased to a certain extent. A detailed physical model was also proposed to depict the change of microstructure during annealing. [ABSTRACT FROM AUTHOR]

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro . Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo , emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned. [ABSTRACT FROM AUTHOR]

The miscibility, crystalline structure and morphology, as well as, properties of Polyamide 6 (PA6)/polyvinylidene fluoride (PVDF) blends (with up to 50 wt% of PVDF) were studied. Small Angle X-ray Scattering study above the melting point of PVDF shows that the blends have very limited miscibility with approximately 5 wt% of PVDF inclusion in PA6 amorphous lamellar region. SAXS results also indicate a certain degree of PA6 inclusion into PVDF region though quantitative evaluation is unavailable with the limited blends studied in this work. The fine PVDF dispersion in the PA6 blends with up to 50 wt% of PVDF with an average size about 150 nm is supposed to be the result of the partial miscibility. The partial miscibility has great effects on the morphology and properties of the blends. Crystallization of both components are suppressed in the blends, especially on the PVDF component, which shows a significantly lowered crystallization temperature (up to 30 °C) during a cooling and a dramatic drop in crystallinity. Morphological studies together with Small Angle Light Scattering (SALS) show that spherulites, consisting of PA6 skeleton with dispersed PVDF domains (∼150 nm) engulfed among PA6 fibrils, are formed in the blends. The PA6 based spherulites become more defective with the increase in PVDF content, resulting in short/broken fibrils and undetectable PA6 spherulites for the blends with 30–50 wt% of PVDF at the temperature over the melting point of PVDF, say 185 °C. The blends show a significantly improved toughness compared with neat PA6, due to the partial miscibility which leads to the fine dispersion of PVDF domains in PA6 spherulites. [ABSTRACT FROM AUTHOR]

Summary The NatB N-terminal acetyltransferase specifically acetylates the N-terminal group of substrate protein peptides starting with Met-Asp/Glu/Asn/Gln. How NatB recognizes and acetylates these substrates remains unknown. Here, we report crystal structures of a NatB holoenzyme from Candida albicans in the presence of its co-factor CoA and substrate peptides. The auxiliary subunit Naa25 of NatB forms a horseshoe-like deck to hold specifically its catalytic subunit Naa20. The first two amino acids Met and Asp of a substrate peptide mediate the major interactions with the active site in the Naa20 subunit. The hydrogen bonds between the substrate Asp and pocket residues of Naa20 are essential to determine the NatB substrate specificity. Moreover, a hydrogen bond between the amino group of the substrate Met and a carbonyl group in the Naa20 active site directly anchors the substrate toward acetyl-CoA. Together, these structures define a unique molecular mechanism of specific N-terminal acetylation acted by NatB. [ABSTRACT FROM AUTHOR]

Background Hyperuricemia (HUA) is the most common disease associated with cardiovascular disease, metabolic syndrome, hypertension, and kidney disease. The objective of the current study was to evaluate the preliminary efficacy, mechanism, and safety of acupuncture on serum uric acid in patients with asymptomatic HUA. Methods A randomized, placebo-controlled trial among 123 patients with asymptomatic HUA was conducted. The acupoints used in the acupuncture group were bilateral Five Shu in Spleen Meridian . Each participant received the intervention once daily for 10 consecutive days. The sham group received the same treatment duration on the same acupoints by the Park Sham Device. All patients underwent measurements of serum or urine creatinine, uric acid, serum lipid profiles, fasting plasma glucose, HbA1c, xanthine oxidase (XOD) and urate-anion exchanger (URAT-1). Results At the end of the intervention, the individuals in the acupuncture group were found to have significantly less levels of serum uric acid than those in the sham group [(453 ± 65 vs. 528 ± 81) μmol/L, p < 0.01]. Acupuncture was effective on increasing the urine uric acid level, urine pH value and 24-hour urine volume than the sham treatment ( p < 0.05 for all). Interestingly, acupuncture significantly decreased the level of URAT-1 ( p < 0.01) but not XOD than that of the sham intervention. The adverse events were that 3 patients experienced severe pain. Conclusions Acupuncture on Five Shu in Spleen Meridian appeared to be safe and efficacious for decreasing serum uric acid in a Chinese HUA patient population. The mechanism might be associated with the decrease level of enzyme URAT-1. Chinese clinical trial registration ChiCTR-TRC-13004122 [ABSTRACT FROM AUTHOR]

• Deformable convolution is used in the feature extraction network. The position and size of the convolution kernel are dynamically adjusted according to the shape of the wheel hub defects. • In this paper, global information is introduced from the spatial location dimension. The spatial dependence between positions is demonstrated by modeling the spatial attention diagram of any two positions in the feature graph, to highlight the wheel hub defect area in the global view and improve the detection effect of defects. • For cascade detectors, feature sharing is carried out in serial manner by decoupled classification and regression branches. • According to the actual production situation, the network structure is optimized, redundant parameters are reduced, and space is compressed. At present, object detection methods based on machine vision have been widely used in the field of industrial defect detection. Wheel hub defects are characterized by multiple scales and complex types. The location, size and affiliation of different defect marks are different, so it is difficult to establish an accurate wheel hub defect detection model. Therefore, a wheel nuclear hub defect detection method based on the DS-Cascade RCNN was proposed. To effectively locate multiscale s, a spatial attention mechanism was added as a wheel hub defect location enhancement module. Then deformable convolution is added, and the position and size of the convolution kernel are adjusted dynamically according to the shape of wheel defects. Finally, the pruning algorithm is used to optimize the improved model and compress the model space without losing the accuracy. The model was evaluated under the wheel dataset. Experimental results show that the proposed method can effectively detect six kinds of wheel hub defects, and the mean Average Precision (mAP) is 95.49%. Multiscale defect location and defect category estimation are realized, which meets the requirements of wheel hub detection in actual production. [ABSTRACT FROM AUTHOR]

We used a porcine model of acute myocardial infarction to study the signal evolution of ischemic myocardium on diffusion-weighted magnetic resonance images (DWI). Eight Chinese miniature pigs underwent percutaneous left anterior descending or left circumflex coronary artery occlusion for 90 minutes followed by reperfusion, which induced acute myocardial infarction. We used DWI preprocedurally and hourly for 4 hours postprocedurally. We acquired turbo inversion recovery magnitude T2-weighted images (TIRM T2WI) and late gadolinium enhancement images from the DWI slices. We measured the serum myocardial necrosis markers myoglobin, creatine kinase-MB isoenzyme, and cardiac troponin I at the same time points as the magnetic resonance scanning. We used histochemical staining to confirm injury. All images were analyzed qualitatively. Contrast-to-noise ratio (the contrast between infarcted and healthy myocardium) and relative signal index were used in quantitative image analysis. We found that DWI identified myocardial signal abnormity early (<4 hr) after acute myocardial infarction and identified the infarct-related high signal more often than did TIRM T2WI: 7 of 8 pigs (87.5%) versus 3 of 8 (37.5%) ( P=0.046). Quantitative image analysis yielded a significant difference in contrast-to-noise ratio and relative signal index between infarcted and normal myocardium on DWI. However, within 4 hours after infarction, the serologic myocardial injury markers were not significantly positive. We conclude that DWI can be used to detect myocardial signal abnormalities early after acute myocardial infarction-identifying the infarction earlier than TIRM T2WI and widely used clinical serologic biomarkers. [ABSTRACT FROM AUTHOR]

[Display omitted] • Several thienopyridine derivatives were synthesized as P2Y 12 receptor inhibitors. • Compound 6b exhibited stronger potency than clopidogrel. • Compound 6b showed the ability to overcome clopidogrel resistance. • Compound 6b exhibited lower risk of bleeding than prasugrel. • Compound 6b showed good stability as non-salt solid. A series of novel thienopyridine derivatives were designed and synthesized as P2Y 12 receptor inhibitors. Several solid compounds were assessed for inhibitory effect where they exhibited stronger potency than clopidogrel. Compound 6b and 6g were evaluated for metabolism to verify that they could overcome clopidogrel resistance and for toxicity where they showed lower toxicity than prasugrel. Compound 6b exhibited lower risk of bleeding than prasugrel and showed good stability under stress testing. Overall, as a promising antiplatelet agent, representative compound 6b showed the following advantages: (1) no drug resistance for CYP2C19 poor metabolizers; (2) higher potency than clopidogrel; (3) lower toxicity than prasugrel; (4) lower risk of bleeding than prasugrel; (5) good stability as a non-salt solid. [ABSTRACT FROM AUTHOR]

A range of neurodegenerative and related aging diseases, such as Alzheimer's disease and type 2 diabetes, are linked to toxic protein aggregation. Yet the mechanisms of protein aggregation inhibition by small molecule inhibitors remain poorly understood, in part because most protein targets of aggregation assembly are partially unfolded or intrinsically disordered, which hinders detailed structural characterization of protein-inhibitor complexes and structural-based inhibitor design. Herein we employed a parallel small molecule library-screening approach to identify inhibitors against three prototype amyloidogenic proteins in neurodegeneration and related proteinopathies: amylin, Aβ and tau. One remarkable class of inhibitors identified from these screens against different amyloidogenic proteins was catechol-containing compounds and redox-related quinones/anthraquinones. Secondary assays validated most of the identified inhibitors. In vivo efficacy evaluation of a selected catechol-containing compound, rosmarinic acid, demonstrated its strong mitigating effects of amylin amyloid deposition and related diabetic pathology in transgenic HIP rats. Further systematic investigation of selected class of inhibitors under aerobic and anaerobic conditions revealed that the redox state of the broad class of catechol-containing compounds is a key determinant of the amyloid inhibitor activities. The molecular insights we gained not only explain why a large number of catechol-containing polyphenolic natural compounds, often enriched in healthy diet, have anti-neurodegeneration and anti-aging activities, but also could guide the rational design of therapeutic or nutraceutical strategies to target a broad range of neurodegenerative and related aging diseases. [Display omitted] • Parallel drug library screening identified catechol-containing compounds as a broad class of amyloid inhibitors. • Multiple secondary assays validated most of the identified inhibitors, including in vivo efficacy of rosmarinic acid. • Aerobic but not anaerobic conditions significantly enhanced anti-amyloid activities of the catechol-containing compounds. • Reducing biochemical agents blocked or diminished amyloid remodeling/inhibition activities of catechol-containing inhibitors. • Explain why catechol-containing compounds, enriched in healthy diet, have anti-neurodegeneration and anti-aging effects. [ABSTRACT FROM AUTHOR]

NLRP3 inflammasome dysregulation has been observed in many human diseases including neurodegenerative disorders. Thus, development of small molecule inhibitors targeting this protein complex represents a promising strategy to achieve disease intervention. In our continuing efforts to develop NLRP3 inhibitors, a recently identified lead inhibitor, YQ128 , was further modified and optimized. The structure-activity relationship studies of this lead compound suggested its flexibility for structural modifications while the sulfonamide and benzyl moiety demonstrated being important for selectivity. Additionally, the systematic SAR studies also provided insights for designing NLRC4 and AIM2 inflammasome inhibitors. A new lead inhibitor, 19 , was identified with improved potency (IC 50 : 0.12 ± 0.01 μM) and binding affinity (K D : 84 nM). Further characterization of this lead compound using wild type and nlrp3−/− mice confirmed its in vivo selective target engagement. PET studies using a radiotracer based on the structure of 19 also demonstrated its improved brain penetration compared to previous lead compounds. These results strongly encourage further testing of 19 in disease models. [Display omitted] • Systematic SAR studies were performed based on the sulfonamide scaffold of YQ128. • Compound 19 demonstrated as an NSI with an IC 50 of 0.12 μM and K D of 84 nM. • Studies of 19 in mice demonstrated its in vivo target engagement. • PET/CT studies of [18F] 19 demonstrated rapid brain uptake and penetration. [ABSTRACT FROM AUTHOR]

Aims/Introduction This study was to assess the association between serum osteocalcin level and glucose metabolism in a Chinese male population. Materials and Methods We carried out a cross-sectional study with a cohort of participants from the Fangchenggang Area Male Health and Examination Survey. The cross-sectional study was carried out among 2,353 men, including 2,139 participants with normal glucose tolerance, 148 with impaired fasting glucose and 66 with type 2 diabetes. A subsample of 1,109 men with measurement of osteocalcin was observed in the cohort. After a 4-year follow-up period, 1,049 non-diabetic and 983 participants with normal glucose tolerance who submitted the available information were enrolled in the cohort. Participants were divided into group-H (≥23.33 ng/ mL) and group-L (<23.33 ng/mL) by osteocalcin level. Results In the cross-sectional study, osteocalcin levels were highest in participants with normal glucose tolerance, followed by those with impaired fasting glucose and type 2 diabetes ( P < 0.001). In partial correlation analysis adjusted for age, serum osteocalcin level was related to glucose level ( r = −0.082, P < 0.001), insulin level ( r = −0.079, P < 0.001) and insulin resistance ( r = −0.065, P = 0.002). Compared with group-H, group-L was associated with an increased risk of type 2 diabetes (odds ratio 2.107, 95% confidence interval 1.123-3.955), impaired fasting glucose (odds ratio 2.106; 95% CI 1.528-2.902), and insulin resistance (odds ratio 1.359, 95% confidence interval 1.080-1.710) adjusted for age, education levels, cigarette smoking and lipid profiles. In the cohort study, the increased risk of impaired fasting glucose was significant in group-L vs group-H (3.3% vs 1.2%, P = 0.026). Conclusions Low serum osteocalcin level was a risk factor for impaired glucose metabolism and subsequent type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background Successful reperfusion is the most effective strategy to reduce ischemic injury in acute myocardial infarction (AMI). Ischemic injury, however, also triggers a secondary ischemia–independent injury, known as reperfusion injury, contributing to the overall infarct size. We hypothesize that inhibition of the Nod-like Receptor Protein-3 (NLRP3) inflammasome limits infarct size following myocardial ischemia/reperfusion (I/R), by inhibiting the inflammatory component of the reperfusion injury. Methods CD-1 male mice underwent transient ligation of the left anterior descending coronary artery for 30 or 75 min followed by reperfusion. Infarct size was measured at 1, 3 and 24 h. A NLRP3 inflammasome inhibitor (NLRP3inh) or vehicle was administrated immediately at time of reperfusion or with a delay of 1 or 3 h of reperfusion. Results A time-dependent increase in infarct size was measured at 1, 3, and 24 h after reperfusion (11 ± 2%, 30 ± 5% and 43 ± 4% of the area at risk respectively; P < 0.001 for trend). NLRP3 myocardial expression was significantly increased at 24 h and 6 h vs 3 h (P < 0.01). Administration of the NLRP3inh at reperfusion did not reduce infarct size at 3 h, while it significantly reduced infarct size at 24 h (− 56% vs vehicle, P < 0.01). The NLRP3inh given 1 h after reperfusion also significantly decreased caspase-1 activity and infarct size measured at 24 h, whereas the NLRP3inh did not when given with a delay of 3 h. Conclusions Pharmacological inhibition of the NLRP3 inflammasome within 1 h of reperfusion limits the secondary inflammatory injury and infarct size following myocardial ischemia–reperfusion in the mouse. [ABSTRACT FROM AUTHOR]

We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer's disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (MMP) and Ca2+ levels in MC65 cells upon removal of tetracycline (TC). In this report, we examined the effects by a bivalent compound with a longer spacer (21MO) in MC65 cells. Our results demonstrated that 21MO suppressed the change of MMP, possibly via interaction with the mitochondrial complex I in MC65 cells. Interestingly, 21MO did not show any effects on the Ca2+ level upon TC removal in MC65 cells. Our previous studies suggested that the mobilization of Ca2+ in MC65 cells, upon withdraw of TC, originated from ER, so the results implicated that 21MO may preferentially interact with mitochondria in MC65 cells under the current experimental conditions. Collectively, the results suggest that bivalent compounds with varied spacer length and cell membrane anchor moiety may exhibit neuroprotective activities via different mechanisms of action. [ABSTRACT FROM AUTHOR]

The drywood termite Cryptotermes domesticus is an important worldwide pest with limited genomic resources that causes substantial damage to dry timber and structural lumber. Here, we performed transcriptome sequencing for Cr. domesticus pseudergate using Illumina paired-end sequencing technology. A total of 108,745,470 clean reads were collected and assembled into 302,979 contigs with an average length of 648 bp and an N50 length of 893 bp. A total of 185,248 unigenes and 100,680 proteins were identified among the assembled contigs. Of these, there were 152,317 (50.27%) contigs with significant similarity to publicly available databases. To understand how the termites respond to phylogenetically diverse wood species, variations in gene expression were examined among pseudergates feeding on three wood species from different plant families, Casuarina equisetifolia (CE), Koompassia excelsa (KE) and Myristica sp . (MS). A total of 417 (118 up-regulated/299 down-regulated), 599 (148 up-regulated/451 down-regulated) and 505 (223 up-regulated/282 down-regulated) differentially expressed genes were detected in KE vs. CE, KE vs. MS and CE vs. MS, respectively. Digital gene expression analysis indicated that different wood species played an important role in the expression of termite genes, such as genes involved in carbohydrate metabolism, and proteins with catalytic activity and hydrolase activity. Additionally, the genes encoding cellulase were identified and analyzed. This study provides the first primary transcriptome of Cr. domesticus and lays a foundation for future functional genomics studies in the feeding responses. [ABSTRACT FROM AUTHOR]

Traditional Chinese Medicine Jianpijiedu decoction (JPJD) could improve the general status of liver cancer patients in clinics, especially the symptoms of decreased food intake and diarrhea. In this study, our results showed that the survival rate of the liver cancer with food restriction and diarrhea (FRD-LC) rats was lower than the liver cancer (LC) rats, and the tumor volume of the FRD-LC rats was higher than the LC rats. It was also shown that the high dose of JPJD significantly improved the survival rate, weight, and organ weight when compared with FRD-LC-induced rats. Moreover, JPJD administration upregulated the mRNA and protein levels of ABCC2 and downregulated the mRNA and protein levels of OATP1B2 in liver tissues. However, opposite results were observed in the cancer tissues. In conclusion, the study indicated that the Chinese Medicine JPJD could contribute to the rats with liver cancer which were pretreated with food restriction and diarrhea by regulating the expression of ABCC2 and OATP1B2 in liver tissues and cancer tissues. [ABSTRACT FROM AUTHOR]

In an effort to combat the multifaceted nature of Alzheimer’s disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC 50 of 111.7 ± 9.0 nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD. [ABSTRACT FROM AUTHOR]

Multiple pathogenic factors have been suggested to play a role in the development of Alzheimer's disease (AD). The multifactorial nature of AD also suggests the potential use of compounds with polypharmacology as effective disease-modifying agents. Recently, we have developed a bivalent strategy to include cell membrane anchorage into the molecular design. Our results demonstrated that the bivalent compounds exhibited multifunctional properties and potent neuroprotection in a cellular AD model. Herein, we report the mechanistic exploration of one of the representative bivalent compounds, 17MN, in MC65 cells. Our results established that MC65 cells die through a necroptotic mechanism upon the removal of tetracycline (TC). Furthermore, we have shown that mitochondrial membrane potential and cytosolic Ca2+ levels are increased upon removal of TC. Our bivalent compound 17MN can reverse such changes and protect MC65 cells from TC removal induced cytotoxicity. The results also suggest that 17MN may function between the Aβ species and RIPK1 in producing its neuroprotection. Colocalization studies employing a fluorescent analog of 17MN and confocal microscopy demonstrated the interactions of 17MN with both mitochondria and endoplasmic reticulum, thus suggesting that 17MN exerts its neuroprotection via a multiple-site mechanism in MC65 cells. Collectively, these results strongly support our original design rationale of bivalent compounds and encourage further optimization of this bivalent strategy to develop more potent analogs as novel disease-modifying agents for AD. [ABSTRACT FROM AUTHOR]

'NBOMe' (dimethoxyphenyl-N-[(2-methoxyphenyl)methyl]ethanamine) derivatives are a new class of designer hallucinogenic drugs widely available on the Internet. Currently, 2-(4-iodo-2,5-dimethoxyphenyl)-N- [(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe) is the most popular abused derivative in the USA. There are little published data on the absorption, metabolism and elimination of 25I-NBOMe, or any of the other NBOMe derivatives. Therefore, there are no definitive metabolite biomarkers. We present the identification of fifteen 25I-NBOMe metabolites in phase I and II mouse hepatic microsomal preparations, and analysis of two human urine samples from 25I-NBOMe-intoxicated patients to test the utility of these metabolites as biomarkers of 25I-NBOMe use. The synthesis of two major urinary metabolites, 2- iodo-4-methoxy-5-[2-[(2-methoxyphenyl) methylamino]ethyl]phenol (2-O-desmethyl-5-I-NBOMe, M5) and 5-iodo-4-methoxy-2-[2-[(2-methox- yphenyl)methylamino]ethyl]phenol (5-O-desmethyl-2-I-NBOMe), is also presented. Seven phase II glucuronidated metabolites of the O-desmethyl or the hydroxylated phase I metabolites were identified. One human urine sample contained 25I-NBOMe as well as all 15 metabolites identified in mouse hepatic microsomal preparations. Another human urine sample contained no parent 25I-NBOMe, but was found to contain three O-desmethyl metabolites. We recommend β-glucuronidase enzymatic hydrolysis of urine prior to 25I-NBOMe screening and the use of M5 as the primary biomarker in drug testing. [ABSTRACT FROM AUTHOR]

The hepatoprotective effect of Gypsophila elegans isoorientin (GEI) was evaluated using a hepatic fibrosis model induced by CCl 4 in rats. The results revealed that GEI significantly prevented CCl 4 -induced liver injury and fibrosis, as evidenced by the attenuation of histopathological changes, the decrease in serum aminotransferase, and the inhibition of collagen accumulation. GEI strongly inhibited lipid peroxidation and recruited anti-oxidative defense system. Moreover, GEI alleviated pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 via inhibiting nuclear factor-κB (NF-κB) activation. In addition, GEI down-regulated the phosphorylation of Smad2/3 and up-regulated the level of hepatic Smad7, thereby inhibiting TGFβ1/Smad signaling pathway. In conclusion, our findings indicate that GEI can inhibit CCl 4 -induced hepatic fibrosis, which may be ascribed to its radical scavenging action, antioxidant activity, and modulation of NF-κB and TGF-β1/Smad signaling pathways. [ABSTRACT FROM AUTHOR]

Insufficient evidence Reference 1 Binkheder S. PhenoDEF: a corpus for annotating sentences with information of phenotype definitions in biomedical literature. B Correction: J Biomed Semantics 13, 17 (2022) b B https://doi.org/10.1186/s13326-022-00272-6 b Following publication of the original article [[1]], we have been notified that the numbering of column 1 in Table 2 is incorrect. [Extracted from the article]

R3734 --> 659.1 --> Neuroinflammation has proven to play an important role in the pathogenesis of neurodegenerative diseases by encouraging the expression and maturation of pro‐inflammatory regulators. Studies have shown the upregulation of pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18 in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), traumatic brain injury (TBI), and many more. The NLRP3 (NOD‐, LRR‐ and pyrin domain‐containing protein 3) inflammasome is the key regulator in the maturation and release of these inflammatory cytokines and is therefore an attractive target for suppressing inflammation. Upon assembly and activation of the multimeric NLRP3 inflammasome complex comprised of NLRP3, ASC protein, and pro‐caspase‐1, autoproteolytic cleavage of pro‐caspase‐1 occurs. Activated caspase‐1 is then able to cleave pro‐IL‐1β and pro‐IL‐18 and release their biologically active forms, IL‐1β and IL‐18, consequently leading to an inflammatory cell death known as pyroptosis (Figure 1). Our recent medicinal chemistry campaign has led to a series of novel small molecule inhibitors that are suggested to selectively target NLRP3 and show both in vitro and in vivo activity to inhibit the release of IL‐1β and IL‐18 with sub‐micromolar potencies. Through various assays and photoaffinity labeling experiments using a chemical probe, we have revealed and validated the mechanisms and binding of our lead compound, YQ128, to NLRP3. YQ128 is able to inhibit caspase‐1 and GSDMD cleavage as well as ASC speck formation in mouse macrophages; however, it has no effect on the NLRP3 expression, suggesting its target is upstream of ASC speck and caspase‐1 but downstream of priming. Through target identification studies using a photoaffinity labeling (PAL) technique, we found that YQ128 specifically interacts with NLRP3, but not other components of the NLRP3 inflammasome complex. Competition studies with the parent compound and other known NLRP3 inhibitors suggested the specific and unique binding of YQ128 to NLRP3. The results from other biological assays proposed its binding to the NACHT domain of NLRP3. Using our chemical probe in a pull‐down assay, we also discovered other potential targets within the inflammasome pathway, including a protein that was recently termed "undruggable". These results suggest a novel mechanism of inhibition by our compounds and further studies are currently underway to improve these inhibitors as potential therapeutics for neuroinflammation in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Aim: The primary objective of this study was to study the effects of 17-methoxyl-7-hydroxybenzene- furanchalcone (MHBFC) on pressure overload-induced cardiac remodeling in rats, as well as the endothelial mechanisms based on PGI2 Methods: Six weeks following surgery, rats were divided randomly into the following groups: a sham group, a model group, an MHBFC 12 mg/kg/day group (MHBFC 12), an indomethacin 2 mg/kg/day group (Indo 2), and an Indo 2+ MHBFC 12 group. The MS 4000 organism signal system was used to record the rats' hemodynamic indices. Additionally, the heart weight was determined, and the cardiac remodeling index was calculated. HE and Masson's stains were utilized to perform histological analyses; the immunofluorescence was used to observe the microvessel density of myocardial tissue; the colorimetric method was used to determine the hydroxyproline content of cardiac tissue; the ELISA method was used to measure the plasma PGI2 content; and transmission electron microscopy was used to observe the ultrastructure of the myocardium. Results: A hyperdynamic circulation state, cardiac remodeling, decreased microvessel density and decreased plasma PGI2 content were each observed in the model group compared with the sham group, in which any changes in the above parameters were effectively reversed by MHBFC. Single-use Indo administration resulted in the progression of these pathophysiological changes; however, MHBFC prevented the worsening of these parameters. Conclusion: MHBFC significantly reverses pressure overload-induced cardiac remodeling, and its mechanism may partially contribute to the amelioration of endothelial cell function and the augmentation of PGI2 synthesis and secretion. [ABSTRACT FROM AUTHOR]

We used Doppler US to evaluate the changes in hepatic arterial hemodynamics that occur following LDLT in pediatric recipients, with a view to assessing the utility of these parameters in predicting early HAT. A retrospective review of 144 pediatric recipients (73 males, 71 females) who underwent routine Doppler US in the first week after LDLT was undertaken, and changes in hepatic arterial hemodynamics were assessed. The HARI and HAPSV were compared in patients with early HAT (defined as occurring in the first postoperative week) and a control group, and the utility of these parameters in predicting early HAT after LDLT was determined. A total of 11 pediatric recipients experienced early HAT, being diagnosed on average four and a half days after LDLT. HARI and HAPSV values were significantly different between the early HAT group and controls. HARI values <0.6 on the day before the onset of early HAT were able to predict HAT development with a sensitivity of 81.8% and specificity of 95.2%. This provides evidence for routine Doppler US examination in these patients and supports consideration of more intensive anticoagulation in these high-risk patients. [ABSTRACT FROM AUTHOR]

An isoflavone was isolated from Trifolium pratense using bioassay-guided screening. The structure of this natural compound was elucidated based on its spectral data, and it was identified as pratensein. The protective effect of pratensein was evaluated using a cognitive impairment model induced by injecting amyloid beta (1–42) (Aβ 1–42 ) into the bilateral hippocampus of rats. The results showed that pratensein treatment significantly protected against Aβ 1–42 -induced cognitive impairments, as evidenced by the improvement in learning and memory and the attenuation of neuronal degeneration and apoptosis in hippocampus. Analysis of the potential mechanisms of action showed that pratensein significantly decreased inflammatory indicators such as MDA, NO, nNOS, IL-1β and TNF-α. Pratensein markedly decreased the content and deposition of β-amyloid peptide through regulating the expressions of Aβ-related genes including APP, BACE1, CatB, NEP and IDE. Moreover, pratensein significantly increased the expressions of synapse plasticity-related proteins, i.e., PSD-95, p-NMDAR1, p-CaMKII, p-PKACβ, PKCγ, p-CREB and BDNF. In addition, pratensein significantly decreased the activity of cholinesterase, then subsequently elevated the level of acetylcholine. In summary, our study indicated that pratensein may have a likely protective effect against Alzheimer's disease (AD) via improving synaptic plasticity and increasing cholinesterase activity. [ABSTRACT FROM AUTHOR]

The high melt strength polypropylene(HMSPP) is fabricated by directpolymerization through controlling the species and ratios of the externalelectron donors in the Ziegler–Natta catalyst system at differentreaction stages. The polypropylene exhibits wide molecular weightdistribution and higher melt strength. The expanded polypropylene(EPP) beads are prepared by the above HMSPP through an autoclave-basedbatch process. The effects of melt strength on the cellular morphologyof EPP are investigated by scanning electron microscope and melt strengthmeter, respectively. Results indicate higher melt strength facilitatesthe control of the foaming process and the cellular structure comparedwith a commercial propylene homopolymer such as T03. The bimodal cellstructure is obtained with the single foaming agent CO2in both of the EPP beads from HMSPP and commercial polypropylene. [ABSTRACT FROM AUTHOR]

In recent years, a large number of designer drugs sold as 'Bath Salts' have appeared on the market. In July of 2011, Raving Dragon Novelty Bath Salts was obtained over the Internet. This product became unavailable in October of that year coinciding with the DEA issuing a temporarily schedule of mephedrone, methylone, and MDPV. Four months later in February of 2012, a new product was released from the same company under the new name Raving Dragon Voodoo Dust. The contents of both products were identified using spectroscopy methods: nuclear magnetic resonance, infrared, UV-visible, tandem mass spectrometry, and high-resolution time-of-flight mass spectrometry. It was determined that Raving Dragon Novelty Bath Salts contained methylone. The replacement product Raving Dragon Voodoo Dust contained the unscheduled drug pentedrone. The Raving Dragon brand of products illustrates the rapid change of ingredients in these products to circumvent laws restricting availability, distribution, and use. [ABSTRACT FROM AUTHOR]

Aims: Effect and mechanism of Yulangsan flavonoid (YLSF) on rat myocardial ischemia/reperfusion injury (MI/RI) has been investigated. Methods: Sprague-Dawley (SD) rats were randomly divided into seven groups (sham group, model group and NS group: 2 mL of normal saline/kg body weight was administered; diltiazem group: 5 mg of diltiazem hydrochloride/kg body weight was administered; YLSFL, YLSFM and YLSFH groups: 20, 40 and 80 mg of YLSF/kg body weight was administered) and the MI/RI model was established. Myocardial infarct area, levels of myocardial enzymes and nitric oxide synthase (NOS) were measured. Caspase-3 and adenine nucleotide translocator-1 (ANT1) mRNA expression were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Pathological structure and cardiocyte ultrastructure were also analysed. Results: Compared with the MI/RI group, pretreatment with YLSF or diltiazem hydrochloride decreased the infarct area, levels of inducible nitric oxide synthase (iNOS), caspase-3 as well as the leakage of myocardial enzyme and increased activities of total nitric oxide synthase (tNOS) as well as constitutive nitric oxide synthase (cNOS). Cellular edema and the infiltration of inflammatory cells were alleviated. Conclusions: The experiment showed that YLSF protected the heart against MI/RI, possibly by reducing lipid peroxidation damage, regulating NOS activity and modulating the apoptosis genes expression. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Only a small proportion of genetic variation in serum ferritin has been explained by variant genetic studies, and genome-wide association study (GWAS) for serum ferritin has not been investigated widely in Chinese population. We aimed at exploring the novel genetic susceptibility to serum ferritin, and performed this two stage GWAS in a healthy Chinese population of 3,495 men aged 20–69 y, including 1,999 unrelated subjects in the first stage and 1,496 independent individuals in the second stage. Serum ferritin was measured with electrochemiluminescence immunoassay, and DNA samples were collected for genotyping. A total of 1,940,243 SNPs were tested by using multivariate linear regression analysis. After adjusting for population stratification, age and BMI, the rs5742933 located in the 5′UTR region of PMS1 gene on chromosome 2 was the most significantly associated with ferritin concentrations (P-combined = 2.329×10−10) (β = −0.11, 95% CI: −0.14, −0.07). Moreover, this marker was about 200kb away from the candidate gene SLC40A1 which is responsible for iron export. PMS1 gene was the novel genetic susceptibility to serum ferritin in Chinese males and its relation to SLC40A1 needs further study. [ABSTRACT FROM AUTHOR]

The expanded polypropylene beads with microcellular structure were prepared by an autoclave-based batch foaming process using non-supercritical CO2 as the foaming agent. Herein, smaller polypropylene micropellets (∼0.6 mm) were obtained from three kinds of polypropylene resin by underwater micro-pelletizer system. The results from differential scanning calorimetry indicated that the double melting peaks of beads moved to higher temperature with increasing saturation temperature and pressure. The kind of comonomer did not exert noticeable influence on the double melting behaviors. The X-ray diffraction of expanded polypropylene bead revealed that characteristic peaks of α-type crystal did not change compared with that of original polypropylene micropellets. The relationship between cell morphology and saturation temperature/pressure of expanded polypropylene beads are discussed preliminarily by scanning electron microscope. [ABSTRACT FROM PUBLISHER]

Highlights: [•] YLSP attenuated morphine withdrawal symptoms. [•] YLSP decreased brain NO levels and NOS activity in morphine dependent rats. [•] YLSP modulated the level of DA as well as NE in NAc, VTA, HIP, and PFC. [ABSTRACT FROM AUTHOR]

Background: Serum carcinoembryonic antigen (sCEA) level might be an indicator of disease. Indeed, an elevated sCEA level is a prognostic factor in colorectal cancer (CRC) patients. However, the genetic determinants of sCEA level in healthy and CRC population remains unclear. Thus we investigated the genetic markers associated with elevated serum sCEA level in these two populations and its clinical implications. Methods and Findings: Genome-wide association study (GWAS) was conducted in a cohort study with 4,346 healthy male adults using the Illumina Omni 1 M chip. Candidate SNPs associated with elevated sCEA levels were validated in 194 CRC patients on ABI Taqman platform. Eight candidate SNPs were validated in CRC patients. The rs1047781 (chr19- FUT2) (A/T) was associated with elevated sCEA levels, and rs8176746 (chr9- ABO) was associated with the regional lymph metastasis in the CRC patients. The preoperative sCEA level was a risk factor for tumor recurrence in 5 years after operation (OR = 1.427, 95% CI: 1.005∼1.843, P = 0.006). It was also one of the risk factors for regional lymph node metastasis (OR = 2.266, 95% CI: 1.196∼4.293, P = 0.012). The sCEA level in rs1047781-T carriers was higher than that in the A carriers in CRC patients without lymph node metastasis (P = 0.006). The regional lymph node metastasis in patients with homozygote AA of rs8176746 was more common than that in the heterozygote AG carriers (P = 0.022). In addition, rs1047781-AT and TT CRC patients exhibited a worse disease-free survival than AA genotype carriers (P = 0.023). Conclusions: We found candidate SNPs associated with elevated sCEA levels in both healthy males and CRC population. Rs1047781 (chr19- FUT2) may be the susceptible locus for recurrence of CRC in a population from Southern China. [ABSTRACT FROM AUTHOR]

We investigated the effects of 17-methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC), which was isolated from the roots of Millettia pulchra (Benth.) Kurz var. Laxior (Dunn) Z.Wei (Papilionaceae) (MKL), on the progression of cardiac hypertrophy to failure in a rat model of abdominal aortic banding (AAB)-induced pressure overloading. Endothelial dysfunction is central to pressure overload-induced cardiac hypertrophy and failure. It would be useful to clarify whether MHBFC could prevent this dysfunction. The effects of pressure overload were assessed in male Sprague–Dawley rats 6 weeks after AAB using the progression of cardiac hypertrophy to heart failure as the endpoint. The AAB-treated rats exhibited a greater progression to heart failure and had significantly elevated blood pressure, systolic and diastolic cardiac dysfunction, and evidence of left ventricular hypertrophy (LVH). LVH was characterized by increases in the ratios of heart and left ventricular weights to body weight, increased myocyte cross-sectional areas, myocardial and perivascular fibrosis, and elevated cardiac hydroxyproline. These symptoms could be prevented by treatment with MHBFC at daily oral doses of 6 and 12 mg/kg for 6 weeks. The progression to cardiac failure, which was demonstrated by increases in relative lung and right ventricular weights, cardiac function disorders and overexpression of atrial natriuretic peptide (ANP) mRNA, could also be prevented. Furthermore, MHBFC partialy rescued the downregulated nitric oxide signaling system, whereas inhibited the upregulated endothelin signaling system, normalizing the balance between these two systems. MHBFC protected the endothelium and prevented the pressure overload-induced progression of cardiac hypertrophy to cardiac failure. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Yulangsan polysaccharide (YLSPS) is often used in popular folk medicine in the Guangxi Zhuang Autonomous Region of China as a chief ingredient of Millettia pulchra, which is used as an hepatic protection, anti-aging and memory improving agent. In this study, the hepatoprotective effects of YLSPS against isoniazid (INH) or rifampicin and isoniazid (RFP+INH)-induced liver injury were investigated in mice. Materials and methods: The liver injury was induced by intragastric administration of INH or RFP+INH daily for 10 days. During the experiment, the model group received INH or RFP+INH only, and the normal control group received an equal volume of saline. Treatment groups received not only INH or RFP+INH but also the corresponding drugs, DDB (200mg/kg/day) or YLSPS (100, 200, and 400mg/kg/day) 2h after the administration of INH or RFP+INH. Results: Analysis experiments showed that YLSPS significantly alleviated liver injury as indicated by the decreased levels of ALT and AST and the increased levels of SOD, GSH and GSH-Px. Moreover, YLSPS could effectively reduce the pathological tissue damage. The research on the mechanisms underlying the hepatoprotective effect showed that YLSPS was able to reduce lipid peroxidation and activate the anti-oxidative defense system. Conclusion: Our results show that YLSPS is effective in attenuating hepatic injury in the INH or RFP+INH-induced mouse model, and could be developed as a new drug for treatment of liver injury. [Copyright &y& Elsevier]

Highlights: [•] PMP significantly ameliorate cognitive disorder induced by d-gal in mice. [•] PMP markedly reduce the content and deposition of β-amyloid peptide (Aβ). [•] PMP enhance the expressions of synapse plasticity-related proteins. [•] PMP reverse the abnormality of Ach level and AChE activity. [ABSTRACT FROM AUTHOR]

Background: The ferritin is an important participant of iron-storage but its regulation and related factors were not well defined. The present objective was to explore the potential association between serum ferritin levels and sex hormones. Methods: 1999 Chinese men in the Fangchenggang Area Male Health and Examination Survey (FAMHES) were recruited in this cross-sectional study. Levels of serum ferritin, total testosterone (free testosterone was calculated from the total one), estradiol and sex hormone-binding protein were detected in venous blood samples. The effects of age, BMI, smoking as well as alcohol consumption were analyzed on ferritin levels, respectively, and then the Pearson’s correlation analysis was used to evaluate the association between ferritin levels and sex hormones adjusting for the above factors. Results: The age, BMI and alcohol consumption significantly affected serum ferritin levels, but there was no significant difference between smokers and nonsmokers. Ferritin levels were significantly and negatively associated with total testosterone (R = −0.205, P< 0.001), sex hormone-binding protein (R = −0.161, P<0.001) and free testosterone (R = −0.097, P<0.001). After age and alcohol consumption were adjusted, the above associations were still significant (R = −0.200, −0.181 and −0.083, respectively, all P<0.001). However, there was only borderline negative association between ferritin levels and estradiol (adjusted R = −0.039, P = 0.083). Conclusion: The large scale of epidemic results showed the significantly negative associations between serum ferritin levels and sex hormones, which may provide more clues to explore the potential regulation and biological mechanism of ferritin. [ABSTRACT FROM AUTHOR]

Abstract: In the present study, we aimed to assess the potential anti-amblyopic effects of l-dopa methyl ester (LDME) on visual cortex area 17 in an amblyopic feline model induced by monocular vision deprivation. After LDME administration, pathophysiologic and ultrastructural observations were utilized to examine the morphological changes of nerve cells in visual cortex area 17. Dopamine (DA) and its metabolite contents in visual cortex area 17 were investigated through HPLC analysis. Apoptotic cells in visual cortex area 17 were evaluated by TUNEL assay. Additionally, the c-fos expression both at gene and protein levels was assessed using RT-PCR and immunohistochemistry analyses, respectively. The contents of DA and its metabolites were elevated in visual cortex area 17. Neuronal rejuvenation which occurred in visual cortex area 17 was observed through anatomical and physiological assessments. Similarly, TUNEL results showed that neuronal apoptosis was inhibited in the visual cortex of amblyopic cats by both l-dopa and LDME therapies. Meanwhile, the c-fos expression was notably up-regulated at both the mRNA and protein levels by the treatments. These findings suggested that LDME treatment could effectively increase DA and its metabolite contents, and restrain the apoptotic process, as well as elevate the c-fos expression in nerve cells of visual cortex area 17. Taken together, LDME might ameliorate the functional cytoarchitecture in visual cortex area 17 through mechanisms that elevate DA content and increase endogenous c-fos expression, as well as inhibit neuronal lesion in visual cortex tissue. [Copyright &y& Elsevier]

Increased serum uric acid (SUA) levels may be involved in the development of non-alcoholic fatty liver disease (NAFLD) in men presenting with metabolic syndrome (MetS) and/or insulin resistance. We aimed to determine the independent relationship between SUA and NAFLD in non-diabetic Chinese male population, and to explore the determinants of SUA levels among indexes of adiposity, lipid, and genotypes pertaining to triglycerides metabolism, inflammation, oxidative stress, and SUA concentrations. A total of 1440 men, classified depending on the presence of ultrasonographically detected NAFLD, underwent a complete healthy checkup program. Genotypes were extracted from our previously established genome-wide association study database. After adjusting for age, smoking, drinking, body mass index, homeostasis model assessment of insulin resistance, C-reactive protein, creatinine, alanine aminotransferase (ALT) and components of metabolic syndrome, the odds ratio for NAFLD, comparing the highest with the lowest SUA quartile, was 2.81 (95% confidence interval 1.66–4.76). A stepwise multivariate linear regression analysis (R2 = 0.238, P<0.001) retained age, waist circumference, serum creatinine, triglycerides, the Q141K variant in ABCG2 (rs2231142) and NAFLD as significant predictors of SUA levels (all P<0.001). Besides, ALT and Met196Arg variant in TNFRSF1B (rs1061622) additionally associated with SUA among individuls with NAFLD. Our data suggest that in Chinese men, elevated SUA is significantly associated with NAFLD, independent of insulin resistance and other metabolic disorders, such as central obesity or hypertriglyceridemia. Meanwhile, among subjects with NAFLD, index of liver damage, such as elevated ALT combined with genetic susceptibility to inflammation associated with increased SUA levels. [ABSTRACT FROM AUTHOR]

Highlights: [•] DMDD attenuates AGEs expression in renal tissue. [•] DMDD blocks NF-κB/TGF-β1 pathway in renal tissue. [•] DMDD relieves renal damage in KKAy mice. [•] DMDD plays an antihyperglycemic effect. [•] DMDD exerts renoprotection in KKAy mice. [Copyright &y& Elsevier]

Abstract: A concise and one-pot cascade method has been developed to achieve the synthesis of difluoroboron-derivatized curcumins (BF2C). Treatment of 2,4-pentanedione with BF3·OEt2, followed by condensation with aldehydes in the presence of tributyl borate and butylamine at 65°C in toluene furnished the corresponding symmetric (s-BF2C) and unsymmetric difluoroboron-derivatized curcumins (us-BF2C) in good (60–99%) and moderate yields (23–42%) within 6–12h, respectively. [Copyright &y& Elsevier]

Abstract: This study was designed to evaluate the potential effects of puerarin (PR), an effective isoflavonoid compound purified from Pueraria lobata, in treating hepatic fibrosis (HF) rats induced by carbon tetrachloride (CCl4, 2mLkg−1 d−1). Compared to model control, PR treatment effectively lowered the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (Alb), total protein (TP) in HF rats. Masson stained analysis showed that the condition of HF rats was mitigated. Meanwhile, the tumor necrosis factor alpha (TNF-α), nuclear factor-kappa B (NF-κB) expressions were significantly down-regulated at protein level by PR intervention. Additionally, the activity of superoxide dismutase (SOD) was elevated, while the content of malondialdehyde (MDA) was lessened in liver tissue. As revealed by immunohistochemistry assay, PR therapy resulted in reduced production of transforming growth factor-βl (TGF-βl). Moreover, it also was attributed to decreased mRNA level of inducible nitric oxide synthase (iNOS) using RT-PCR analysis. These findings demonstrate that puerarin successfully reverses hepatotoxicity in CCl4-induced HF rats via the underlying mechanisms of regulating serum enzymes and attenuating TNF-α/NF-κB pathway for anti-inflammation response, as well as improving metabolic function in liver tissue. [Copyright &y& Elsevier]

Summary: Background: Ubiquitin carboxy-terminal hydrolase (UCH-L1) has been established as a reliable and potential biomarker of neuronal damage after acute neurologic insults such as ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury. The effects of seizures on UCH-L1 levels in cerebrospinal fluid (CSF) has not been investigated in epileptic patients. The aim of the present study was to evaluate whether CSF UCH-L1 levels are a reliable marker of brain damage from epileptic seizures. Methods: Thirty-three patients with epilepsy (mean age 45 years) participated. Twenty-five patients had generalized seizures and eight had partial seizures. CSF was sampled by lumbar puncture. The control samples were obtained from 23 adult patients on whom lumbar puncture was performed to exclude neurological disease. CSF UCH-L1 levels were determined using an enzyme-linked immunosorbent assay (ELISA) kit. Results: Patients with epilepsy had significantly elevated CSF levels of UCH-L1 after seizures compared with controls (p <0.001). CSF UCH-L1 levels were significantly higher in patients with generalized seizures than in patients with partial seizures and controls (p <0.001). Moreover, patients with repetitive generalized tonic–clonic (GTC) seizures had higher CSF UCH-L1 levels than those with a single GTC seizure (p <0.001). CSF UCH-L1 levels in seizure patients showed strong correlation with severity of seizures (r =0.56) and seizure duration (r =0.77). Conversely, CSF UCH-L1 levels in seizure patients did not correlate with the age of patients, duration of epilepsy, age of first seizure, time from last seizure or number of seizures. Conclusions: Our results suggest that UCH-L1 may serve as a novel biomarker for neuronal damage after epileptic seizure. [Copyright &y& Elsevier]

In our effort to develop selective sphingosine kinase-2 (SphK2) inhibitors as pharmacological tools, a thiazolidine-2,4-dione analogue, 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145), was synthesized and biologically characterized. Biochemical assay results indicate that K145 is a selective SphK2 inhibitor. Molecular modeling studies also support this notion. In vitro studies using human leukemia U937 cells demonstrated that K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways. K145 also significantly inhibited the growth of U937 tumors in nude mice by both intraperitoneal and oral administration, thus demonstrating its in vivo efficacy as a potential lead anticancer agent. The antitumor activity of K145 was also confirmed in a syngeneic mouse model by implanting murine breast cancer JC cells in BALB/c mice. Collectively, these results strongly encourage further optimization of K145 as a novel lead compound for development of more potent and selective SphK2 inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: The overall process of field emission can be dominated by the contact resistance between the single wall carbon nanotubes (SWCNTs) and the substrate. In order to reduce the contact resistance, we present a wet chemical process of constructing Ag–SWCNTs hybrid nanostructure. Constructing Ag–SWCNTs emitters could improve the electrical contact by increasing the contact area between SWCNTs and substrate. Contact resistance is greatly reduced compared to that of pristine SWCNTs. Field emission properties of Ag–SWCNTs hybrid emitters including current density and emitting image are remarkably improved. Field emission properties based on the modified Fowler–Nordheim (F–N) equation are discussed. Our studies show that this method can enhance the field emission properties of the SWCNTs by improving the contact resistance and is a promising way for mass production of SWCNTs for field emission display. [Copyright &y& Elsevier]

Abstract: This study was designed to investigate the potential effects of 14days’ intragastrically given of cinnamon polyphenols (CPS) in treating diabetic mice induced by intraperitoneal injection of streptozotocin (150mgkg−1) and fed high-sugar, high-fat diet. The diabetic mice model was successfully established through determining on fasting blood-glucose (FBG) test. As revealed by glucose oxidase (GOD) and radioimmunoassay (RIA), both dimethyldiguanide (DC, 0.6gkg−1 d−1) and CPS (0.3, 0.6, 1.2gkg−1 d−1) treatments significantly resulted in down-regulation of blood glucose and insulin levels in serum, while the levels of oxidative stress markers were markedly lowered through ELISA assay. Meanwhile, the pathological damage in islet with pancreatic beta cells was ameliorated by treatment of CPS at different doses, as shown in HE stain. At the same time, the treatments also caused notable reduction of iNOS, NF-κB expressions showing in Western blot analysis. These findings demonstrate that cinnamon polyphenols can exert the hypoglycemic and hypolipidemic effects through the mechanisms that may be associated with repairing pancreatic beta cells in diabetic mice and improving its anti-oxidative capacity, as well as attenuating cytotoxicity via inhibition of iNOS, NF-κB activation. [Copyright &y& Elsevier]

Objective To examine the association of endogenous sex hormones and sex hormone-binding globulin (SHBG) with C-reactive protein ( CRP) in Chinese men. Design and participants The study population comprised 1989 men at baseline recruitment of a population-based cohort in China. Participant information on risk factors was collected by a face-to-face interview and clinical examination. All subjects in the study were without taking any kind of medication for anti-inflammation purpose or treatment of hypogonadism and with CRP value less than 10 mg/l. Data were analysed using linear regression analyses. Results Higher levels of total testosterone ( TT, β = −0·114, 95% CI, −0·162 to −0·065), free testosterone (β = −0·059, 95% CI, −0·106 to −0·012) and SHBG (β = −0·116, 95% CI, −0·169 to −0·063) were statistically significantly related to lower levels of CRP, after adjustment for age, waist circumference ( WC), triglycerides, high-density lipoprotein cholesterol, fasting glucose, insulin, smoking status, hypertension, diabetes and family history of hypertension or diabetes. In the subgroup of men with body mass index ≥ 27·5 kg/m2 or with metabolic syndrome, findings for TT and SHBG were more pronounced, whereas the associations of TT with CRP were attenuated and nonstatistically significant among subjects with WC ≥ 90 cm or with insulin resistance. No associations were observed between estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and CRP. Conclusions We have confirmed the association of androgens with reduced inflammation as measured by CRP in Chinese men. This is independent of conventional cardiovascular risk factors and is explained in part by markers of central obesity and insulin resistance, rather than metabolic syndrome. [ABSTRACT FROM AUTHOR]

Abstract: Background: Prohibitin (PHB) is an evolutionarily conserved multifunctional protein with ubiquitous expression. However, its molecular roles are largely unknown. Methods: To better understand the function of prohibitin protein in silkworm (BmPHB), its coding sequence was isolated from a cDNA library of silkworm pupae. An His-tagged BmPHB fusion protein was expressed in Escherichia coli Rosetta (DE3) and purified with affinity and reversed-phase chromatography. Purified rBmPHB was used to generate anti-BmPHB polyclonal antibody. The subcellular localization of BmPHB was analysed by immunohistochemistry. Results: BmPHB gene has an ORF of 825bp, encoding a predicted peptide with 274 amino acid residues. Immunostaining indicate that prohibitin is expressed in nucleus and predominately in cytoplasm. Western blot analyses indicated that, in the fifth instar larva, BmPHB was expressed descendingly in gonad, malpighian tubule, trachea, fatty body, intestine, and head. However, no expression was detected in larva''s silk gland and epidermis. In addition, BmPHB was expressed in the nascent egg, larva and pupa, but not in the moth. Conclusions: The expression of BmPHB gene presents differential characteristic in different stage and tissues. It may play important roles in the development of silkworm. General significance: Studies on prohibitin have been still restricted to a few specific insects and insect cell lines such as Drosophila, Acyrthosiphon pisum and mosquito cell lines, not yet in silkworm. This is a first characterization of prohibitin in silkworm, B. mori. [Copyright &y& Elsevier]

Abstract: Dengue virus (DENV) capsid (C) proteins are the major structural component of virus particles. This study aimed to identify the host interacting partners of DENV C protein that could contribute to viral pathogenesis. DENV C protein was screened against human liver cDNA yeast two-hybrid library. We identified calcium modulating cyclophilin-binding ligand (CAML) as a novel interacting partner of DENV C protein. We report for the first time that CAML influenced DENV production. DENV production was significantly attenuated in CAML knock-down cells at 36h post-infection. CAML did not influence DENV entry, genome uncoating, viral transcription, viral translation and virus secretion. Our study pinpointed that CAML influenced the process of apoptosis by altering mitochondrial membrane potential and caspase-3 activation from 36h post-infection. Over-expression of CAML protected Huh7 cells from apoptosis and knock down of CAML favoured apoptosis following infection with DENV. We also showed that CAML expression was up-regulated during DENV infection. Increased CAML levels protected DENV-infected cells from undergoing apoptosis by preventing mitochondrial damage and caspase-3 activation which in turn favoured DENV production from 36h post-infection. Overall, this study demonstrated that DENV manipulated the levels of CAML to subvert the apoptotic process which in turn favoured efficient virus production. [Copyright &y& Elsevier]