ER-anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6.

Excessive deposition of extracellular matrix, mainly collagen protein, is the hallmark of organ fibrosis. The molecular mechanisms regulating fibrotic protein biosynthesis are unclear. Here, we find that chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a plasma membrane receptor for prostaglandin D2, is trafficked to the endoplasmic reticulum (ER) membrane in fibroblasts in a caveolin-1-dependent manner. ER-anchored CRTH2 binds the collagen mRNA recognition motif of La ribonucleoprotein domain family member 6 (LARP6) and promotes the degradation of collagen mRNA in these cells. In line, CRTH2 deficiency increases collagen biosynthesis in fibroblasts and exacerbates injury-induced organ fibrosis in mice, which can be rescued by LARP6 depletion. Administration of CRTH2 N-terminal peptide reduces collagen production by binding to LARP6. Similar to CRTH2, bumetanide binds the LARP6 mRNA recognition motif, suppresses collagen biosynthesis, and alleviates bleomycin-triggered pulmonary fibrosis in vivo. These findings reveal a novel anti-fibrotic function of CRTH2 in the ER membrane via the interaction with LARP6, which may represent a therapeutic target for fibrotic diseases.

Screening and identification of potential hypoglycemic and hypolipidemic compounds from aqueous extract of Scutellaria baicalensis Georgi root combing affinity ultrafiltration with multiple drug targets and in silico analysis.

INTRODUCTION: Scutellaria baicalensis Georgi, a traditional Chinese medicine, is widely applied to treat various diseases among people, especially in East Asia. However, the specific active compounds in S. baicalensis aqueous extracts (SBAEs) responsible for the hypoglycemic and hypolipidemic properties as well as their potential mechanisms of action remain unclear. OBJECTIVES: This work aimed to explore the potential hypoglycemic and hypolipidemic compounds from SBAE and their potential mechanisms of action. METHODOLOGY: The in vitro inhibitory tests against lipase and α-glucosidase, and the effects of SBAE on glucose consumption and total triglyceride content in HepG2 cells were first performed to evaluate the hypoglycemic and hypolipidemic effects. Then, affinity ultrafiltration liquid chromatography-mass spectrometry (LC-MS) screening strategy with five drug targets, including α-glucosidase, α-amylase, protein tyrosine phosphatase 1B (PTP1B), lipase and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) was developed to screen out the potential active constituents from SBAE, and some representative active compounds were further validated. RESULTS: SBAE displayed noteworthy hypoglycemic and hypolipidemic properties, and 4, 10, 4, 8, and 8 potential bioactive components against α-amylase, α-glucosidase, PTP1B, HMGCR, and lipase were initially screened out, respectively. The interaction network was thus constructed between the potential bioactive compounds screened out and their corresponding drug targets. Among them, baicalein, wogonin, and wogonoside were revealed to possess remarkable hypoglycemic and hypolipidemic effects. CONCLUSION: The potential hypolipidemic and hypoglycemic bioactive compounds in SBAE and their mode of action were initially explored through ligand-target interactions by combining affinity ultrafiltration LC-MS strategy with five drug targets.

Novel Engineered SARS-CoV-2 HR1 Trimer Exhibits Improved Potency and Broad-Spectrum Activity against SARS-CoV-2 and Its Variants.

The ongoing pandemic of COVID-19, caused by SARS-CoV-2, has substantially increased the risk to global public health. Multiple vaccines and neutralizing antibodies (nAbs) have been authorized for preventing and treating SARS-CoV-2 infection. However, the emergence and spread of the viral variants may limit the effectiveness of these vaccines and antibodies. Fusion inhibitors targeting the HR1 domain of the viral S protein have been shown to broadly inhibit SARS-CoV-2 and its variants. In theory, peptide inhibitors targeting the HR2 domain of the S protein should also be able to inhibit viral infection. However, previously reported HR1-derived peptide inhibitors targeting the HR2 domain exhibit poor inhibitory activities. Here, we engineered a novel HR1 trimer (HR1MFd) by conjugating the trimerization motif foldon to the C terminus of the HR1-derived peptide. HR1MFd showed significantly improved inhibitory activity against SARS-CoV-2, SARS-CoV-2 variants of concern (VOCs), SARS-CoV, and MERS-CoV. Mechanistically, HR1MFd possesses markedly increased α-helicity, thermostability, higher HR2 domain binding affinity, and better inhibition of S protein-mediated cell-cell fusion compared to the HR1 peptide. Therefore, HR1MFd lays the foundation to develop HR1-based fusion inhibitors against SARS-CoV-2. IMPORTANCE Peptides derived from the SARS-CoV-2 HR1 region are generally poor inhibitors. Here, we constructed a trimeric peptide HR1MFd by fusing the trimerization motif foldon to the C terminus of the HR1 peptide. HR1MFd was highly effective in blocking transductions by SARS-CoV-2, SARS-CoV-2 variants, SARS-CoV, and MERS-CoV pseudoviruses. In comparison with HR1M, HR1MFd adopted a much higher helical conformation, better thermostability, increased affinity to the viral HR2 domain, and better inhibition of S protein-mediated cell-cell fusion. Overall, HR1MFd provides the information to develop effective HR1-derived peptides as fusion inhibitors against SARS-CoV-2 and its variants.

Comparative transcriptome analysis of Saposhnikovia divaricata to reveal drought and rehydration adaption strategies.

BACKGROUND: Water scarcity has become one of the most prevalent environmental factors adversely affecting plant growth and development. Different species have developed multiple ways of drought resistance. Saposhnikovia divaricata is a commonly used traditional herb in East Asia. However, limited information is available on the drought response of this herb and further clarification of underlying molecular mechanism remains a challenge. METHODS AND RESULTS: In this study, a comparative transcriptome analysis was firstly conducted to identify the major pathways and candidate genes involved in the drought adaptive response of S. divaricata. The seedlings of S. divaricata were subjected to progressive drought by withholding water for 16 days followed by 8 days of rehydration. Transcriptome analysis identified a total of 89,784 annotated unigenes. The number of differentially expressed genes (DEGs) gradually increased with the deepening of drought and decreased after rehydration. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested genes related to oxidoreductase activity, carbohydrate metabolism, plant hormone signaling pathway and secondary metabolism were important in drought response of S. divaricata. Specific genes involved in reactive oxygen species scavenging system (POD, Cu/Zn-SOD, APX), abscisic acid and jasmonic acid signaling pathway (PYL4, PP2Cs, JAR1, JAZ) and phenylpropanoid biosynthesis (4CL, CCR, CAD) underwent dynamic alterations under drought and rehydration. Finally, the expression pattern of 12 selected DEGs from the transcriptomic profiling was validated by real-time quantitative PCR. CONCLUSION: Our study laid a foundation for understanding the stress response of S. divaricata and other Apiaceae family plant at molecular level.

Optimization of Tungsten Heavy Alloy Cutting Parameters Based on RSM and Reinforcement Dung Beetle Algorithm.

Tungsten heavy alloys (WHAs) are an extremely hard-to-machine material extensively used in demanding applications such as missile liners, aerospace, and optical molds. However, the machining of WHAs remains a challenging task as a result of their high density and elastic stiffness which lead to the deterioration of the machined surface roughness. This paper proposes a brand-new multi-objective dung beetle algorithm. It does not take the cutting parameters (i.e., cutting speed, feed rate, and depth of cut) as the optimization objects but directly optimizes cutting forces and vibration signals monitored using a multi-sensor (i.e., dynamometer and accelerometer). The cutting parameters in the WHA turning process are analyzed through the use of the response surface method (RSM) and the improved dung beetle optimization algorithm. Experimental verification shows that the algorithm has better convergence speed and optimization ability compared with similar algorithms. The optimized forces and vibration are reduced by 9.7% and 46.47%, respectively, and the surface roughness Ra of the machined surface is reduced by 18.2%. The proposed modeling and optimization algorithms are anticipated to be powerful to provide the basis for the parameter optimization in the cutting of WHAs.

Niacin Attenuates Pulmonary Hypertension Through H-PGDS in Macrophages.

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling, accompanied by varying degrees of perivascular inflammation. Niacin, a commonly used lipid-lowering drug, possesses vasodilating and proresolution effects by promoting the release of prostaglandin D2 (PGD2). However, whether or not niacin confers protection against PAH pathogenesis is still unknown. OBJECTIVE: This study aimed to determine whether or not niacin attenuates the development of PAH and, if so, to elucidate the molecular mechanisms underlying its effects. METHODS AND RESULTS: Vascular endothelial growth factor receptor inhibitor SU5416 and hypoxic exposure were used to induce pulmonary hypertension (PH) in rodents. We found that niacin attenuated the development of this hypoxia/SU5416-induced PH in mice and suppressed progression of monocrotaline-induced and hypoxia/SU5416-induced PH in rats through the reduction of pulmonary artery remodeling. Niacin boosted PGD2 generation in lung tissue, mainly through H-PGDS (hematopoietic PGD2 synthases). Deletion of H-PGDS, but not lipocalin-type PGDS, exacerbated the hypoxia/SU5416-induced PH in mice and abolished the protective effects of niacin against PAH. Moreover, H-PGDS was expressed dominantly in infiltrated macrophages in lungs of PH mice and patients with idiopathic PAH. Macrophage-specific deletion of H-PGDS markedly decreased PGD2 generation in lungs, aggravated hypoxia/SU5416-induced PH in mice, and attenuated the therapeutic effect of niacin on PAH. CONCLUSIONS: Niacin treatment ameliorates the progression of PAH through the suppression of vascular remodeling by stimulating H-PGDS-derived PGD2 release from macrophages.

Association between frailty index based on routine laboratory tests and risk of cerebral small vessel disease in elderly patients: a hospital-based observational study.

BACKGROUND: The association between frailty and cerebral small vessel disease (CSVD) remains controversial due to the use of different methods to assess frailty, including physical frailty phenotype and frailty scores containing measures of cognition. A frailty index based on laboratory tests (FI-Lab), which assesses frailty by the combination of routine laboratory measures and several vital signs, is independent of cognition and function status. We aimed to evaluate the association of FI-Lab with CSVD. METHODS: An observational study was carried out in a hospitalized cohort of older patients with minor ischemic stroke or TIA. The FI-Lab was constructed by 20 routine laboratory tests, plus systolic blood pressure, diastolic blood pressure, and pulse pressure. Manifestations of CSVD including white matter hyperintensity (WMH), silent lacunar infarcts, microbleed, enlarged perivascular spaces (EPVS), as well as deep brain atrophy, were measured on magnetic resonance imaging (MRI). An ordinal score system constructed by WMH, EPVS, silent lacunar infarcts, and microbleed was used to reflect the total burden of CSVD. The associations between FI-lab and CSVD were examined by logistic regression analysis and ordinal regression. RESULTS: A total of 398 patients were recruited from January 2016 to December 2018. The mean FI-Lab value was 0.26 ± 0.11. The prevalence of extensive periventricular WMH, extensive deep WMH, extensive basal ganglia EPVS, extensive centrum semiovale EPVS, silent lacunar infarcts, and deep microbleed was 26.1, 66.6, 68.6, 80.7, 32.9, and 6.5%, respectively. A higher FI-Lab value was associated with increased risks of extensive deep WMH (OR = 1.622; 95% CI, 1.253 ~ 2.100), extensive basal ganglia EPVS (OR = 1.535; 95% CI, 1.187 ~ 1.985), extensive centrum semiovale EPVS (OR = 1.584; 95% CI, 1.167 ~ 2.151), silent lacunar infarcts (OR = 1.273; 95% CI, 1.007 ~ 1.608), and higher total burden of CSVD. These associations remained after the adjustment of potential confounding factors. CONCLUSION: This study demonstrated that a higher FI-Lab score might be associated with the presence of WMH, EPVS, silent lacunar infarcts, as well as severe total CSVD burden in older patients with minor stroke or TIA. The FI-Lab provides a basis for the prediction of CSVD.

Screening and characterisation of potential antioxidant, hypoglycemic and hypolipidemic components revealed in Portulaca oleracea via multi-target affinity ultrafiltration LC-MS and molecular docking.

INTRODUCTION: Portulaca oleracea is a commonly used nutritional vegetable and traditional herbal medicine with plenty of nutrients and manifold pharmacological activities. However, the potential active ingredients for its remarkable antioxidant, hypoglycemic and hypolipidemic activities remain unexplored. OBJECTIVES: The present study aims to systematically evaluate the antioxidant activities of different extracts of P. oleracea and screen bioactive ligands that can interact with α-glucosidase, pancreatic lipase, and superoxide dismutase (SOD). METHODS: In this research, the antioxidant activities of different parts of P. oleracea and their corresponding total phenolic content (TPC) and total flavonoid content (TFC) were systematically determined. Subsequently, a multi-target affinity ultrafiltration method was developed using affinity ultrafiltration with SOD, α-glucosidase, and pancreatic lipase coupled to liquid chromatography-mass spectrometry (UF-LC-MS). Later, molecular docking was used to further investigate the possible interaction mechanism between these ligands and target enzymes. RESULTS: Among them, the ethyl acetate (EA) fraction showed the highest antioxidant activity along with the highest TPC and TFC, and four compounds in the EA fraction were quickly retrieved as potential SOD, α-glucosidase, and pancreatic lipase ligands, respectively. Molecular docking revealed that these potential ligands exhibited strong binding ability and inhibitory activities on SOD, α-glucosidase, and pancreatic lipase. CONCLUSION: The present study revealed that P. oleracea can be used as a functional food with excellent antioxidant, hypoglycemic and hypolipidemic effects. Meanwhile, the integrated strategy based on multi-target UF-LC-MS and molecular docking also provided a powerful tool and a multidimensional perspective for further exploration of active ingredients in P. oleracea responsible for the antioxidant, hypoglycemic and hypolipidemic activities.

Loss of DP1 Aggravates Vascular Remodeling in Pulmonary Arterial Hypertension via mTORC1 Signaling.

Rationale: Vascular remodeling, including smooth muscle cell hypertrophy and proliferation, is the key pathological feature of pulmonary arterial hypertension (PAH). Prostaglandin I2 analogs (beraprost, iloprost, and treprostinil) are effective in the treatment of PAH. Of note, the clinically favorable effects of treprostinil in severe PAH may be attributable to concomitant activation of DP1 (D prostanoid receptor subtype 1).Objectives: To study the role of DP1 in the progression of PAH and its underlying mechanism.Methods: DP1 levels were examined in pulmonary arteries of patients and animals with PAH. Multiple genetic and pharmacologic approaches were used to investigate DP1-mediated signaling in PAH.Measurements and Main Results: DP1 expression was downregulated in hypoxia-treated pulmonary artery smooth muscle cells and in pulmonary arteries from rodent PAH models and patients with idiopathic PAH. DP1 deletion exacerbated pulmonary artery remodeling in hypoxia-induced PAH, whereas pharmacological activation or forced expression of the DP1 receptor had the opposite effect in different rodent models. DP1 deficiency promoted pulmonary artery smooth muscle cell hypertrophy and proliferation in response to hypoxia via induction of mTORC1 (mammalian target of rapamycin complex 1) activity. Rapamycin, an inhibitor of mTORC1, alleviated the hypoxia-induced exacerbation of PAH in DP1-knockout mice. DP1 activation facilitated raptor dissociation from mTORC1 and suppressed mTORC1 activity through PKA (protein kinase A)-dependent phosphorylation of raptor at Ser791. Moreover, treprostinil treatment blocked the progression of hypoxia-induced PAH in mice in part by targeting the DP1 receptor.Conclusions: DP1 activation attenuates hypoxia-induced pulmonary artery remodeling and PAH through PKA-mediated dissociation of raptor from mTORC1. These results suggest that the DP1 receptor may serve as a therapeutic target for the management of PAH.

Correlations between phytochemical fingerprints of Moringa oleifera leaf extracts and their antioxidant activities revealed by chemometric analysis.

INTRODUCTION: Moringa oleifera Lam. is widely cultivated and applied in tropical and subtropical areas. Numerous studies have been focused on the antioxidant capacity of M. oleifera leaves, but its correlated bioactive phytochemicals remain elusive. OBJECTIVE: In order to search for the corresponding chemical compounds from M. oleifera leaves responsible for their antioxidant activity, the correlations between phytochemical fingerprints of 15 batches of M. oleifera leaves and their antioxidant activities were investigated by using chemometric analysis. MATERIAL AND METHODS: Fifteen batches of M. oleifera leaves were extracted with 90% ethanol solution, and their phytochemical fingerprints and antioxidant activities were estimated by using high-performance liquid chromatography-ultraviolet-electrospray ionisation tandem mass spectrometry (HPLC-UV/ESI-MS/MS), and three detected methods, namely 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assay and ferric-reducing antioxidant power (FRAP) assay, respectively. Chemometric analysis was then applied to reveal the correlations between their phytochemical fingerprints and corresponding antioxidant capacity. RESULTS: Fifteen M. oleifera leaf extracts exhibited strong antioxidant activities, in which 24 common compounds were identified by LC-MS. Furthermore, the partial least squares (PLS) analysis indicated that compounds 14, 16, 18 and 23 were the main potential effective components in at least two antioxidant tests. They were identified as kaempferol 3-O-rutinoside, quercetin 3-O-(6″-malonyl-glucoside), kaempferol 3-O-glucoside, and quercetin derivative, respectively. CONCLUSION: The correlations between phytochemical fingerprints of M. oleifera leaf extracts and their corresponding antioxidant capacities were revealed by chemometric analysis, which provides an alternative method for screening for potential bioactive compounds with antioxidant capacity from M. oleifera leaves.

Towards a Clustering Guided Hierarchical Framework for Sensor-Based Activity Recognition.

Human activity recognition plays a prominent role in numerous applications like smart homes, elderly healthcare and ambient intelligence. The complexity of human behavior leads to the difficulty of developing an accurate activity recognizer, especially in situations where different activities have similar sensor readings. Accordingly, how to measure the relationships among activities and construct an activity recognizer for better distinguishing the confusing activities remains critical. To this end, we in this study propose a clustering guided hierarchical framework to discriminate on-going human activities. Specifically, we first introduce a clustering-based activity confusion index and exploit it to automatically and quantitatively measure the confusion between activities in a data-driven way instead of relying on the prior domain knowledge. Afterwards, we design a hierarchical activity recognition framework under the guidance of the confusion relationships to reduce the recognition errors between similar activities. Finally, the simulations on the benchmark datasets are evaluated and results show the superiority of the proposed model over its competitors. In addition, we experimentally evaluate the key components of the framework comprehensively, which indicates its flexibility and stability.

Identifying the Active Site on Graphene Oxide Nanosheets for Ambient Electrocatalytic Nitrogen Reduction.

Identifying the active sites on graphene oxide (GO) nanosheets is of great importance. In situ electroreduction at different potentials is applied to control the oxygenated groups on GO surfaces. Both experiments and theoretical calculations suggest the C═O group is critical for N2 adsorption and activation, guaranteeing the ambient electrocatalytic N2 reduction.

Verteporfin Promotes the Apoptosis and Inhibits the Proliferation, Migration, and Invasion of Cervical Cancer Cells by Downregulating SULT2B1 Expression.

BACKGROUND Cervical cancer threatens women's health worldwide. Verteporfin (VP), a small-molecule YAP1 inhibitor, inhibits cancer cell growth. This study investigated whether VP could inhibit the proliferation and promote the apoptosis of cervical cancer cells by decreasing SULT2B1 expression. MATERIAL AND METHODS Normal and cancerous cervical cell proliferation after VP treatment was detected by CCK-8 assay. HeLa cell migration, invasion, and apoptosis after VP treatment and transfection were analyzed by wound healing assay, transwell assay, and TUNEL assay, respectively. The expression of related proteins was determined by western blot analysis. Western blot and RT-qPCR analysis detected mRNA and protein expression of SULT2B1. RESULTS Different VP concentrations (0.5, 1, 2, and 5 µM) inhibited the viability of HeLa cells and had no obvious effect on H8 cells. Therefore, 5 µM VP was selected for subsequent experiments. VP inhibited the proliferation, migration, and invasion of HeLa cells and promoted their apoptosis. Bcl-2 expression decreased, and expression of Bax, caspase-3, and caspase-9 in VP-treated HeLa cells increased. SULT2B1 expression increased in cervical cancer cells compared with normal cervical cells. Furthermore, SULT2B1 expression increased in HeLa cells and VP suppressed SULT2B1 expression. SULT2B1 overexpression reduced the inhibiting effect of VP on the proliferation, migration, and apoptosis of HeLa cells, and reduced VP effect on apoptosis of HeLa cells. SULT2B1 overexpression upregulated the Bcl-2 expression and downregulated the expression of Bax, caspase-3, and caspase-9 in VP-treated HeLa cells. CONCLUSIONS VP inhibited the proliferation, migration, and invasion and promoted apoptosis of cervical cancer cells by decreasing SULT2B1 expression.

Recent Advances in Molecular Docking for the Research and Discovery of Potential Marine Drugs.

Marine drugs have long been used and exhibit unique advantages in clinical practices. Among the marine drugs that have been approved by the Food and Drug Administration (FDA), the protein-ligand interactions, such as cytarabine-DNA polymerase, vidarabine-adenylyl cyclase, and eribulin-tubulin complexes, are the important mechanisms of action for their efficacy. However, the complex and multi-targeted components in marine medicinal resources, their bio-active chemical basis, and mechanisms of action have posed huge challenges in the discovery and development of marine drugs so far, which need to be systematically investigated in-depth. Molecular docking could effectively predict the binding mode and binding energy of the protein-ligand complexes and has become a major method of computer-aided drug design (CADD), hence this powerful tool has been widely used in many aspects of the research on marine drugs. This review introduces the basic principles and software of the molecular docking and further summarizes the applications of this method in marine drug discovery and design, including the early virtual screening in the drug discovery stage, drug target discovery, potential mechanisms of action, and the prediction of drug metabolism. In addition, this review would also discuss and prospect the problems of molecular docking, in order to provide more theoretical basis for clinical practices and new marine drug research and development.

Research advances in traditional and modern use of Nelumbo nucifera: phytochemicals, health promoting activities and beyond.

Nelumbo nucifera, or sacred lotus, has been valuable for us to use as vegetable, functional food, and herb medicine for over 2,000 years. The purpose of this article is to systematically review the traditional/modern uses, chemical compositions and pharmacological activities on different parts of N. nucifera. Traditionally, this plant has been used to treat chronic dyspepsia, hematuria, insomnia, nervous disorders, cardiovascular diseases, and hyperlipidemia. Now, phytochemical investigations on different parts of N. nucifera have indicated a wide spectrum of at least 255 constituents belonging to different chemical groups, including proteins, amino acids, polysaccharides, starch, flavonoids, alkaloids, essential oils, triterpenoids, steroids, and glycosides. Meanwhile, its pharmacological activities, including anti-obesity, antioxidant, anti-inflammatory, cardiovascular, hepatoprotective, hypoglycemic, hypolipidemic, antitumor, memory-improving and antiviral activities, have also been reviewed, together with its applications in health food industry and clinic uses of its single plant or herbal formulae. Herein, this review will provide state-of-the-art overview on its traditional and modern uses in food industry and medicines, together with the comprehensive profiles of phytochemicals, and health promoting bioactivities of this valuable plant. In addition, the new perspectives and future challenges in the research on lotus are also outlined.

Thiol-ene click reaction-induced fluorescence enhancement by altering the radiative rate for assaying butyrylcholinesterase activity.

Butyrylcholinesterase (BChE) generally acts as an important plasma biomarker for clinical diagnosis due to its major contribution to human plasma cholinesterase levels, but its current fluorometric assay relying on fluorogenic substrates frequently suffers from the lack of sufficiently fast response time and specific recognition of substrates relative to the traditional Ellman's method. In this work, we report a fluorescent molecular probe for assaying BChE activity based on thiol-triggered fluorescence enhancement via thiol-ene click reactions. A low-temperature experiment and theoretical analysis exclude the possibility of weak fluorescence of the probe caused by an intramolecular photoinduced electron transfer process and support the main cause of an ultraslow radiative rate due to the introduction of two acrylyl groups. This probe has sensitive fluorescence responses to thiols via thiol-ene click chemistry, and it can distinguish between glutathione and cysteine or homocysteine in different emission colors. The rapid reaction kinetics of this probe enables it to monitor hydrolysis reactions catalyzed by butyrylcholinesterase (BChE) in a real-time manner. This probe is used to develop the first fluorometric assay of BChE activity based on fluorescence enhancement triggered by thiol-ene click chemistry using butyrylthiocholine as the substrate. The established BChE assay shows excellent sensitivity, and is capable of avoiding the interference from glutathione and acetylcholinesterase (AChE) in a complex matrix. The inhibition test of tacrine on BChE with this assay substantiates its feasibility in screening potential inhibitors of BChE. This work demonstrates a design strategy of fluorescent probes lighted up by thiol-ene click reactions, reveals the main cause of thiol-triggered fluorescence enhancement by altering the radiative rate, and provides the first fluorometric assay of BChE based on rapid thiol-ene click reactions.

Viscosity-sensitive thiolated gold nanoclusters with diffusion-controlled emission for intracellular viscosity imaging.

A unique diffusion-dependent emission phenomenon of gold nanoclusters was discovered, and can be regulated by the variation in viscosity and temperature. This specific property of gold nanoclusters was further used for viscosity monitoring in live cells, and the results demonstrated that gold nanoclusters are capable of real-time monitoring the abnormal viscosity change inside the cells.

Activating Graphyne Nanosheet via sp-Hybridized Boron Modulation for Electrochemical Nitrogen Fixation.

Exploring new metal-free catalysts with high activity for nitrogen reduction reaction (NRR) is highly desirable but remains a big challenge. Graphyne (GY) is a typical two-dimensional carbon material with many excellent properties. However, the NRR has rarely been envisaged on a GY-based metal-free catalyst up to now. Density functional theory calculations reveal that although pristine GY is inactive for N2 reduction, boron modulation can endow it with efficient activity toward NRR. Natural bond orbitals analysis, spin/charge density distributions, and free energy change diagrams are performed and discussed. Three boron doping formats including sp2-substituted, sp-substituted, and adsorbed configuration are considered. The obtained data show sp-substitution will induce local moderate spin and charge densities at the boron site on the GY surface, which is convenient for N2 adsorption and activation, and conductive to N-related intermediates formation and transformation. Moreover, the incorporated sp-hybridized boron can provide one empty p orbital and one occupied p orbital around itself, which plays a key role as an electron reservoir to accept electrons from and donate electrons to the adsorbed N-related species, and thus facilitate N2 reduction and ammonia synthesis. Henceforth, it provides more opportunities for preparing GY and other carbon materials as efficient catalysts toward renewable energy conversion and storage.

The association of circulating irisin with metabolic risk factors in Chinese adults: a cross-sectional community-based study.

BACKGROUND: Irisin is a myokine that leads to increased energy expenditure by stimulating the browning of white adipose tissue. We aimed to investigate the association of serum irisin levels with metabolic parameters in middle aged Chinese population. METHODS: The study was based on a cross-sectional analysis of data from 524 nondiabetic subjects aged 40~65. All participants were recruited from a screening survey for Metabolic Syndrome in a community in Southwest China, including 294 subjects categorized as overweight (defined as BMI≧25 kg/m2) and 230 subjects as normal control (defined as 18.5≦BMI < 25 kg/m2). Serum irisin concentration was quantified by enzyme linked immunosorbent assay (ELISA). The relationship of irisin with metabolic factors was determined by Pearson correlation. Multivariate linear regression was used to analyze the association of irisin with insulin resistance. Logistic regression was performed to assess the association of irisin with odds of overweight. RESULTS: Serum irisin levels were significantly lower in nondiabetic overweight subjects compared with control (11.46 ± 4.11vs14.78 ± 7.03 µg/mL, p = 0.02). Circulating irisin was positively correlated with quantitative insulin sensitivity check index (QUICKI, r = 0.178, p = 0.045) and triglycerides (r = 0.149, p = 0.022); while irisin was negatively correlated with waist circumference (WC, r = - 0.185, p = 0.037), waist-to-hip ratio (WHR, r = - 0.176, p = 0.047), fasting insulin (r = - 0.2, p = 0.024), serum creatinine (r = - 0.243, p = 0.006), homeostasis model assessment for insulin resistance (HOMA-IR, r = - 0.189, p = 0.033). Multiple linear regression showed that irisin was inversely associated with HOMA-IR (ß = - 0.342 ± 0.154, p = 0.029). Higher irisin was associated with decreased odds of being overweight (OR = 0.281, ß = - 1.271, p = 0.024). CONCLUSIONS: We found that serum irisin levels were lower in overweight subjects. Moreover, serum irisin levels were inversely correlated with adverse metabolic parameters including WC, WHR, creatinine, HOMA-IR and fasting insulin, suggesting that irisin may play a role in obesity related insulin resistance.

Comparative and chemometric analysis of correlations between the chemical fingerprints and anti-proliferative activities of ganoderic acids from three Ganoderma species.

INTRODUCTION: Investigation on ganoderic acids (GAs) from different cultivars and origins of Ganoderma species, regarding to their composition, contents and bioactivities, will be of great importance for the development and quality control of Ganoderma-based healthcare products or drugs. OBJECTIVE: Comparative and chemometric analysis of different Ganoderma species were conducted to reveal the correlations between their chemical fingerprints and anti-proliferative activities. METHODOLOGY: Six Ganoderma samples with different origins and parts of fruiting body (pileus and stipe) were extracted with chloroform and enriched by a SPE-C18 cartridge. The eluents were used for high-performance liquid chromatography ultraviolet electrospray ionisation tandem mass spectrometry (HPLC-UV/ESI-MS/MS) analysis and cytotoxicity assay with three cancer cell lines (SGC-7901, HT-29 and Hep G2). Chemometric analysis was applied to correlate their chemical compositions and corresponding bioactivities. RESULTS: Sixteen peaks (accounting for 70% of the total peak areas) were identified as GAs, and their contents ranged from 0.368 to 10.8 µg/g in various Ganoderma species. The extracts from three Ganoderma species had significant anti-proliferative activities (inhibitory rates ranged from 70.8% to 80.7%), and extracts from Lurongzhi showed remarkable inhibition to all three cancer cells (inhibitory rates range from 81.6% to 92.1%). Finally, chemometric analysis revealed that 3,7,12-trihydroxy-4,4,14-trimethyl-11,15-dioxochol-8-en-24-oic acid and 12-acetoxy-15-hydroxy-4,4,14-trimethyl-3,7,11-trioxochol-8-en-24-oic acid were the two compounds with most potential anti-proliferative activity for SGC-7901. CONCLUSION: The correlations between chemical fingerprints and anti-proliferative activities of various Ganoderma species give remarkable insight into the true bioactive components of chemical markers for the quality assessment of the Ganoderma resources, and provide a good guidance for the study on the chemical spectrum-bioactivity relationship.