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Lead (II) (Pb(II)) is widespread in water and very harmful to creatures, and the efficient removal of it is still challenging. Therefore, we prepared a novel sponge-like polymer-based absorbent (poly(amic acid), PAA sponge) with a highly porous structure using a straightforward polymer self-assembly strategy for the efficient removal of Pb(II). In this study, the effects of the pH, dosage, adsorption time and concentration of Pb(II) on the adsorption behavior of the PAA sponge are investigated, revealing a rapid adsorption process with a removal efficiency up to 89.0% in 2 min. Based on the adsorption thermodynamics, the adsorption capacity increases with the concentration of Pb(II), reaching a maximum adsorption capacity of 609.7 mg g−1 according to the Langmuir simulation fitting. Furthermore, the PAA sponge can be efficiently recycled and the removal efficiency of Pb(II) is still as high as 93% after five adsorption–desorption cycles. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy analyses reveal that the efficient adsorption of Pb(II) by the PAA sponge is mainly due to the strong interaction between nitrogen-containing functional groups and Pb(II), and the coordination of oxygen atoms is also involved. Overall, we propose a polymer self-assembly strategy to easily prepare a PAA sponge for the efficient removal of Pb(II) from water. [ABSTRACT FROM AUTHOR]

The facile preparation of non-noble metal nanoparticle loaded carbon nanomaterials is promising for efficient oxygen reduction reaction (ORR) electrocatalysis. Herein, a facile preparation strategy is proposed to prepare nitrogen-doped carbon sponge loaded with fine cobalt nanoparticles by the direct pyrolysis of the cobalt ions adsorbed polymeric precursor. The polymeric sponge precursor with continuous framework and high porosity is formed by the self-assembly of a poly(amic acid). Taking advantage of the negatively charged surface and porous structure, cobalt ions can be efficiently adsorbed into the polymeric sponge. After pyrolysis, fine cobalt nanoparticles covered by carbon layers are formed, while the sponge-like structure of the precursor is also well-preserved in order to give cobalt nanoparticles loaded nitrogen-doped carbon sponges (Co/CoO@NCS) with a high loading content of 44%. The Co/CoO@NCS exhibits promising catalytic activity toward ORR with a half-wave potential of 0.830 V and a limiting current density of 4.71 mA cm−2. Overall, we propose a facile polymer self-assembly strategy to encapsulate transition metal nanoparticles with high loading content on a nitrogen-doped carbon sponge for efficient ORR catalysis. [ABSTRACT FROM AUTHOR]

Signaling between the C C chemokine receptor 2 (CCR2) with its ligand, monocyte chemoattractant protein-1 (MCP-1) promotes cancer progression by directly stimulating tumor cell proliferation and downregulating the expression of apoptotic proteins. Additionally, the MCP-1/CCR2 signaling axis drives the migration of circulating monocytes into the tumor microenvironment, where they mature into tumor-associated macrophages (TAMs) that promote disease progression through induction of angiogenesis, tissue remodeling, and suppression of the cytotoxic T lymphocyte (CTL) response. In order to simultaneously disrupt MCP-1/CCR2 signaling and target CCR2-expressing cancer cells for drug delivery, KLAK-MCP-1 micelles consisting of a CCR2-targeting peptide sequence (MCP-1 peptide) and the apoptotic KLAKLAK peptide were synthesized. In vitro , KLAK-MCP-1 micelles were observed to bind and induce cytotoxicity to cancer cells through interaction with CCR2. In vivo, KLAK-MCP-1 micelles inhibited tumor growth (34 ± 11%) in a subcutaneous B16F10 murine melanoma model despite minimal tumor accumulation upon intravenous injection. Tumors treated with KLAK-MCP1 demonstrated reduced intratumor CCR2 expression and altered infiltration of TAMs and CTLs as evidenced by immunohistochemical and flow cytometric analysis. These studies highlight the potential application of CCR2-targeted nanotherapeutic micelles in cancer treatment. Unlabelled Image • KLAK-MCP-1 micelles combine apoptotic peptides (KLAK) with CCR2-binding ligands (MCP-1) for targeted therapy of CCR2+ cancer. • KLAK-MCP-1 micelles exhibited CCR2-dependent binding and toxicity to cancer cells and monocytes in vitro. • KLAK-MCP-1 micelles inhibited tumor growth and altered tumor-infiltrating macrophage and cytotoxic T lymphocyte populations. [ABSTRACT FROM AUTHOR]

Androgen receptor (AR) regulation pathways are essential for supporting the growth and survival of prostate cancer cells. Recently, sub-populations of prostate cancer cells have been identified with stem cell features and are associated with the emergence of treatment-resistant prostate cancer. Here, we explored the function of AR in prostate cancer-associated fibroblasts (CAFs) relative to growth and stem cell-associated characteristics. CAFs were isolated from the murine cPten-/-L prostate cancer model and cultured with human prostate cancer epithelial (hPCa) cells. A murine-specific AR antisense oligonucleotide (ASO) was used to suppress the expression of AR in the CAF cells. CAFs express low, but significant levels of AR relative to fibroblasts derived from non-malignant tissue. CAFs promoted growth and colony formation of hPCa cells, which was attenuated by the suppression of AR expression. Surprisingly, AR-depleted CAFs promoted increased stem cell marker expression in hPCa cells. Interferon gamma (IFN-γ) and macrophage colony-stimulating factor (M-CSF) were increased in AR-depleted CAF cells and exhibited similar effects on stem cell marker expression as seen in the CAF co-culture systems. Clinically, elevated IFN-γ expression was found to correlate with histologic grade in primary prostate cancer samples. In summary, AR and androgendependent signaling are active in CAFs and exert significant effects on prostate cancer cells. IFN-γ and M-CSF are AR-regulated factors secreted by CAF cells, which promote the expression of stem cell markers in prostate cancer epithelial cells. Understanding how CAFs and other constituents of stromal tissue react to anti-cancer therapies may provide insight into the development and progression of prostate cancer. [ABSTRACT FROM AUTHOR]

This study aims to explore the impact of symbolic and numerical representations in asymmetric visual search. Heterogeneous and homogeneous mathematical units, letters, symbols and numbers were used in the first and second experiments, respectively. Target was searched among 6 or 12 stimuli. Analysis showed that the search efficiency was greatest in LaS (large among small), but the performance decreased significantly in SaS (small among small). Moreover, LaS was faster than SaL (small among large). However, SaL was faster than LaL (large among large) and LaL was faster than SaS. The findings of this study showed that the search efficiency was indirectly proportional to the number of stimuli. This implies that processing of visual stimuli of different sizes and appearance was asymmetric, all requiring varied attention. In summary, these findings strengthen the integration theory, similarity theory and guided search model. • The more obvious the difference between target and interference items, the faster the visual search speed. • Symbolic and numerical representations affected the asymmetric visual search together in the more difficult task. • Symbolic and numerical representations affected the asymmetric visual search together in heterogeneaous materials. • Task difficulty influenced the joint mechanism of symbolic and numerical representations in asymmetric visual search. • Integration theory, similarity theory and guided search model were strengthened. [ABSTRACT FROM AUTHOR]

Summary: Type 2 (non-insulin-dependent) diabetes mellitus is a progressive metabolic disorder arising from genetic and environmental factors that impair beta cell function and insulin action in peripheral tissues. We identified reduced diacylglycerol kinase δ (DGKδ) expression and DGK activity in skeletal muscle from type 2 diabetic patients. In diabetic animals, reduced DGKδ protein and DGK kinase activity were restored upon correction of glycemia. DGKδ haploinsufficiency increased diacylglycerol content, reduced peripheral insulin sensitivity, insulin signaling, and glucose transport, and led to age-dependent obesity. Metabolic flexibility, evident by the transition between lipid and carbohydrate utilization during fasted and fed conditions, was impaired in DGKδ haploinsufficient mice. We reveal a previously unrecognized role for DGKδ in contributing to hyperglycemia-induced peripheral insulin resistance and thereby exacerbating the severity of type 2 diabetes. DGKδ deficiency causes peripheral insulin resistance and metabolic inflexibility. These defects in glucose and energy homeostasis contribute to mild obesity later in life. [Copyright &y& Elsevier]

Effects of diverse stimuli, including insulin, muscle contraction, and phorbol 12-myristate-13-acetate (PMA), were determined on phosphorylation of mitogen-activated protein kinase (MAPK) signaling modules (c-Jun NH(2)-terminal kinase [JNK], p38 MAPK, and extracellular signal-related kinase [ERK1/2]) in skeletal muscle from lean and ob/ob mice. Insulin increased phosphorylation of JNK, p38 MAPK, and ERK1/2 in isolated extensor digitorum longus (EDL) and soleus muscle from lean mice in a time- and dose-dependent manner. Muscle contraction and PMA also elicited robust effects on these parallel MAPK modules. Insulin action on JNK, p38 MAPK, and ERK1/2 phosphorylation was significantly impaired in EDL and soleus muscle from ob/ob mice. In contrast, muscle contraction-mediated JNK, p38 MAPK, and ERK1/2 phosphorylation was preserved. PMA effects on phosphorylation of JNK and ERK1/2 were normal in ob/ob mice, whereas effects on p38 MAPK were abolished. In conclusion, insulin, contraction, and PMA activate MAPK signaling in skeletal muscle. Insulin-mediated responses on MAPK signaling are impaired in skeletal muscle from ob/ob mice, whereas the effect of contraction is generally well preserved. In addition, PMA-induced phosphorylation of JNK and ERK1/2 are preserved, whereas p38 MAPK pathways are impaired in skeletal muscle from ob/ob mice. Thus, appropriate MAPK responses can be elicited in insulin-resistant skeletal muscle via an insulin-independent mechanism. [ABSTRACT FROM AUTHOR]

The stimuli‐responsive transition of nanostructures from amorphous to crystalline state is of high interest in polymer science, but is still challenging. Herein, the transformation of amorphous nanobowls to crystalline ellipsoids triggered by UV induced trans‐cis isomerization is demonstrated, using an azobenzene‐containing amphiphilic homopolymer (PAzoAA) as a building block. The amide bond and azobenzene pendants are introduced to the side chain of PAzoAA to afford hydrogen bonding and π–π interactions, which promote the formation of nanobowls rather than spherical nanostructures. Upon exposure to UV irradiation, trans‐cis isomerization of azobenzene pendants occurs, leading to the increase of hydrophilicity and destruction of π–π interaction, further resulting in the disassembly of the nanobowls. Then the PAzoAA re‐assembles to form crystalline ellipsoids instead of amorphous nanostructures when recovered at 70 °C without UV light. Further, it is confirmed that the high incubation temperature after UV irradiation is critical for the cis‐trans transformation and the high mobility of the polymer chains to facilitate the regular rearrangement of azobenzene pendants. Overall, a facile method to achieve the transformation of amorphous nanobowls to crystalline ellipsoids is proposed, which may bring new insight into preparation of crystalline nanoparticles using amorphous precursors. [ABSTRACT FROM AUTHOR]

• MiRNA and lncRNA can be used as potential biomarkers for gout. • Noncoding RNA mediates four pathogenesis processes of gout. • The possible therapeutic targets of miRNAs and lncRNAs in gout. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are both types of noncoding RNA. They have been demonstrated to be involved in the regulation of various human inflammatory diseases and can be used as biomarkers for disease diagnosis and prognosis, and even be developed into new drugs. Gout is an arthritic disease caused by the deposition of monosodium urate crystal (MSU) in the joints, which can lead to acute inflammation and damage adjacent tissue. Recent studies have shown that miRNAs and lncRNAs mediate the progress of gout. Based on the pathogenesis of gout, including hyperuricemia, MSU deposition, acute gouty arthritis and gouty bone erosion, this paper reviewed the role of miRNAs and lncRNAs in the processes and the possible therapeutic targets of miRNAs and lncRNAs in gout. [ABSTRACT FROM AUTHOR]

Does reading Pinyin, a Roman alphabet transcription of Chinese, cause the implicit activation of the corresponding Chinese character? To address this question, we carried out two experiments with adult Chinese learners, measuring interference in character reading in a modified Stroop task. Participants first made a meaning judgment on a Pinyin word, and then judged the printed color of a character that was either visually related or unrelated to the character that corresponded to the Pinyin word. A character orthographic interference effect was observed for advanced Chinese learners but not intermediate Chinese learners. The proficiency-dependent emergence of this interference effect suggests its dependence on Chinese character reading experience. For models of Chinese reading, the results demonstrate the role of the character as a gateway to meaning that, through reading experience, comes to be routinely involved in reading for meaning, whether the input is a character or an alphabetic spelling. [ABSTRACT FROM AUTHOR]

Written word recognition in Chinese links the perception of individual characters with whole words. With experience in reading, a high-quality word representation can provide top-down influence on the perception of its constituent characters, thus producing a word superiority effect (WSE). In experiments using the Reicher–Wheeler paradigm, we examined the WSE in two-character words for native Chinese readers (Experiment 1) and low-proficiency adult Chinese learners with Thai (Experiment 2a) and Indonesian (Experiment 2b) as native language backgrounds. For native Chinese readers, the WSE was smaller for high-frequency than low-frequency characters, reflecting rapid access to more frequently experienced characters and a consequent reduction of top-down word-level effects. Learners of Chinese, however, showed a strong WSE for both low-frequency and high-frequency characters, reflecting less well-established character representations combined with word-level knowledge sufficient to support character recognition. The results suggest that native Chinese readers develop strong representations at both the character and the word level, while low-proficiency Chinese learners are more dependent on the word level. We discuss the possibility that a word-level emphasis Chinese foreign language instruction is one reason for this pattern. [ABSTRACT FROM AUTHOR]

In view of the high incidence of diabetic retinopathy and the functionality of long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) in different disease models, the present study aimed to investigate the role of MEG3 in diabetic retinopathy. In the study, patients with diabetic retinopathy, diabetic patients without retinopathy as well as healthy people were included. Fasting blood was extracted from each participant. Serum MEG3 levels were detected by everse transcription-quantitative polymerase chain reaction (RT-qPCR) and serum vascular endothelial growth factor (VEGF) and transforming growth factor-ß1 (TGF-ß1) levels were detected by ELISA. Also, the effects of high glucose treatment on the expression of MEG3 and VEGF and the effects of MEG3 overexpression on expression of VEGF and TGF-ß1 in high glucose-treated ARPE-19 cells were detected by RT-qPCR and western blot analysis to determine the mRNA and protein levels, respectively. It was indicated that serum levels of MEG3 were significantly lower, while the serum levels of VEGF and TGF-ß1 were significantly higher in patients with diabetic retinopathy and diabetic patients without retinopathy compared with the healthy controls. Furthermore, slight differences were found between patients with diabetic retinopathy and diabetic patients without retinopathy; however, these differences were not significant. The findings indicated that high glucose upregulated the expression of VEGF mRNA and downregulated the expression of MEG3, MEG3 overexpression reduced the increased expression levels of VEGF and TGF-ß1 induced by high glucose treatment. Therefore, it was concluded that lncRNA MEG3 overexpression may inhibit the development of diabetic retinopathy by inhibiting TGF-ß1 and VEGF expression. [ABSTRACT FROM AUTHOR]

The Werner syndrome protein ( WRN) is a nuclear protein required for cell growth and proliferation. Loss-of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases. How loss of WRN limits cell proliferation and induces replicative senescence is poorly understood. Here, we show that WRN depletion leads to a striking metabolic shift that coordinately weakens the pathways that generate reducing equivalents for detoxification of reactive oxygen species and increases mitochondrial respiration. In cancer cells, this metabolic shift counteracts the Warburg effect, a defining characteristic of many malignant cells, resulting in altered redox balance and accumulation of oxidative DNA damage that inhibits cell proliferation and induces a senescence-like phenotype. Consistent with these findings, supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN-knockdown cancer cells. These results demonstrate that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress. [ABSTRACT FROM AUTHOR]

A series of benzopyran derivatives was synthesized and their insulin-sensitizing activities were evaluated in 3T3-L1 cells. Compounds 6 and 11 exhibited more potent insulin-sensitizing activity than rosiglitazone. [Copyright &y& Elsevier]

Non-alcoholic steatohepatitis (NASH) is the progressive stage of non-alcoholic fatty liver disease that may ultimately lead to cirrhosis and liver cancer, and there are few therapeutic options for its treatment. Physalin B (PB), a withanolide isolated from Physalis species (Solanaceae), exhibits a broad spectrum of biological activities, however, the potential role of PB in NASH has not been evaluated. The present study investigated the protective effects of PB against NASH and further elucidated the mechanisms of PB in hepatic autophagy and oxidative stress in vitro and in vivo. We conducted a series of experiments using methionine-choline deficient (MCD) diet induced NASH mice and cultured L02 cells. Serum markers of liver injury, morphology, and the histology of liver tissues were investigated. Western blot assays and quantitative real-time PCR were used to investigate the hepatoprotective effect of PB. PB significantly ameliorated hepatic injury, including hepatic index, transaminase activities, histology, and inflammation in MCD-induced mice. Moreover, PB markedly increased the expression of P62 and the ratio of LC3Ⅱ/Ⅰ in vitro and in vivo. Furthermore, PB promoted the interaction between endogenous KEAP1 and P62, reduced the interaction between KEAP1 and NRF2, activated the nuclear translocation of NRF2 and NRF2 target gene expression, and ultimately attenuated oxidative stress. In addition, knockdown of P62 blocked PB-mediated activation of NRF2 in L02 cells. These results clearly indicated that PB ameliorated NASH by stimulating autophagy and P62-KEAP1-NRF2 antioxidative signaling, suggesting that PB is expected to become a novel therapeutic drug for NASH. Image 1 • PB attenuated NASH progression. • PB upregulated the autophagy activity. • PB upregulated the expression and nuclear translocation of NRF2. • PB increased P62 expression and interfered with the interaction between KEAP1 and NRF2. [ABSTRACT FROM AUTHOR]

Recently, cosmic ray albedo neutron decay (CRAND) has been identified as the main source of relativistic electrons measured at the inner edge of inner radiation belt. Here we introduce a drift‐source model that includes azimuthal drift and a CRAND electron source to simulate the quasi‐trapped electron distribution measured by the DEMETER satellite during 20–30 April 2010. The simulated longitude distribution of quasi‐trapped electron fluxes at the inner edge of inner radiation belt successfully reproduces the DEMETER observations, confirming CRAND as the main source for these electrons. Furthermore, a comparison of the energy spectrum and the L distribution of the quasi‐trapped relativistic electrons between simulations and observations further suggests that CRAND is likely the dominant source for 300–700‐keV quasi‐trapped electrons at L < 2 and L ≈ 3. Plain Language Summary: Cosmic rays are mostly high‐energy protons origin form supernovae in our galaxy. By interacting with neutral atoms in the Earth's upper atmosphere, cosmic rays can produce albedo neutrons with a mean lifetime of 887 s. An albedo neutron decays into a proton, an electron, and an antineutrino. This process is called cosmic ray albedo neutron decay, or CRAND. Li et al. (2017; https://doi.org/10.1038/nature24642) find that quasi‐trapped electrons near the inner edge of the inner radiation belt measured by the Colorado Student Space Weather Experiment CubeSat are CRAND‐produced. CRAND‐produced electrons can accumulate during the drift and electron flux increase with longitude before reaching South Atlantic Anomaly. In return, the quasi‐trapped electron fluxes can be used to infer the neutron density in the near‐Earth space. Here we report a modeling study to reproduce this drift accumulation process. Key Points: The first modeling effort is made for quasi‐trapped electrons from CRAND in the inner radiation beltThe simulated longitude distribution of quasi‐trapped electrons from CRAND reproduces the observationsQuantitative understanding of the CRAND‐produced electrons in the inner belt and slot region is achieved based on the modeling effort [ABSTRACT FROM AUTHOR]

Free fatty acid receptor 1 (FFAR1/GPR40) attracted significant attention as a potential target for developing novel antidiabetic drugs because of its unique mechanism in glucose homeostasis. Several reports have expressed concerns about central nervous system (CNS) penetration of GPR40 agonists, which is possibly attributed to their high lipophilicity and low total polar surface area. Herein, we report our efforts to improve the physicochemical properties and pharmacokinetic profiles of LY2881835, a GPR40 agonist that had undergone Phase I clinical trial, through a series of structural optimizations. We identified an orally efficacious compound, 15k , which possessed increased plasma exposure, prolonged half-life and reduced CNS exposure and liver to plasma distribution ratio compared with LY2881835. 15k is a potentially valuable lead compound in the development of safe and efficacious GPR40-targeted drugs to treat type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Adipose triglyceride lipase ( ATGL) is a rate-limiting enzyme that mobilizes fatty acids from cellular triglyceride stores. Metabolic syndrome, which refers to a group of abnormalities that occur together and increase the risk of coronary artery disease, stroke, type 2 diabetes, and cachexia, can be treated using ATGL-specific inhibitors. Atglistatin ( 1) is the first small-molecule inhibitor of ATGL. In this study, we designed and synthesized 29 Atglistatin derivatives and evaluated their inhibition of forskolin-stimulated lipolysis in 3T3-L1 adipocytes as an indicator of their potential to inhibit ATGL in adipose tissues. Among all the tested Atglistatin analogs, we previously found that the thiourea compound 9e showed potent ATGL inhibitory activity in vitro, which was much stronger than that of Atglistatin, and its inhibitory activity in vivo was similar to that of Atglistatin. This tool compound could be used to study the pathophysiology and druggability of ATGL in animal models of metabolic disease and cachexia. [ABSTRACT FROM AUTHOR]

Many transverse studies have found that athletes can better anticipate the outcome of sequential actions belonging to their domain of motor expertise than non-athletes. However, few studies have causally investigated this issue. Using badminton training as an example, the present study attempted to explore whether sports training affected the same-domain action anticipation ability of adult novices and the related neural mechanisms. To address this issue, participants in the training group attended a 12-week badminton training course (1 h/time, 3 times/week). Both the training and control groups were asked to view badminton video clips and predict the landing position of a shuttle before and after 12 weeks. Compared to the control group, the training group showed a decrease in the inverse efficiency score, indicating that badminton training did improve trainees’ action anticipation ability. Furthermore, the training group produced larger N2 and P3 components of event-related potential after the training. These findings suggest that sport training may affect inhibitory processes and memory encoding during same-domain action anticipation. [ABSTRACT FROM AUTHOR]

The system of polarimetric SAR is introduced and internal calibration schemes are discussed. The measurement method of crosstalk between horizontal (H) and vertical (V) polarization channels using internal calibration loops is proposed. Couplers at H and V polarization antennas are designed to hold different coupling factors to make the crosstalk measurable. The compensation model for the polarization scattering matrix is proposed and discussed. As a result, the crosstalk can be tracked with internal calibration and the polarization scattering matrix can be compensated. Simulations are conducted to research the measurement accuracy of crosstalk. [ABSTRACT FROM AUTHOR]

Interferogram denoising is important for height reconstruction and deformation measurement. For high-resolution interferograms over heterogeneous areas, local biases and resolution losses may appear due to the violation of the local stationarity assumption. To address this problem, an iteratively refined nonlocal filter is proposed, whose estimation is refined iteratively by jointly using the amplitude, interferometric phase, coherence, and the pre-estimated patches. For nonlocal interferometric synthetic aperture radar (InSAR) techniques, the similarity of two pixels is computed via their surrounding patches, followed by the maximum likelihood weighted averaging of similar pixels. In this letter, the outliers in the search window is identified before the weight calculation. If the normalized probability density function (NPDF) of the central pixel and other surrounding pixels in the search window is less than the preset threshold, the pixel will be assigned with the minimum weight in the search window. Moreover, the denoising weight is calculated not only depending on the probabilistic patch-based (PPB) similarity, but also the coherence of the pixels in the search window. Both simulated and real data experiments are used to validate the effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

Inspired by natural 11 β -HSD1 inhibitors hupehenols A - E, a ring-focused strategy was applied for the synthesis of 35 structurally diverse dammarane-type derivatives. These derivatives were effectively prepared from protopanaxadiol based on the modification of rings A and D. Among these compounds, ten were identified as selective 11 β -HSD1 inhibitors (IC 50 range: 101–1047 nM, SI range: 8–169) which exhibited inhibitory activities against human or mouse 11 β -HSD1. Otherwise, we found 23a could selectively inhibit both human and mouse 11 β -HSD1 with IC 50 value of 994 and 213 nM (SI > 10 and > 47), respectively. Additionally, the molecular modelling results of 23a docking into the human and mouse 11 β -HSD1 were in good agreement with the results from the enzyme inhibitory experiment. Moreover, valuable structural-activity relationship (SAR) information of dammarane-type 11 β -HSD1 inhibitor was summarized. [ABSTRACT FROM AUTHOR]

Twelve cembranoids, deheiculatins A-L, were isolated from the leaves and twigs of Macaranga deheiculata . Their structures were elucidated on the basis of spectroscopic data. Five of these compounds displayed moderate inhibitory activity against human and/or mouse 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). 20-Oxygenated cembranes are rare. [ABSTRACT FROM AUTHOR]

Phenotypic screening still plays an important role in discovering new drugs, especially for diseases with complex pathogenesis, such as diabetes. As excessive gluconeogenesis is considered an important factor in the occurrence of hyperglycemia in T2DM, we previously screened our compounds library for active molecules which inhibit gluconeogenesis, resulting in the discovery of SL010110 with a unique mechanism, different from metformin and a thienopyridine derivative (DMT). The SARs study of SL010110 led to the discovery of 10v. Compared with SL010110 , 10v showed improved anti-gluconeogenesis potency and pyruvate tolerance. A further pharmacokinetic study demonstrated that 10v displayed a relatively short half-life, moderate volume of distribution, and moderate to high oral bioavailability. In vivo chronic experiments showed an improved capability of 10v in ameliorating hyperglycemia as the 5 mg/kg 10v treatment greatly reduced non-fasting and fasting blood glucose levels, making it a promising candidate for the treatment of T2DM. The progression from in vitro screening to in vivo testing of the derivatized compounds provided a useful phenotypic screening drug discovery strategy based on the inhibition of gluconeogenesis. [Display omitted] • Systematic SAR investigation of furan-2-carboxylic acid derivatives. • 10v exhibited best anti-gluconeogenesis potency in vitro among all derivatives. • 10v showed superb pyruvate tolerance and oral bioavailability in vivo. • 10v displayed improved effect on ameliorating hyperglycemia in ob/ob mice. • Both pharmacokinetic and pharmacodynamic of 10v supported its further development. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a gastrointestinal disease with complex etiology, and the shortage of the treatment further intensifies the need to discover new therapies based on novel mechanisms and strategies. TGR5 and DPP4 are beneficial to treat UC through multiple mechanisms, notably increasing GLP-2 levels by promoting secretion and inhibiting degradation respectively. However, some unwanted systemic effects caused by systemic exposure hinder development, especially the gallbladder-filling effects. Herein, we firstly reported a series of high-potency gut-restricted TGR5-DPP4 bifunctional molecules by gut-restriction and multitarget strategies to utilize the positive impacts of TGR5 and DPP4 on UC and avoid unwanted systemic effects. In particularly, racemic compound 15 , a high-potency TGR5-DPP4 bifunctional molecule, showed favorable intestinal distribution, preferable efficacy in mice colitis model and good gallbladder safety. Therefore, the feasibility of gut-restricted TGR5-DPP4 bifunctional molecule was confirmed for the treatment UC, providing a new insight into the development of anti-UC drugs. [Display omitted] • High potency TGR5-DPP4 bifunctional molecule was first reported. • Is a gut-restriction molecule with TGR5 agonistic and DPP4 inhibitory effects. • Is effective against UC and circumvents the gallbladder-filling effects. • Gut-restriction and multitarget strategies are suitable for developing anti-UC drugs. [ABSTRACT FROM AUTHOR]

Diacylglycerols (DAGs) are important lipid intermediates and have been implicated in human diseases. Isomerism complicates their mass spectrometric analysis; in particular, it is difficult to identify fatty acid substituents and locate the double bond positions in unsaturated DAGs. We have developed an analytical strategy using ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) in conjunction with dimethyl disulfide (DMDS) derivatization and collision cross-section (CCS) measurement to characterize DAGs in biological samples. The method employs non-aqueous reversed-phase chromatographic separation and profile collision energy (CE) mode for MS E and MS/MS analyses. Three types of fragment ions were produced simultaneously. Hydrocarbon ions ( m/z 50–200) obtained at high CE helped to distinguish unsaturated and saturated DAGs rapidly. Neutral loss ions and acylium ions ( m/z 300–400) produced at low CE were used to identify fatty acid substituents. Informative methyl thioalkane fragment ions were used to locate the double bonds of unsaturated DAGs. Mono-methylthio derivatives were formed mainly by the reaction of DAGs with DMDS, where methyl thiol underwent addition to the first double bond farthest from the ester terminus of unsaturated fatty acid chains. The addition of CCS values maximized the separation of isomeric DAG species and improved the confidence of DAG identification. Fourteen DAGs were identified in mouse myotube cells based on accurate masses, characteristic fragment ions, DMDS derivatization, and CCS values. [ABSTRACT FROM AUTHOR]

G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon-like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC 50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved β-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and β-cell function, suggesting its promising potential for the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Sixteen new walsucochinoids are described. Some of these compounds exhibit 11β-HSD1 inhibitory activity. [ABSTRACT FROM AUTHOR]

Chemical investigation of the cupules of Lithocarpus polystachyus resulted in the identification of four 3,4- seco -homo-cycloartane and one homo-cycloartane derivatives named lithocarpic acids O–S. Their structures were determined based on extensive 1D/2D NMR, IR, MS spectroscopic analyses and chemical methods. Lithocarpic acid O ( 1 ) exhibited inhibitory activities on mouse and human isozymes of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with IC 50 values of 0.49 and 1.1 μM, respectively. [ABSTRACT FROM AUTHOR]

Persistent activation of hepatic gluconeogenesis is a main cause of fasting hyperglycemia in patients with type 2 diabetes (T2D), and the salt-induced kinase 1 (SIK1) acts as a key modulator in regulating hepatic gluconeogenesis. Recently, we first reported phanginin A (PA, 1), a natural cassane diterpenoid isolated from the seeds of Caesalpinia sappan , exhibited potent anti-diabetic effect through activation of SIK1 and increasing PDE4 activity to inhibit hepatic gluconeogenesis pathway by suppressing the cAMP/PKA/CREB pathway in the liver. In present study, we designed and prepared 25 PA derivatives and their structure−activity relationship (SAR) for gluconeogenesis inhibitory activity were established. Among them, compound 7 exhibited remarkable inhibitory activity on hepatic gluconeogenesis by enhancing the SIK1 phosphorylation and ameliorated the hyperglyceamia of type 2 diabetic mice. Our results supported that compound 7 could be served as a potential candidate for the treatment of T2D. [Display omitted] • Twenty-five phanginin A derivatives were designed and synthesized. • SAR for phanginin A analogues on gluconeogenesis inhibitory activity were discussed. • 7 suppressed gluconeogenesis by activating SIK1 to inhibit cAMP/CREB pathway. • 7 be a potential candidate for the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: A series of 4-benzofuranyloxynicotinamide derivatives were identified to be novel, potent, and orally available TGR5 agonists. Among them, compound 9r had the highest potency in vitro (hTGR5 EC50 = 0.28 nM, mTGR5 EC50 = 0.92 nM). Further in vivo studies disclosed that 9r could effectively lower the blood glucose, but meantime caused an increase in the gallbladder volume of mice. Subsequent research toward eliminating the gallbladder toxicity resulted in compound 19 with low permeability. Although the EC50 of mTGR5 of 19 was larger one order than that of 9r, it still had good glucose-lowing activity. Nevertheless, 19 also caused the adverse effects to the gallbladder. The drug levels detection disclosed that the concentration of 19 was only lower than that of 9r in plasma but was higher in bile and gallbladder tissue. This result indicated that low exposure in plasma could not guarantee low exposure in bile and gallbladder tissue, and thus resulting in the gallbladder toxicity of 19. [Copyright &y& Elsevier]

Abstract: A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC50 =0.017μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4=1324; DPP-9/DPP-4=1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague–Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent. [Copyright &y& Elsevier]

Abstract: TGR5, a GPCR, is involved in energy and glucose homeostasis, and as such, is a target for the treatment of diabetes, obesity and other metabolic syndromes. A new class of TGR5 agonists based on a 4-phenyl pyridine scaffold was designed, synthesized and evaluated in vitro and in vivo. Extensive structure–activity relationship studies are reported herein. The most potent compounds 15a, 18b and 18c showed comparable activity with the lead compound 2. 15a had the best potency in vitro but displayed an unfavorable pharmacokinetic profile and was found to be ineffective during an oral glucose tolerance test in imprinting control region mice at a dose of 50 mg/kg. [Copyright &y& Elsevier]

Abstract: The biological screening of a collection of nature occurring diterpenoids against 11β-HSD1 resulted in the discovery of the lead compound 1b, which pointed to the therapeutic potential for type 2 diabetes. Subsequently, an optimization project was initiated. Starting from compound 1b and its counterpart 2, the hemi-synthesis was performed on kaurenic acid scaffolds yielding 36 derivatives. Further evaluations on both human and mouse 11β-HSD revealed that seven urea derivatives exhibited significant improved potency and selectivity. Especially, the urea 19a has an IC50 (human 11β-HSD1) = 9.4 nM and selectivity index (human 11β-HSD) > 10,649. The 2D and 3D binding models of the complex 19a/11β-HSD1 were generated using docking simulations. Based on the results, the structural–activity relationships (SARs) of compounds 1b and 2 were also discussed. [Copyright &y& Elsevier]

4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamidederivativesas potent and orally efficacious TGR5 agonists are reported. Several4-phenoxynicotinamide derivatives were found to activate human andmouse TGR5 (hTGR5 and mTGR5) with EC50values in the lownanomolar range. Compound 23g, with an EC50value of 0.72 nM on hTGR5 and an EC50value of 6.2 nMon mTGR5, was selected for further in vivo efficacy studies. Thiscompound exhibited a significant dose-dependent glucagon-like peptide-1(GLP-1) secretion effect. A single oral dose of 23g(50mg/kg) significantly reduced blood glucose levels in db/dbmice and caused a 49% reduction in the area under the blood glucosecurve (AUC)0–120 minfollowing an oral glucosetolerance test (OGTT) in imprinting control region (ICR) mice. However, 23gstimulated gallbladder filling, which might result inside effects to the gallbladder. [ABSTRACT FROM AUTHOR]

Abstract: Dual-target-directed agents simultaneously inhibiting glycogen phosphorylase (GP) and activating glucokinase (GK) could decelerate the inflow of glucose from glycogenolysis and accelerate the outflow of glucose in the liver, therefore allow for a better control over hyperglycaemia in a synergetic manner. A series of hybrid compounds were designed by structure-assisted and ligand-based strategies. In vitro bioassays found two novel compounds (1j, 6g) worthy of further optimization on balance of dual action to GP and GK. In addition, for single-target activity, two compounds exhibited more potent GP inhibitory activity and four compounds showed better GK activation than their corresponding references. [Copyright &y& Elsevier]

Abstract: RuCl3/NaIO4-initiated oxidation of oxiranemethanols was investigated, and two products, oxirane-2-carboxylic acid and (5′-oxotetrahydrofuran-3-yl)acetic acid, were obtained in variant ratios. The product structures were determined and a tentative mechanism involving oxidation-rearrangement-oxidation process was proposed. Glucokinase enzymatic assay revealed that oxiranecarboxamides 4a–c retained moderate GK activation potency with amide 4a showing an EC50 value of 584nM and a high activation fold of 3.14. However, (5′-oxotetrahydrofuran-3-yl)acetamide 11a is inactive. This study not only provided an alternative protocol to access (5′-oxotetrahydrofuran-3-yl)acetic acid analogs, but also yielded nanomolar GA activators (esp. 4a) for further structure–activity relationship study. [Copyright &y& Elsevier]

Mesenchymal epithelial transition factor (c-Met) is an attractive target for cancer therapy. Three-dimensional pharmacophore hypotheses were built based on a set of known structurally diverse c-Met inhibitors. The best pharmacophore model, which identified inhibitors with an associated correlation coefficient of 0.983 between their experimental and estimated IC values, consisted of two hydrogen-bond acceptors, one hydrophobic, and one ring aromatic feature. The highly predictive power of the model was rigorously validated by test set prediction and Fischer's randomization method. The high values of enrichment factor and receiver operating characteristic (ROC) score indicated the model performed fairly well at distinguishing active from inactive compounds. The model was then applied to screen compound database for potential c-Met inhibitors. A filtering protocol, including druggability and molecular docking, were also applied in hits selection. The final 38 molecules, which exhibited good estimated activities, desired binding mode and favorable drug likeness were identified as potential c-Met inhibitors. Their novel backbone structures could be served as scaffolds for further study, which may facilitate the discovery and rational design of potent c-Met kinase inhibitors. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC50 values of 28.3 and 44.8nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds. [Copyright &y& Elsevier]

Abstract: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has attracted considerable attention as a potential target for the treatment of diabetes and metabolic syndrome. Herein we report the design, synthesis and efficacy evaluation of novel amide and urea 11β-HSD1 inhibitors. Structure–activity relationship studies led to the identification of 10c, which was efficacious in a diabetic ob/ob mouse model and reduced fasting and non-fasting blood glucose levels after ip dosing. [Copyright &y& Elsevier]

Abstract: Three novel triterpenoids, pseudoferic acids A and B (1 and 2) possessed a unique 16,24-cyclo-26-norlanostane skeleton, and pseudoferic acid C (3) featured a cis-fused D/E-ring system, were isolated from the root bark of Pseudolarix kaempferi. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compounds 2 and 3 exhibited weak inhibitory activities against 11β-HSD1 (11β-hydroxysteroid dehydrogenase 1) with IC50 values of 0.44 (mouse 11β-HSD1) and 0.75μM (human 11β-HSD1), respectively. [Copyright &y& Elsevier]

The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of cellular growth, survival and proliferation. mTOR and PI3K have attracted particular attention as cancer targets. These kinases belong to the phosphatidylinositol-3-kinase-related kinase (PIKK) family and therefore have considerable homology in their active sites. To accelerate the discovery of inhibitors with selective activity against mTOR and PI3K as cancer targets, in this work, a homology model of mTOR was developed to identify the structural divergence in the active sites between mTOR and PI3Kα. Furthermore, two highly predictive comparative molecular similarity index analyses (CoMSIA) models were built based on 304 selective inhibitors docked into mTOR and PI3Kα, respectively (mTOR: q = 0.658, r = 0.839; PI3Kα: q = 0.540, r = 0.719). The results showed that steric and electrostatic fields have an important influence on selectivity towards mTOR and PI3Kα-a finding consistent with the structural divergence between the active sites. The findings may be helpful in investigating selective mTOR/PI3Kα inhibitors. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 2 (CDK2) has appeared as an important drug target over the years with a multitude of therapeutic potentials. To design compounds with enhanced inhibitory potencies against CDK2, 3D-QSAR and molecular fragment replacement studies were performed on the pyrazolo[4,3-h]quinazoline derivatives, a class of potent CDK2 inhibitors. The contours of 3D-QSAR model revealed important structural features of the inhibitors related to the active site of CDK2. Based on the pyrazolo[4,3-h]quinazoline core, the different substituents at three important points were replaced with diverse molecular fragments. The compounds resulting from fragments assembly with pyrazolo[4,3-h]quinazoline core were then scored with the robust 3D-QSAR model. Furthermore, the absorption, distribution, metabolism and excretion properties of these compounds were predicted by Volsurf to eliminate inappropriate compounds. Thirty-one new potential compounds were finally obtained. These results initiated us to further optimise and design new potential inhibitors. [ABSTRACT FROM PUBLISHER]

Abstract: Kansuinone (1), a rearranged euphane triterpenoid containing a spiro [5,6] ring system, was isolated from the roots of Euphorbia kansui. Its structure and stereochemistry were elucidated on the basis of spectroscopic, CD, and computational methods. Kansuinone (1) exhibited inhibitory activity against human and mouse 11β-HSD1 (11β-hydroxysteroid dehydrogenase type 1), with IC50 values of 1.12 and 1.08μM, respectively. [ABSTRACT FROM AUTHOR]

Background and Purpose: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an attractive therapeutic target of type 2 diabetes and metabolic syndrome. Emodin, a natural product and active ingredient of various Chinese herbs, has been demonstrated to possess multiple biological activities. Here, we investigated the effects of emodin on 11beta-HSD1 and its ability to ameliorate metabolic disorders in diet-induced obese (DIO) mice.Experimental Approach: Scintillation proximity assay was performed to evaluate inhibition of emodin against recombinant human and mouse 11beta-HSDs. The ability of emodin to inhibit prednisone- or dexamethasone-induced insulin resistance was investigated in C57BL/6J mice and its effect on metabolic abnormalities was observed in DIO mice.Key Results: Emodin is a potent and selective 11beta-HSD1 inhibitor with the IC(50) of 186 and 86 nM for human and mouse 11beta-HSD1, respectively. Single oral administration of emodin inhibited 11beta-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11beta-HSD1 in vivo. In DIO mice, oral administration of emodin improved insulin sensitivity and lipid metabolism, and lowered blood glucose and hepatic PEPCK, and glucose-6-phosphatase mRNA.Conclusions and Implications: This study demonstrated a new role for emodin as a potent and selective inhibitor of 11beta-HSD1 and its beneficial effects on metabolic disorders in DIO mice. This highlights the potential value of analogues of emodin as a new class of compounds for the treatment of metabolic syndrome or type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: A series of N-thiazole substituted arylacetamides were designed on the basis of metabolic mechanism of the aminothiazole fragment as glucokinase (GK) activators for the treatment of type 2 diabetes. Instead of introducing a substituent to block the metabolic sensitive C-5 position on the thiazole core directly, a wide variety of C-4 or both C-4 and C-5 substitutions were explored. Compound R-9k bearing an iso-propyl group as the C-4 substituent was found possessing the highest GK activation potency with an EC50 of 0.026μM. This compound significantly increased both glucose uptake and glycogen synthesis in rat primary cultured hepatocytes. Moreover, single oral administration of compound R-9k exerted significant reduction of blood glucose levels in both ICR and ob/ob mice. These promising results indicated that compound R-9k is a potent orally active GK activator, and is warranted for further investigation as a new anti-diabetic treatment. [Copyright &y& Elsevier]

Abstract: Rare merosesquiterpenoids, craterellins A–C (1–3), were isolated from cultures of basidiomycete Craterellus odoratus together with the previously known massarinolin C (4). Structures of 1–3 were elucidated on the basis of extensive spectroscopic analysis. Compounds 1–3 possess a rare, epoxymethylenecyclohexanetriol-bicyclofarnesane sesquiterpene hybrid skeleton. Compounds 1–4 were evaluated for their inhibitory activities against two isozymes of 11β-hydroxysteroid dehydrogenases (11β-HSD1 and 11β-HSD2). [Copyright &y& Elsevier]

Abstract: A series of benzamide derivatives which can simultaneously inhibit glycogen phosphorylase (GP) and activate glucokinase (GK) were prepared and evaluated. The structure–activity relationships (SAR) of these compounds were also presented. Among these, compounds 12, 13l, 13q, and 13v showed moderate activities towards both GK and GP. Compound 13h inhibited hLGP with an IC50 of 8.95μM and activated GK with an EC50 of 1.87μM. The possible binding modes of compounds 12, 13l, 13h, and 13q with GP and GK were also explored by molecular docking simulation. [Copyright &y& Elsevier]

Abstract: PPARγ and 11β-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARγ agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11β-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of α-aryloxy-α-methylhydrocinnamic acids as dual functional agents which activate PPARγ and inhibit 11β-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARγ (EC50 =6.76μM) and 11β-HSD1 (IC50 =0.76μM) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile. [Copyright &y& Elsevier]