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The ability to differentiate stimuli that predict fear is critical for survival; however, the underlying molecular and circuit mechanisms remain poorly understood. We combined transgenic mice, in vivo transsynaptic circuit-dissecting anatomical approaches, optogenetics, pharmacological methods, and electrophysiological recording to investigate the involvement of specific extended amygdala circuits in different fear memory. We identified the projections from central lateral amygdala (CeL) protein kinase C δ (PKCδ)–positive neurons and somatostatin (SST)-positive neurons to GABAergic (gamma-aminobutyric acidergic) and glutamatergic neurons in the ventral part of the bed nucleus of stria terminalis (vBNST). Prolonged optogenetic activation or inhibition of the PKCδCeL-vBNST pathway specifically reduced context fear memory, whereas the SSTCeL-vBNST pathway mainly reduced tone fear memory. Intriguingly, optogenetic manipulation of vBNST neurons that received the projection from PKCδCeL neurons exerted bidirectional regulation of context fear, whereas manipulation of vBNST neurons that received the projection from SSTCeL neurons could bidirectionally regulate both context and tone fear memory. We subsequently demonstrated the presence of δ and κ opioid receptor protein expression within the CeL-vBNST circuits, potentially accounting for the discrepancy between prolonged activation of GABAergic circuits and inhibition of downstream vBNST neurons. Finally, administration of an opioid receptor antagonist cocktail on the PKCδCeL-vBNST or SSTCeL-vBNST pathway successfully restored context or tone fear memory reduction induced by prolonged activation of the circuits. Together, these findings establish a functional role for distinct CeL-vBNST circuits in the differential regulation and appropriate maintenance of fear. [ABSTRACT FROM AUTHOR]

As a prominent feature of gout, monosodium urate (MSU) crystal deposition induces gout flares, but its impact on immune inflammation in gout remission remains unclear. Using single-cell RNA sequencing (scRNA-seq), we characterize the transcription profiling of peripheral blood mononuclear cells (PBMCs) among intercritical remission gout, advanced remission gout, and normal controls. We find systemic inflammation in gout remission with MSU crystal deposition at the intercritical and advanced stages, evidenced by activated inflammatory pathways, strengthened inflammatory cell-cell interactions, and elevated arachidonic acid metabolic activity. We also find increased HLA-DQA1 high classic monocytes and PTGS2 high monocytes in advanced gout and overactivated CD8+ T cell subtypes in intercritical and advanced gout. Additionally, the osteoclast differentiation pathway is significantly enriched in monocytes, T cells, and B cells from advanced gout. Overall, we demonstrate systemic inflammation and distinctive immune responses in gout remission with MSU crystal deposition, allowing further exploration of the underlying mechanism and clinical significance in conversion from intercritical to advanced stage. [Display omitted] • Systemic inflammation in remission gout with MSU crystal deposition is observed • HLA-DQA1 high CD14+ monocytes boost immune responses and bone erosion in advanced gout • CD8+ T cells are overactivated in remission gout at intercritical and advanced stage • Upregulation of PTGS2 in monocyte subtypes promotes AA metabolism in advanced gout Gu et al. find systemic inflammation and immune responses in remission gout with MSU crystal deposition by scRNA-seq analysis of PBMCs from gout patients and healthy volunteers. The findings reveal MSU crystal-related immune cell expression changes, which provide potential anti-inflammatory therapeutic targets in remission gout. [ABSTRACT FROM AUTHOR]

We present a rare male fetus with karyotype of mosaic 45,X that comprises two types of aberrant Y chromosomes arising de novo (Yq12 deletion and isodicentric Yq11.22). Both types of the aberrant Y chromosomes lack the AZFc region which are expected to result in oligospermia but unaffected male external genitalia. Genetic analyses by karyotyping, chromosome microarray (CMA), and multiplex ligation-dependent probe amplification (MLPA) for the fetus revealed conflicting results. Additional molecular cytogenetics tools including fluorescence in situ hybridization (FISH) and multicolor banding (mBAND) were performed, which help resolving the discrepancy and delineated the composition of the aberrant Y chromosomes. This report highlighted the importance of incorporating multiple genetic technologies for accurate characterization of complex chromosomal rearrangements, which aid in the prenatal diagnosis and genetic counseling. [ABSTRACT FROM AUTHOR]

Two new lignan derivatives and nine known compounds were isolated from the EtOAc and n -BuOH extracts of Millettia dorwardi Coll. Et. Hemsl. The structures of the compounds were determined by 1D and 2D NMR, CD and HRMS. Then, cytotoxic effects of these compounds were evaluated against five cancer cell lines (HepG2, HCT116, MCF7, Raji and KG-1). Results showed the isolated compounds have no obvious cytotoxic activity, but millepurpan ( 5 ) showed moderate growth inhibitory activity against Raij and KG-1 cells, with IC 50 values of 36.13 and 30.11 μM, respectively. Further activity evaluation revealed that millepurpan ( 5 ) could induce G1 arrest and apoptosis in KG-1 cells. The lignan skeleton was isolated from Millettia genus for the first time and all compounds were firstly reported from Millettia dorwardi Coll. Et. [ABSTRACT FROM AUTHOR]

A highly selective and sensitive enzyme-linked immunosorbent assay (ELISA) was developed for the detection of malachite green (MG) using a molecularly imprinted polymer (MIP) film as bionic antibody. The MIP film, based on the self-polymerization of dopamine, was fabricated on the surfaces of a 96-well microplate. It showed specific recognition for MG in aqueous solution. A direct competitive ELISA method was established with the sensitivity reaching 10.31 μg L −1 and the detection limit being 0.3 μg L −1 . The cross-reactivity of two structural analogues to MG was less than 10%. The average recovery tested by MG standard spiking was 88.8% for bass and 90.4% for water, and the relative standard deviations were less than 3.6%. All the above results indicated that the developed method could be used to detect MG in fish and water samples rapidly, specifically and accurately. [ABSTRACT FROM AUTHOR]

Objective With the growing need for reliable and durable upper arm hemodialysis access, we sought to compare the performance of a novel modified nontransposed brachiobasilic arteriovenous fistula (mNT-BBAVF) with that of the more traditional brachiocephalic arteriovenous fistula (BCAVF). Methods Briefly, to construct an mNT-BBAVF, an incision is made on the ulnar side of the elbow. The brachial artery and basilic vein are then isolated, and a side-to-side anastomosis is performed without transposition of the basilic vein. Next, the proximal basilic vein and the perforating veins within the surgical field are ligated. In this study, we retrospectively reviewed the medical records of all patients who underwent either an mNT-BBAVF or a BCAVF between January 2011 and October 2014 to compare 1-year primary unassisted patency, cumulative patency, and complications. We also examined hemodynamic parameters of vessels in each fistula type. Results We identified a total of 84 patients: 45 had a BCAVF, and 39 had an mNT-BBAVF. The two groups were well matched for baseline characteristics. Maturation rates at 1 month were 97% for mNT-BBAVF and 96% for BCAVF. The 1-year primary unassisted patency was significantly higher in the mNT-BBAVF group than that in the BCAVF group (87% vs 67%; hazard ratio, 2.86; 95% confidence interval, 1.11-6.40; P = .03), although cumulative patency did not differ (90% vs 73%; hazard ratio, 2.80; 95% confidence interval, 0.98-6.96 ; P = .06). There were no differences in thrombosis, failure of maturation, bleeding, steal syndrome, arm swelling, aneurysm, and stenosis between the two groups during the 12-month study. Importantly, diameters and blood flow volumes of the proximal cephalic vein, distal cephalic vein, and distal basilic vein in patients who received an mNT-BBAVF increased significantly after 12 months. All three vessels met the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria for fistula maturation and were available for dialysis cannulation, whereas only the proximal cephalic vein in the BCAVF group met the maturation criteria and could be used for cannulation. Conclusions mNT-BBAVF appeared to be an effective alternative to BCAVF for upper arm hemodialysis access. [ABSTRACT FROM AUTHOR]

Abstract: A series of phosphorylated flavonoids were synthesized and investigated in vitro as inhibitors of pancreatic cholesterol esterase (CEase) and acetylcholinesterase (AChE). The results showed that most of the synthesized compounds exhibited nanomolar potency against CEase, much better than the parent flavonoids. Furthermore, these phosphorylated flavonoids demonstrated good to high selectivity for CEase over AChE, which only showed micromolar potency inhibition of AChE. The most selective and potent inhibitor of CEase (3e) had IC50 value of 0.72 nM and 11800-fold selectivity for CEase over AChE. The structure–activity relationships revealed that the free hydroxyl group at position 5 and phosphate group at position 7 of the phosphorylated flavonoids are favorable to the inhibition of CEase. The inhibition mechanism and kinetic characterization studies indicated that they are irreversible competitive inhibitors of CEase. [Copyright &y& Elsevier]

Highlights: [•] Phosphorylated flavonoids were screened as inhibitors of porcine liver CE. [•] Six tested compounds showed potency against CE with IC50 values below 5.0nM. [•] These compounds demonstrated similar levels of inhibition toward CEase and CE. [•] They were identified as irreversible competitive inhibitors of CE. [Copyright &y& Elsevier]

Highlights: [•] An efficient Suzuki reaction has been developed. [•] A series of 2-(1-(E)-alkenyl)phenylphosphonates were synthesized. [•] The reactions are quite general. [•] The reactions proceed in good yields. [Copyright &y& Elsevier]

Abstract: Iodide salt, such as NaI, KI or n-Bu4NI (TBAI), rather than bromide or chloride salt, was found to play a key role in the Pd(0)-catalyzed Heck reaction of aryl nonaflates and terminal alkenes. In the presence of PdCl2(PPh3)2, NaI or TBAI in DMF, a class of 2-(1-alkenyl)phenylphosphonates was first synthesized via the reaction of o-phosphonylphenyl nonaflates with alkenes, the yields, regioselectivities and stereoselectivities were much dependent on the nature of the substituents. In case of the aryl nonaflates without bearing the sterically hindered phosphonyl group with the alkenes, the reactions proceeded more smoothly under the same conditions, leading to the linear products regioselectively in good to excellent yields. A rationale for this reaction is discussed. [Copyright &y& Elsevier]

Abstract: Objective: To explore the apoptotic role of amylin on human mesangial cell (MC). Materials and methods: Primarily cultured human MCs were applied and treated with fresh amylin preparation. Human MCs were identified by the morphology and immunofluorescence staining. The apoptotic cells were determined by ultrastructure changes, TUNEL, and DNA fragmentation analysis. Propidium iodide staining and flow cytometry was employed for quantitative measurement of apoptosis. Results: Under the light and transmission electronic microscopy (TEM), the human MCs with condensed chromatin, plasma shrinkage, marginated nuclear chromatin or apoptotic body were observed in amylin-treated MCs. Positive TUNEL staining, hypolipoid DNA peak, and typical DNA “ladder” pattern were also detected in amylin-treated MCs. Quantitative analysis of the apoptotic MCs showed that human amylin induced an increase of the percentage of apoptotic cells in a dose-dependent manner. Amylin nano-scale fibrils (5–18nm) in diameter were detected in the cultured solution using negative staining under the TEM. Compared to the control, no significant changes of lactate dehydrogenase release were observed in amylin-treated MCs (P >0.05). Conclusions: Fibrillogenic amylin evokes the apoptosis of human MCs in vitro, which may explain the mechanism of the hypocellular mesangial damage and progressive glomerulosclerosis of the patients with diabetic nephropathy. [Copyright &y& Elsevier]

Abstract: A series of 4-halophosphaisocoumarins were prepared with high regioselectivity in good to excellent yields under mild conditions by the reaction of 2-(1-alkynyl)phenylphosphonic acid diesters with I2 in CHCl3 or ICl in CH2Cl2, or by the reaction of 2-(1-alkynyl)phenylphosphonic acid monoesters with NBS or NCS in DMF. Whether the alkynylphosphonates could cyclize or not was affected by the substituents, reaction solvents and electrophiles. A rationale for this reaction is discussed. [Copyright &y& Elsevier]

Background For patients undergoing lumbar spinal surgery, many surgeons routinely perform laboratory tests within 3 days after surgery. However, few studies have reported the necessity for routine laboratory tests for patients with uncomplicated cases within 3 days after surgery. Methods We performed a retrospective study of patients with lumbar degenerative disease who had undergone lumbar spinal surgery from May 2014 to May 2017. The perioperative patient information was recorded. The abnormal postoperative laboratory tests were recorded. Finally, the incidence and risk factors for patients requiring postoperative clinical treatment were analyzed. Results A total of 1915 patients were included in the present study. Postoperative laboratory tests had been ordered for 870 patients (45.43%). Of these patients, only a small proportion had required postoperative clinical intervention to treat abnormal serum hemoglobin (2.53%), albumin (1.95%), serum potassium (0.92%), or serum calcium (6.55%) levels. Multivariate logistic regression analysis showed that female gender and operative time were risk factors for the need for blood transfusion after lumbar spinal surgery. Age and operative time were risk factors for patients requiring albumin supplementation after lumbar spinal surgery. Finally, intraoperative blood loss and operative time were independent risk factors for patients requiring calcium supplementation after surgery. Conclusions Owing to the small number of postoperative clinical interventions for abnormal laboratory test results, we believe that the use of routine laboratory tests within 3 days after lumbar spinal surgery for patients with uncomplicated cases are unnecessary. Our results showed that operative time is a potential risk factor for the necessity for clinical treatment after lumbar spinal surgery. [ABSTRACT FROM AUTHOR]

Magnetic molecularly imprinted polymers (MMIPs) were synthesized through precipitation polymerization using malachite green (MG) as template, methacrylic acid as monomer, ethylene dimethacrylate as crosslinker, and Fe 3 O 4 magnetite as magnetic component. MMIPs were characterized by scanning electron microscopy, Fourier transform infrared spectrometry, and vibrating sample magnetometry. Under the optimum condition, the MMIPs obtained exhibited quick binding kinetics and high affinity to MG in the solution. Scatchard plot analysis revealed that the MMIPs contained only one type of binding site with dissociation constant of 24.0 μg mL −1 . The selectivity experiment confirmed that the MMIPs exhibited higher selective binding capacity for MG than its structurally related compound (e.g., crystal violet). As a sorbent for the extraction of MG in sample preparation, MMIPs together with the absorbed analytes could easily be separated from the sample matrix with an external magnet. After elution with methanol/acetic acid (9:1, v/v), MG in the eluent was determined by high-performance liquid chromatography coupled with UV detector with recoveries of 94.0–115%. Results indicated that the as-prepared MMIPs are promising materials for MG analysis in aquatic products. [ABSTRACT FROM AUTHOR]

Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) is regulated by a myriad of signaling cascades including glycogen synthase kinase (GSK) 3β and plays a Janus role in podocyte injury. In vitro, lipopolysaccharide (LPS) or adriamycin (ADR) elicited podocyte injury and cytoskeletal disruption, associated with NFκB activation and induced expression of NFκB target molecules, including pro-survival Bcl-xL and podocytopathic mediators like MCP-1, cathepsin L, and B7-1. Broad-range inhibition of NFκB diminished the expression of all NFκB target genes, restored cytoskeleton integrity, but potentiated apoptosis. In contrast, blockade of GSK3β by lithium or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) mitigated the expression of podocytopathic mediators, ameliorated podocyte injury, but barely affected Bcl-xL expression or sensitized apoptosis. Mechanistically, GSK3β was sufficient and essential for RelA/p65 phosphorylation, specifically at serine 467, which specifies the expression of selective NFκB target molecules, including podocytopathic mediators, but not Bcl-xL. In vivo, lithium or TDZD-8 therapy improved podocyte injury and proteinuria in mice treated with LPS or ADR, concomitant with the suppression of podocytopathic mediators, but retained Bcl-xL in glomerulus. Broad-range inhibition of NFκB conferred similar but much weakened antiproteinuric and podoprotective effects accompanied with a blunted glomerular expression of Bcl-xL and marked podocyte apoptosis. Thus, the GSK3β-dictated fine-tuning of NFκB may serve as a novel therapeutic target for podocytopathy. [ABSTRACT FROM AUTHOR]

• GDF11 overexpression virus has neuroprotective effects on stroke in MCAO rats. • rGDF11 has neurorestorative effects on stroke in MCAO rats. • Both reduce the infarct volume, the apoptotic cells and improve motor function. • Both elevate the expression of p-Smad2/3 and promote neurogenesis and angiogenesis. Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β (TGF-β) superfamily, regulates various biological processes in mammals. The effect of GDF11 in brain injury has not been fully elucidated. Our aim was to investigate the effects of GDF11 in cerebral ischemic injury. The expression level of GDF11 increased significantly in the peri -infarct cerebral cortex. Next, the effect of the intracerebroventricular injection of a GDF11 overexpression lentivirus or rGDF11 was investigated in middle cerebral artery occlusion (MCAO) rats. The preventative effects of the GDF11 overexpression virus on stroke were observed. The delivery of the lentivirus into rats before MCAO significantly reduced the infarct volume and the percentage of apoptotic cells and improved motor function in MCAO rats. Furthermore, it elevated the expression of p-Smad2/3 and promoted neurogenesis and angiogenesis in the ipsilateral SVZ during ischemic injury. More importantly, the therapeutic effects of rGDF11 on stroke were subsequently explored. The results in MCAO rats treated with rGDF11 were found similar to that in those treated with the GDF11 overexpression lentivirus. Together, these findings indicate that GDF11 has neuroprotective and neurorestorative effects in cerebral ischemic injury and provide new insights into the function and mechanism of GDF11 in stroke models. [ABSTRACT FROM AUTHOR]

In this paper, molecular imprinting and photonic crystal techniques were combined to construct a four-channel sensor array for the simultaneous identification of various sulfonamides. The assay was composed of four units. Three of these units were prepared using sulfaguanidine, sulfamethazine, or sulfathiazole as template molecules. The fourth unit was prepared without a template molecule. The preparation was optimized to obtain maximum identification with a molar ratio of template, monomer, and cross-linker of 1:50:10. The response time was as short as 10 min. For demonstration, six sulfonamides were selected as analytes. The Bragg diffraction patterns of analytes at different concentrations were measured using the sensor array. Data obtained were analyzed using linear discrimination analysis (LDA) and principal component analysis (PCA). LDA can be applied for SAs discrimination. The message ratios of 87.6%, 94.4%, and 95.8% for six SAs at 10−4 mol L−1, 10−6 mol L−1, and 10−8 mol L−1 were achieved using LDA. The sensor array identified the mixture containing various SAs with an LDA coefficient of 86.1%, thereby indicating that the sensor array had a strong anti-interference ability. The sensor array was used to identify six SAs in fish samples. The measured data in spiked samples were consistent with the fingerprint collected from standard solutions. The accuracy rate reached 90.9%, indicating that the array can be used to identify SAs from food samples. Image 1 • Photonic crystal imprinting array was firstly reported for sulfonamide discrimination. • The applicable concentration range of sulfonamide is wide (10−4–10−8 mol/L). • The response is rapid and label-free. • The array was applicable in food analysis. [ABSTRACT FROM AUTHOR]

Abstract It is known that inflammation and oxidative stress have strong influences on chronic kidney disease (CKD). As an antioxidant, bilirubin is currently under extensive scrutiny. However, there are disagreements with regard to the oxidative and antioxidative roles of serum uric acid (SUA). This study aimed to investigate the relationship between serum bilirubin and the progression of renal function in CKD patients with hyperuricemia (HUA). This retrospective longitudinal study included 427 CKD patients. The endpoint was renal replacement therapy or death. Patients were divided into the following two groups according to the SUA level: HUA group (SUA ≥ 420 μmol/L for men; SUA ≥ 360 μmol/L for women) and normal uric acid level (NUA) group. A Cox proportional hazards model was used to evaluate the risk factors for renal outcomes in the two patient groups. The median follow-up time was 36 months. In the Cox regression analysis, the risk of renal outcomes in patients with serum indirect bilirubin (IBIL) levels >4.55 μmol/L was 0.15 times the risk in patients with serum IBIL levels ≤4.55 μmol/L (hazard ratio = 0.15, p =.013). Our findings suggest that a high serum IBIL level might be a protective factor for the progression of renal function in CKD patients with HUA. Highlights • We evaluated the relationship between bilirubin and renal function in CKD with HUA. • A high IBIL level might be protective for renal function in CKD with HUA. • IBIL plays a protective role in renal function may through its antioxidant property. • There may exist an interaction between bilirubin and UA in oxidative stress [ABSTRACT FROM AUTHOR]

Background Oxidative stress and inflammation play pivotal roles in chronic kidney disease (CKD). Bilirubin is an endogenous anti-inflammatory antioxidant. However, the relationship between serum bilirubin and renal outcomes in CKD is controversial. We explored the association of serum bilirubin levels with renal outcomes in Han Chinese patients with CKD. Methods Clinical and laboratory data were collected from 316 patients with CKD. The primary clinical endpoint was renal replacement therapy or death. The association between serum bilirubin and clinical parameters was assessed by correlation analysis. Multiple Cox regression analysis was used to explore the relationship between serum bilirubin and renal outcomes in patients with CKD. Results Serum total and indirect bilirubin were positively correlated with estimated glomerular filtration rate, but negatively correlated with 24-h urine protein in patients with CKD. Serum total and indirect bilirubin were inversely associated with CKD stages in patients with CKD stages 1–5. Multiple Cox regression analysis demonstrated that the higher concentration of serum total bilirubin was independently associated with better renal outcomes in CKD. Conclusions Our results suggest that serum total bilirubin may have protective effects on kidneys. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is a major and dangerous human pathogen that causes a range of clinical manifestations of varying severity, and is the most commonly isolated pathogen in the setting of skin and soft tissue infections, pneumonia, suppurative arthritis, endovascular infections, foreign-body associated infections, septicemia, osteomyelitis, and toxic shocksyndrome. Honokiol, a pharmacologically active natural compound derived from the bark of Magnolia officinalis , has antibacterial activity against Staphylococcus aureus which provides a great inspiration for the discovery of potential antibacterial agents. Herein, honokiol derivatives were designed, synthesized and evaluated for their antibacterial activity by determining the minimum inhibitory concentration (MIC) against S. aureus ATCC25923 and Escherichia coli ATCC25922 in vitro . 7c exhibited better antibacterial activity than other derivatives and honokiol. The structure-activity relationships indicated piperidine ring with amino group is helpful to improve antibacterial activity. Further more, 7c showed broad spectrum antibacterial efficiency against various bacterial strains including eleven gram-positive and seven gram-negative species. Time-kill kinetics against S. aureus ATCC25923 in vitro revealed that 7c displayed a concentration-dependent effect and more rapid bactericidal kinetics better than linezolid and vancomycin with the same concentration. Gram staining assays of S. aureus ATCC25923 suggested that 7c could destroy the cell walls of bacteria at 1 × MIC and 4 × MIC. [ABSTRACT FROM AUTHOR]

A sensitive fluorescence sensor for the detection of malachite green (MG) was fabricated by grafting molecularly imprinted polymers (MIPs) onto the surface of CdTe quantum dots (QDs). The MIP-coated QDs were synthesized via a reverse microemulsion method using (3-aminopropyl)triethoxysilane (APTES) and tetraethyl orthosilicate (TEOS) as functional monomer and cross-linker, respectively. The optimum molar ratio of MG, functional monomer and cross-linker was 1:3:10. The MIP-coated QDs exhibited uniform spheres with diameter around 49 nm and excellent fluorescence emission at λ ex 370 nm. A linear relationship with two segments between the relative fluorescence intensities and the MG concentrations ranging from 0.08 to 20 μmol·L −1 could be obtained with a detection limit of 12 μg·kg −1 . The fluorescent probe was successfully applied to the determination of MG in fish samples with the spiked recoveries ranging from 94.3% to 109.5% which were in accordance with those of the measurement by HPLC-UV. [ABSTRACT FROM AUTHOR]

Five new flavonoids, griffinones A–E ( 1 – 5 ), a new biphenylneolignan, griffilignan A ( 6 ) and ten known compounds were isolated from the n -hexane and EtOAc extracts of Millettia griffithii . The structures of the new compounds were determined by 1D and 2D NMR, and by HRMS. The anti-inflammatory activity of the isolated compounds was evaluated on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cells. Among the isolated compounds, compounds 1 , 2 and 14 showed significant anti-inflammatory activity with IC 50 values of 20.4, 2.1 and 35.7 μM, respectively and no obvious toxicities were observed at 100 μM. Western blot and PCR assay further showed that inhibition of nitric oxide production by compound 2 was associated with suppression of iNOS expression. Modeling studies suggested that the amino group, phenyl ring as well as the isopentenyl tails of compound 2 could help bind to iNOs. [ABSTRACT FROM AUTHOR]

Aims Paraquat (PQ) is a pesticide highly toxic to human beings, and a well-known trigger of oxidative stress. Although several animal models of PQ poisoning have been developed, some disadvantages limit their application in vivo. A zebrafish model was used in the present study to better define mechanisms of oxidative stress injury induced by PQ. Main methods The toxicity of PQ was evaluated in the AB strain of zebrafish, and apoptosis was assessed by acridine orange staining. Macrophage migration was identified using the TG ( zlyz : EGFP ) transgenic strain, and angiogenesis was observed using the fli1a-EGFP casper strain. Following the validation of gene changes by zebrafish-based in vivo quantitative real-time PCR, network analysis was performed using the Ingenuity Pathway Analysis software. Key findings We first established the LC 50 of PQ in the zebrafish model, and then found that robust oxidative stress and antioxidant genes were activated after PQ exposure. Moreover, apoptosis and distinct macrophage activation and migration were identified for the first time in PQ-exposed zebrafish. Utilizing this model, both extrinsic and intrinsic pathways involved in PQ-induced apoptosis were elucidated. We further demonstrated that macrophage migration was specifically induced by PQ, and that Rho family members and JNK-MMP13 signaling participated in this process. Significance Zebrafish is a promising tool for investigating the mechanisms of oxidative stress injury induced by PQ, and for screening effective anti-oxidant drugs. [ABSTRACT FROM AUTHOR]

Aims Hyperphosphatemia is associated with accelerated vascular endothelial dysfunction in patients with chronic kidney disease (CKD). The purpose of this study is to investigate the molecular mechanisms underlying hyperphosphatemia-caused endothelial dysfunction. Main methods The metabolic fingerprinting of human umbilical vein endothelial cells (HUVECs) subjected to hyperphosphatemia was characterized using an integrated metabolomics approach. HUVECs cultured in physiologically simulated hyperphosphatemia with or without phosphonoformic acid, a sodium-dependent phosphate transporter inhibitor (N = 6) were collected for metabolomics analysis. Multivariate principle component analysis and partial least squares discriminant analysis were applied to analyze the metabolic data. The key metabolites were confirmed by quantitative analysis using liquid chromatography coupled with tandem mass spectrometer (LC–MS/MS). Key findings 36 metabolites were significantly altered in HUVECs following the challenges of hyperphosphatemia mimic, involving several metabolic pathways (all P < 0.05). Among them, ornithine increased significantly in the HUVECs mediated by hyperphosphatemia mimic, and its levels positively correlated with cell apoptosis rate ( r = 0.674, P = 0.002), and several additional metabolites in multiple metabolic pathways. The changes in the levels of ornithine and other several metabolites were supported by subsequent quantitative analyses using LC–MS/MS. Further study demonstrated that the increase in ornithine level may result from the increased expression of arginase 2 in HUVECs, which mediates the hydrolysis of arginine to form ornithine. Significance This is the first study demonstrating ornithine a key molecule mediating hyperphosphatemia-induced apoptosis of ECs. Arginase 2 may be a therapeutic target for hyperphosphatemia-associated cardiovascular events. [ABSTRACT FROM AUTHOR]

Aims Hyperphosphatemia is an independent risk factor of cardiovascular events in the patients with chronic kidney disease. High phosphate can induce endothelial cell apoptosis, but the exact mechanism is not clear. This study fills this knowledge gap. Materials and methods Microarray analysis was used to identify differentially expressed gene profiles in human umbilical vein endothelial cells (HUVECs) in high phosphate (3.0 mM) and normal phosphate (1.0 mM) medium. Microarray informatics analysis was used to explore key pathways and genes. High phosphate-induced apoptosis is marked by annexin V-FITC/PI staining and cleavage of caspase-3. Immunoblotting and quantitative real-time PCR were performed to identify the microarray analysis. Key findings Our microarray informatics analysis reveals that the mitogen-activated protein kinase (MAPK) plays a key role. As suggested by gene coexpression network analysis, bone morphogenetic protein 4 (BMP4) gene is a potential key regulatory gene in high phosphate environment. Both the expressions of BMP4 protein and mRNA are decreased. Extracellular regulated protein kinases (ERKs) are activated, while the inhibition of ERK by U0126 increases the expression of BMP4. Both recombinant BMP4 protein pretreatment and U0126 pretreatment reduce the apoptosis of endothelial cells in simulated hyperphosphatemia. However, BMP4 protein pretreatment had no effect on the activation of ERK MAPK pathway. Significance Our results indicate that the inhibition of ERK MAPK pathway protects endothelial cells from apoptosis by upregulating bone morphogenetic protein 4 in endothelial cells exposed to hyperphosphatemia. Our study provides potential molecular targets for developing new strategies to reduce the endothelial cell apoptosis induced by high phosphate. [ABSTRACT FROM AUTHOR]

Aims Paraquat Poisoning (PQ) can cause illness and death, and its main causes of mortality are acute respiratory failure and lung fibrosis. Early recognition of this condition and early treatment are vital. Thus, it is of importance to target the key genes controlling pathogenesis in the early stage of PQ. Main methods C57BL/6 mice were used for Paraquat intragastric administration as a model of PQ. Following a gene chip-based screening, the change of gene expression in the lung was further validated by bioinformatic analyses, co-expression network construction and real-time RT-PCR, Western blot and immunofluorescence assays. Key findings 2287 genes with differential expression were identified at the very early stage of PQ. From these, 76 genes that were linked to mitochondrion function were further pursued. Among these genes, PSTK was a phosphorylase kinase which serves a protective role in oxidative stress lung damage. PSTK was the central gene in a 30-gene network that is important for mitochondrial complex I assembly, mitochondrial apoptosis and mitochondrial fatty acid beta-oxidation, suggesting that they could conceivably be related to the pathogenesis of PQ induced lung damage. Lastly, we confirmed that PSTK was lowered in rodent lungs following PQ. Significance PSTK emerges as a central gene in a network of mitochondrial function genes in PQ exposed mice. The functional role of PSTK in PQ induced lung injury warrants further examination. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: To investigate the effects of aqueous extract of Astragali Radix (ARE) on the oxidative stress status and endothelial nitric oxide synthase level in adriamycin (ADR) nephropathy rats. Materials and methods: ADR nephropathy rats were randomly treated with ARE (2.5g/kg/d, n =6, ARE group), or benazepril (10mg/kg/d, n =6, angiotensin-converting enzyme inhibitor (ACEI) group) for ten weeks. Serum urea nitrogen, creatinine, albumin, total protein, cholesterol and 24-h urinary protein concentration were determined. Renal cortex catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), malondialdehyde (MDA) activities, and 24-h urinary NO3 −/NO2 − excretion were determined by chromatometry. Renal cortex cyclic guanosine monophosphate (cGMP) level was measured by enzyme immunoassay and eNOS expression was determined by immunohistochemistry. Results: ARE and ACEI treatments could remarkably reduce more 24h urinary protein excretion than that in ADR group (88.32±9.96mg, 81.78±16.28mg vs. 153.91±28.63mg, P <0.01), and there was no difference between ARE and ACEI group. Renal cortex CAT, GSH-Px activities in ARE and ACEI group were significantly higher than ADR group, and renal cortex SOD activity in ARE group was higher than ADR group. Renal cortex MDA activity, cGMP level, and glomerular and tubular eNOS expression in ARE and ACEI group were lower than that in ADR group, and 24-h urinary NO3 −/NO2 − excretion in ARE group was lower than ADR group. Renal cortex MDA content (r =0.895, P <0.01), cGMP content (r =0.666, P <0.01) and eNOS expression in glomerulus (r =0.910, P <0.01) were strongly positively associated with 24h urinary protein excretion. And renal cortex SOD content was negatively associated with 24h urinary protein excretion (r =−0.861, P <0.01). Conclusions: ARE may ameliorate the proteinuria by suppressing the over expression of eNOS, and inhibiting the oxidative injury in ADR nephropathy rats. [Copyright &y& Elsevier]

Abstract: Due to the importance of pancreatic cholesterol esterase (CEase) as a potential target in atherosclerosis and for the development of hypocholesterolemic agents, there are increasing interests in designing and synthesizing CEase inhibitors. In the present study, we prepared forty-five isocoumarin phosphorus analogues (i.e., phosphaisocoumarins) and investigated the inhibition of these compounds on the CEase. The results showed that some phosphaisocoumarins could act as potent inhibitors of CEase. The most potent inhibitors, compounds 9d, 10a and 12e give IC50 values of 4.8 μM, 2.3 μM and 1.9 μM, respectively. The inhibition mechanism and kinetic characterization studies indicate that they are reversible competitive inhibitors. [Copyright &y& Elsevier]

Magnolol and honokiol are the two major active ingredients with similar structure and anticancer activity from traditional Chinese medicine Magnolia officinalis , and honokiol is now in a phase I clinical trial (CTR20170822) for advanced non-small cell lung cancer (NSCLC). In search of potent lead compounds with better activity, our previous study has demonstrated that magnolol derivative C2 , 3-(4-aminopiperidin-1-yl)methyl magnolol, has better activity than honokiol. Here, based on the core of 3-(4-aminopiperidin-1-yl)methyl magnolol, we synthesized fifty-one magnolol derivatives. Among them, compound 30 exhibited the most potent antiproliferative activities on H460, HCC827, H1975 cell lines with the IC 50 values of 0.63–0.93 μM, which were approximately 10- and 100-fold more potent than those of C2 and magnolol, respectively. Besides, oral administration of 30 and C2 on an H460 xenograft model also demonstrated that 30 has better activity than C2. Mechanism study revealed that 30 induced G0/G1 phase cell cycle arrest, apoptosis and autophagy in cancer cells. Moreover, blocking autophagy by the autophagic inhibitor enhanced the anticancer activity of 30 in vitro and in vivo , suggesting autophagy played a cytoprotective role on 30 -induced cancer cell death. Taken together, our study implied that compound 30 combined with autophagic inhibitor could be another choice for NSCLC treatment in further investigation. New Magnolol Derivatives Synthesized for the Treatment of NSCLCHere, fifty-one magnolol derivatives were synthesized based on the core of 3-(4-aminopiperidin-1-yl)methyl magnolol, and compound 30 exhibited the most potent antiproliferative activities on H460, HCC827, H1975 cell lines with the IC 50 values of 0.63–0.93 μM. Mechanism study revealed that blocking autophagy by the autophagic inhibitor enhanced the anticancer activity of 30 in vitro and in vivo , suggesting autophagy played a cytoprotective role on 30 -induced cancer cell death. Image 1 • Series of magnolol derivatives were designed and synthesized. • Compound 30 exhibited potent antiproliferative activities in vitro and in vivo. • SAR, in vitro metabolism, and antitumor mechanism were investigated. • Blocking autophagy could enhance the anticancer activity of 30. [ABSTRACT FROM AUTHOR]

• NK cells are activated rather than suppressed in PQ-induced lung injury. • The NK cells are reduced in acute PQ poisoning model. • Depletion of NK cells in vivo attenuates PQ-induced lung injury. • Depletion of NK cells reverses the PQ induced-macrophages polarization. Acute lung injury is the main causative factor in paraquat dichloride (PQ)-induced mortality. The innate immune system-triggered detrimental inflammatory cascade plays a vital role in PQ-induced acute lung injury. However, the role of natural killer (NK) cells, which are essential for innate response, in PQ-induced acute lung injury remains largely unknown. Here, we found that in an acute PQ poisoning model, depletion of NK cells attenuated PQ-induced lung injury by inhibiting macrophage polarization towards the M1 type. Specifically, the percentages of NK cells were reduced in the lung, spleen, and peripheral blood in a murine model of acute PQ poisoning. NK cells were aberrantly activated, evidenced by upregulation of the activating markers CD69, CD107a, and NKG2D and downregulation of the inhibitive marker KLRG1. Further, NK-specific depletion in mice greatly prolonged the survival time and ameliorated reactive oxygen species-induced damage following PQ treatment compared with the control group. Importantly, NK cell depletion alleviated macrophage and neutrophil infiltration in the lung and reversed PQ induced-macrophage polarization towards the pro-inflammatory M1 type. Our study demonstrates a crucial role of NK cells and NK cell-to-macrophage interaction in PQ-induced acute lung injury. [ABSTRACT FROM AUTHOR]

The ring-opening copolymerization of lactide with carbonate is an available strategy to incorporate reactive groups to the pendent sites of copolymer for further functional modification. A series of random and block copolymers were synthesized from l -lactide (L -LA) and 2-bromomethyl-2-methyltrimethylene carbonate (BMTC) using dodecanol as initiator and stannous octoate as catalyst. The structures of the copolymers were characterized by nuclear magnetic resonance (1H NMR, 13C NMR), gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). The composition of the copolymers can be controlled through changing the feed ratios of n BMTC / n L -LA. It was found the random P(BMTC- co - L LA) copolymers had the semicrystalline characteristic due to the relative long block-like segments of P L LA (L L , P L LA = 5.3–7.3) and the polar interactions from bromo groups, but their crystallinity (X c, P L LA) and melting temperature (T m, P L LA) decreased when the BMTC content increased. The X c, P L LA and T m, P L LA of P(BMTC- b -P L LA) block copolymers were relatively higher than the corresponding random copolymers, and approached gradually to the pure P L LA with the increase of the molecular weight of P L LA block. Finally, the pendent bromo groups of P(BMTC- co - L LA) were easily transformed into azides, which could proceed the azide-alkyne click reaction smoothly and quantitatively at room temperature. Image 1 • Bromine-functionalized poly(carbonate-co-lactide)s were synthesized successfully. • The composition and structure of the copolymers could be controlled precisely. • The random P(BMTC- co - L LA) copolymers exhibited the characteristic of semicrystalline. • Bromine-functionalized poly(carbonate-co-lactide)s could undergo post-polymerization modification easily and efficiently. [ABSTRACT FROM AUTHOR]