Factors affecting continuous renal replacement therapy duration in critically ill patients: A retrospective study.

INTRODUCTION: This study aimed to analyze the factors affecting continuous renal replacement therapy (CRRT) duration in critically ill patients and provide a reference for clinical treatment. MATERIAL AND METHODS: We divided patients into regional citrate anti-coagulation (RCA) and low-molecular-weight-heparin (LMWH) groups according to the anti-coagulation method and collected the relevant data, to analyze the factors associated with CRRT time. RESULTS: Compared with the LMWH group, the RCA group had a longer mean treatment time (55.36 ± 22.57 vs. 37.65 ± 27.09 h, p < 0.001), lower transmembrane pressure, and lower filter pressure, regardless of vascular access site. Multivariable linear regression analysis showed a significant correlation between anti-coagulation patterns, filter pressure at CRRT discontinuation, nurses' level of intensive care unit experience, pre-machine fibrinogen level, and CRRT time. CONCLUSION: Anti-coagulation is the most important factor affecting CRRT duration. Filter pressure, nurses' level of intensive care unit experience, and fibrinogen level also affecting CRRT duration.

New 7-Chloro-9-methyl-2-phenyl-3,4-dihydro-ß-carbolin-2-iums as Promising Fungicide Candidates: Design, Synthesis, and Bioactivity.

As our further research, a series of new 7-chloro-9-methyl-2-phenyl-3,4-dihydro-ß-carbolin-2-iums were designed and synthesized. Twelve compounds were found with excellent inhibition activity in vitro on three to five out of six phytopathogenic fungi, superior to standard drugs thiabendazole and/or azoxystrobin. Especially, 18 displayed the highest activity against three out of the fungi and the highest comprehensive activity for all of the fungi. The test in vivo revealed that 18 at 50 µg/mL was able to completely control Physalospora piricola infections in apples over 8 days. Scanning/transmission electron microscopic observations found that 18 could damage the hyphal integrity and cell membrane structure of P. piricola. The safety evaluation showed that 18 had no effect on the germination rate of cowpea seed at ≤200 µg/mL. The SAR revealed that the combination of 7-Cl and 2'- or 4'-alkyl is conducive to improvement of the activity. Thus, 7-chloro-9-methyl-2-phenyl-3,4-dihydro-ß-carbolin-2-ium is a promising antifungal lead scaffold.

Simple Analogues of Quaternary Benzo[c]phenanthridine Alkaloids: Discovery of a Novel Antifungal 2-Phenylphthalazin-2-ium Scaffold with Excellent Potency against Phytopathogenic Fungi.

Inspired by sanguinarine and chelerythrine, a novel antifungal 2-phenylphthalazin-2-ium scaffold as a simple analogue was designed. Most of the 30 compounds showed excellent inhibition activity against almost all eight phytopathogenic fungi, far superior to sanguinarine and chelerythrine. A third of the compounds were more active than azoxystrobin in most cases. Compounds 26 and 27 showed the highest total activity against all the fungi with EC50 means of ca. 4.6 µg/mL. Fusarium solani showed the highest susceptibility with an EC50 mean of 3.62 µg/mL to 19 compounds. A concentration of 25.0 µg/mL 27 can fully control the Colletotrichum gloeosporioides infection in apples over 9 days. Electron microscopic observations showed that 27 was able to damage the structures of the hypha and cell membrane. The structure-activity relationship showed that the presence of electron-withdrawing groups on the C-ring increases the activity against most of the fungi. Thus, 2-phenylphthalazin-2-ium compounds represent promising leads for the development of novel fungicides.

Design, synthesis and biological evaluation of novel neuchromenin analogues as potential antifungal agents.

In continuation of our program to discover new potential antifungal agents, thirty-two neuchromenin analogues were synthesized and characterized by the spectroscopic analysis. By using the mycelium growth rate method, the target compounds were evaluated systematically for antifungal activities in vitro against six plant pathogenic fungi, and structure-activity relationships (SAR) were derived. Compounds 6b-c, and 6l showed obvious inhibition activity on each of the fungi at 50 µg/mL. For the corresponding fungi, 7 of the compounds showed average inhibition rates of >80% at 50 µg/mL; especially, compounds 6b, 6d-e, and 6i-l displayed more potent antifungal activity against A. solani than that of thiabendazole (a positive control). Moreover, compound 6c also exhibited good activity against C. lunata with EC50 values of 12.7 µg/mL, and the value was much superior to that of thiabendazole (EC50 = 59.7 µg/mL). SAR analysis showed that the presence of conjugated structure, bearing a C=C bond conjugated to the C=O group, obviously decreased the activity; the type and position of the substituted R5 significantly influenced the activity. Furthermore, the significantly bioactive compounds 6b-e, 6g, 6i and 6l showed very low toxicities against HL-7702, BEL-7402 and HCT-8 cells. Resistance development assay indicated that compounds 6b-e and 6l failed to induce the two tested strains of fungi to develop resistance. SEM analysis initially revealed that compound 6d may exert its antifungal effect by damaging fungal cell wall.

New 2-aryl-6-methyl-3,4-dihydro-ß-carbolin-2-iums as potential antifungal agents: Synthesis, bioactivity and structure-activity relationship.

Thirty new title compounds along with five known analogues were prepared from commercially available 2-arylhydrazin-1-ium chlorides and α-ketoglutaric acid. The mycelium growth rate method was used to evaluate inhibition activity against six strains of plant pathogenic fungi. Most of the compounds displayed the activity for each the fungi at 150 µΜ, higher than azoxystrobin, a positive drug. Compound 6-2 showed the lowest average IC50 value of 4.58 µg/mL for all the fungi where F. solani exhibited the highest susceptibility to most of the compounds. For F. solani, some compounds were more active with IC50 values of 2.67-8.48 µM than thiabendazole (IC50 = 9.30 µM) and/or carbendazim (IC50 = 3.36 µM). The SAR showed that the activity is significantly affected by substituents on the A-ring and/or D-ring along with the degree of unsaturation of the C-ring. Thus, a series of new ß-carboline compounds with potent antifungal potential were found.

Bidirectional effects of moxifloxacin on the pro­inflammatory response in lipopolysaccharide­stimulated mouse peritoneal macrophages.

Sepsis is a systemic inflammatory condition in response to life­threatening infections, and macrophages are a key source of inflammatory cytokines. Moxifloxacin (MXF) has antibacterial activity in Gram­positive and Gram­negative bacteria. The present study investigated the effects of MXF on a lipopolysaccharide (LPS)­stimulated inflammatory response and gene expression in macrophages. Peritoneal macrophages were isolated from male C57BL/6J mice and treated with LPS and/or MXF. The mRNA and protein expression of toll­like receptor 4 (TLR4), sphingosine kinase 1 (SPHK1) and nuclear factor (NF)­κB was determined by quantitative polymerase chain reaction, western blotting and immunofluorescence analysis. The expression of tumor necrosis factor (TNF)­α and interleukin (IL)­6 was determined with ELISAs. The data demonstrated that MXF dose­dependently decreased the viability of macrophages, and 8 and 16 µg/ml MXF prevented the LPS­induced increase in TLR4, SPHK1, NF­κB p65, TNF­α and IL­6 expression. The inhibition was most effective at a concentration of 16 µg/ml MXF, whereas, 64 µg/ml MXF exerted a pro­inflammatory effect. Collectively, the data demonstrated a bidirectional effect of MXF: Lower MXF concentrations (8 and 16 µg/ml) inhibited the inflammatory response; however, a higher MXF concentration (64 µg/ml) had a pro­inflammatory effect on LPS­treated mouse peritoneal macrophages. In conclusion, these results suggested the importance of MXF as an inhibitor of the inflammatory response at an optimal dose. MXF inhibition of the inflammatory response may be mediated by TLR4 signaling.

Bioactivity and structure-activity relationship of cinnamic acid derivatives and its heteroaromatic ring analogues as potential high-efficient acaricides against Psoroptes cuniculi.

A series of cinnamic acid derivatives and its heteroaromatic ring analogues were synthesized and evaluated for acaricidal activity in vitro against Psoroptes cuniculi, a mange mite. Among them, eight compounds showed the higher activity with median lethal concentrations (LC50) of 0.36-1.07mM (60.4-192.1µg/mL) and great potential for the development of novel acaricidal agent. Compound 40 showed both the lowest LC50 value of 0.36mM (60.4µg/mL) and the smallest median lethal time (LT50) of 2.6h at 4.5mM, comparable with ivermectin [LC50=0.28mM (247.4µg/mL), LT50=8.9h], an acaricidal drug standard. SAR analysis showed that the carbonyl group is crucial for the activity. The type and chain length of the alkoxy in the ester moiety and the steric hindrance near the ester group significantly influence the activity. The esters were more active than the corresponding thiol esters, amides, ketones or acids. Replacement of the phenyl group of cinnamic esters with α-pyridyl or α-furanyl significantly increase the activity. Thus, a series of cinnamic esters and its heteroaromatic ring analogues with excellent acaricidal activity emerged.

Design, Bioactivity and structure-activity of 3-Arylpropionate Derivatives as Potential High-Efficient Acaricides against Psoroptes Cuniculi.

A series of 3-aryl propionic esters and their analogues were designed and evaluated for acaricidal activity in vitro against Psoroptes cuniculi, a mange mite. The structure-activity relationship (SAR) was also discussed. The results showed that 6 compounds possessed the excellent activity (LC50 = 0.17-0.24 mM, LT50 = 1.5-2.9 h), superior to ivermectin (LC50 = 0.28 mM, LT50 = 8.9 h) (P < 0.05), a standard drug. Furthermore, 7 compounds showed the good activity (LC50 = 0.25-0.37 mM, LT50 < 3.9 h), slightly lower or close to that of ivermectin. One compound displayed super-fast acaricidal property, far superior to ivermectin. SAR analysis found that the ester group is vital for the activity and the small steric hindrance adjacent to the ester group is advantageous for the high activity. The

[LncRNA MALAT1 Modulates the Immunoreaction of Rats with Lipopolysaccharide-induced Sepsis by Targeting the miR-146a/NF-κB P65 Pathway].

OBJECTIVE: To determine the regulatory and molecular mechanism of lncRNA MALAT1 in response to sepsis induced by lipopolysaccharide (LPS) in rats. METHODS: The expressions of lncRNA MALAT1 and miR-146a in U937 cells and peripheral blood samples of the rats with and without LPS-induced sepsis were detected using quantitative real-time reverse transcription PCR (qRT-PCR). The relationship between lncRNA MALAT1 and miR-146a was affirmed through luciferase assay. The expressions of p-P65, P65, TNF-α and iNOS were tested by Western blot. The expressions of TNF-α and iNOS in the lung tissues of the rats were measured by immunohistochemistry. RESULTS: The rats with LPS-induced sepsis had higher expressions of lncRNA MALAT1 in U937 cells than those without sepsis (P<0.001). In comparison with scramble, si-MALAT1 attenuated the expression of lncRNA MALAT1 and increased the expression of miR-146a (P<0.001). MiR-146a was the target of lncRNA MALAT1. si-MALAT1 decreased the p-P65/P65 ratio and and the expressions of TNF-α and iNOS in the rats with LPS-induced sepsis. In contrast, miR-146a inhibitor increased p-P65/P65 ratio and the expressions of TNF-α and iNOS in the rats with LPS-induced septis (P<0.001). Co-transfection with si-MALAT1 attenuated the elevated level of p-P65/P65 ratio and expressions of TNF-α and iNOS resulting from miR-146a inhibitor (P<0.001). LPS and scramble decreased the expression of miR-146a and increased the p-P65/P65 ratio compared with the healthy controls (P<0.01). Compared with scramble, si-MALAT1 increased the expression of miR-146a and attenuated the p-P65/P65 ratio (P<0.01). Higher numbers of TNF-α and iNOS positive cells were found in those with LPS-induced sepsis and those with scramble interventions (P<0.001). Compared with scramble, si-MALAT1 reduced the number of TNF-α and iNOS positive cells (P<0.01). CONCLUSIONS: LncRNA MALAT1 modulates the immunoreaction of rats with LPS -induced sepsis by targeting miR-146a/NF-κB P65.

Cytotoxic activity, apoptosis induction and structure-activity relationship of 8-OR-2-aryl-3,4-dihydroisoquinolin-2-ium salts as promising anticancer agents.

As our continuing research, a series of 2-aryl-8-OR-3,4-dihydroisoquinolin-2-ium bromides were evaluated for cytotoxic activity on cancer cells and apoptosis induction in the present study. SAR was derived also. Among them, 23 compounds showed the higher cytotoxicity on MKN-45 cells with IC50 values of 1.99-11.3µM than a standard anticancer drug cis-platinum (IC50=11.4µM) or their natural model compound chelerythrine (IC50=12.7µM); 16 compounds possessed the medium to high activity on NB4 cells with IC50 values of 1.67-4.62µM. SAR analysis showed that both substitution patterns of the N-aromatic ring and the type of 8-OR significantly impact the activity. AO/EB staining and flow cytometry analysis with Annexin V/PI double staining showed that the compounds were able to induce apoptosis in a concentration-dependent manner. The results above suggested that the title compounds are a class of promising compounds for the development of new anti-cancer drugs.

Synthesis and in Vitro Antifungal Activities of Novel Benzamide Derivatives Containing a Triazole Moiety.

The study reported the synthesis and antifungal activities in vitro against six phytopathogenic fungi of 17 novel N-[2-hydroxy-3,3-dimethyl-2-[(1H-1,2,4-triazol-1-yl)methyl]butyl]benzamide derivatives. All the target compounds were synthesized and elucidated by means of MS, high resolution (HR)-MS, IR, (1)H- and (13)C-NMR analysis. The results showed that almost all the derivatives exhibited good activities against each of the tested fungi at the concentration of 50 µg/mL. Among them, 6h displayed excellent activity against Alternaria alternata with the median effective concentration value (EC50) of 1.77 µg/mL, superior to myclobutanil (EC50=6.23 µg/mL), a commercial fungicide with broad-spectrum bioactivities for plant protection and high-efficiency. Compound 6k showed the broadest antifungal spectrum, demonstrating positive activities against the corresponding fungi with EC50 values ranging from 0.98 to 6.71 µg/mL. Furthermore, 6e to 6i revealed good activities against Alternaria solani with EC50 values of 1.90, 4.51, 7.07, 2.00 and 5.44 µg/mL, respectively. The preliminary analysis of structure-activity relationship (SAR) demonstrated that the presence of F or Cl on the benzene ring remarkably improved the activity, while the introduction of 4-OMe or CF3 group decreased the activity in varying degrees. Thus, the present results strongly suggest that N-[2-hydroxy-3,3-dimethyl-2-[(1H-1,2,4-triazol-1-yl)methyl]butyl]benzamide derivatives should be promising candidates for the development of novel antifungal agents in the effective control of phytopathogenic fungi.

2-(Substituted phenyl)-3,4-dihydroisoquinolin-2-iums as novel antifungal lead compounds: biological evaluation and structure-activity relationships.

The title compounds are a class of structurally simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs). In order to develop novel QBA-like antifungal drugs, in this study, 24 of the title compounds with various substituents on the N-phenyl ring were evaluated for bioactivity against seven phytopathogenic fungi using the mycelial growth rate method and their SAR discussed. Almost all the compounds showed definite activities in vitro against each of the test fungi at 50 µg/mL and a broad antifungal spectrum. In most cases, the mono-halogenated compounds 2-12 exhibited excellent activities superior to the QBAs sanguinarine and chelerythrine. Compound 8 possessed the strongest activities on each of the fungi with EC50 values of 8.88-19.88 µg/mL and a significant concentration-dependent relationship. The SAR is as follows: the N-phenyl group is a high sensitive structural moiety for the activity and the characteristics and position of substituents intensively influence the activity. Generally, electron-withdrawing substituents remarkably enhance the activity while electron-donating substituents cause a decrease of the activity. In most cases, ortha- and para-halogenated isomers were more active than the corresponding m-halogenated isomers. Thus, the title compounds emerged as promising lead compounds for the development of novel biomimetic antifungal agrochemicals. Compounds 8 and 2 should have great potential as new broad spectrum antifungal agents for plant protection.

Synthesis and in vitro antifungal activities of new 2-aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium bromides.

2-Aryl-3,4-dihydroisoquinolin-2-iums might be considered as a class of simple analogues of natural quaternary benzo[c]phenanthridine alkaloids. In this paper, 26 new 2-aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium bromides with various substituents in N-aromatic ring were synthesized from commercially available 1,3-benzodioxole in good to excellent yields. All the compounds were elucidated by MS, high resolution (HR)-MS, IR, (1)H- and (13)C-NMR analysis, and evaluated for antifungal activities in vitro against Alternaria alternate, Curvularia lunata and Fusarium oxysporum sp. niveum at 50 µg/mL. Most of the compounds showed higher activities against all the test fungi than their natural model compounds sanguinarine and chelerythrine. For A. alternate and Curvularia lunata, most of them were also more active than thiabendazole, a commercial fungicide standard. The structure-activity relationship indicated that the substituent in N-aromatic ring and its position had significant effect on the activity. The general trend was that halogen atoms and CF3 remarkably enhanced the activity while CH3 and OCH3 decreased the activity. Generally, o-substituted isomers were more active than m- and p-substituted isomer. The present results suggest that the title compounds are potential for the development of new isoquinoline antimicrobial agents.

Synthesis of 2-aryl-3,4-dihydroisoquinolin-2-ium bromides and their in vitro acaricidal activity against Psoroptes cuniculi.

By employing sanguinarine, a natural active quaternary isoquinoline alkaloid, as a model molecule, a series of structurally simple quaternary 2-aryl-3,4-dihydroisoquinolin-2-ium compounds were designed and synthesized and evaluated for in vitro acaricidal activity against P. cuniculi. A new approach towards the title compounds was developed with isochroman as starting material. The results showed that 22 of 24 tested compounds displayed the activity in varying degrees at 0.4 mg/mL. Fourteen compounds were significantly more effective than ivermectin, a standard acaricide, and 6-methoxy dihydrosanguinarine, a derivative of sanguinarine (p<0.05). And their comprehensive relative activity was 1.4 to 16.5 times than that of ivermectin and 1.5 to 18.8 times than that of 6-methoxy dihydrosanguinarine. The structure-activity relationship indicated that the introduction of a substituent to N-benzene ring, especially halogen atom and trifluoromethyl group, led to great improvement of the activity. The position of fluorine atom, methyl group and hydroxyl group made very significant effects on the activity. It was concluded that 2-aryl-3,4-dihydroisoquinolin-2-iums are very promising candidates for the development of new isoquinoline acaricidal agents.

In vitro antifungal activity of sanguinarine and chelerythrine derivatives against phytopathogenic fungi.

In order to understand the antifungal activity of some derivatives of sanguinarine (S) and chelerythrine (C) and their structure-activity relationships, sixteen derivatives of S and C were prepared and evaluated for in vitro antifungal activity against seven phytopathogenic fungi by the mycelial growth rate method. The results showed that S, C and their 6-alkoxy dihydro derivatives S1-S4, C1-C4 and 6-cyanodihydro derivatives S5, C5 showed significant antifungal activity at 100 µg/mL against all the tested fungi. For most tested fungi, the median effective concentrations of S, S1, C and C1 were in a range of 14-50 µg/mL. The structure-activity relationship showed that the C=N+ moiety was the determinant for the antifungal activity of S and C. S1-S5 and C1-C5 could be considered as the precursors of S and C, respectively. Thus, the present results strongly suggested that S and C or their derivatives S1-S5 and C1-C5 should be considered as good lead compounds or model molecules to develop new anti-phytopathogenic fungal agents. can't login to work station for 2hrs--took 2 hrs vacation

Isolation, identification and antimicrobial activities of two secondary metabolites of Talaromyces verruculosus.

From the ethyl acetate extract of the culture broth of Talaromyces verruculosus, a rhizosphere fungus of Stellera chamaejasme L., (-)-8-hydroxy-3-(4-hydroxypentyl)-3,4-dihydroisocoumarin (1) and (E)-3-(2,5-dioxo-3-(propan-2-ylidene)pyrrolidin-1-yl)acrylic acid (2) were isolated and evaluated for their antimicrobial activities. Their structures were elucidated by UV, IR, MS, 1H-NMR, 13C-NMR and 2D NMR spectra. Compound 1 exhibited the significant activities in vitro against two strains of bacteria and four strains of fungi. Compound 2 gave slight activities on the fungi at 100 µg mL(-1), but no activities on the bacteria. Compound 1 should be considered as a new lead or model compound to develop new isocoumarin antimicrobial agents.

Structural modification of sanguinarine and chelerythrine and their in vitro acaricidal activity against Psoroptes cuniculi.

Sanguinarine (1) and chelerythrine (2) are two quaternary benzo[c]phenanthridine alkaloids (QBAs). Eighteen derivatives of 1 and 2 were synthesized by modification of C=N(+) bond and evaluated for their in vitro acaricidal activity against Psoroptes cuniculi, a mange mite. A new method was developed to prepare 6-alkoxy dihydro derivatives of 1 and 2 (1a-e, 2a-e). Among all the compounds, only 6-alkoxy dihydrosanguinarines (1a-e) showed significant acaricidal activity at 5.0 mg/mL and 1a possessed the strongest activity (50% lethal concentrations (LC(50))=339.70±0.75 mg/L, 50% lethal time (LT(50))=6.53±0.04 h), comparable with a standard drug ivermectin (LC(50)=168.19±11.79 mg/L, LT(50)=16.54±0.11 h). The iminium moiety in 1 and 2 was proven to be the determinant for their acaricidal properties. 6-Alkoxy dihydro derivatives (1a-e, 2a-e) were prodrugs of 1 and 2. Compared with 7,8-dimethoxy groups, 7,8-methylenedioxy group was able to significantly improve the bioactivity. The present results suggested that QBAs are promising candidates or lead compounds for the development of new isoquinoline acaricidal agents.

Structural modification of sanguinarine and chelerythrine and their antibacterial activity.

In this study, five derivatives of sanguinarine (1) and chelerythrine (2) were prepared, with 1 and 2 as starting materials, by reduction, oxidation and nucleophilic addition to the iminium bond C=N+. The structures of all compounds were elucidated on account of their MS, ¹H-NMR and ¹³C-NMR data. The antibacterial activities of all compounds were screened, using Staphylococcus aureus, Escherichia coli, Aeromonas hydrophila and Pasteurella multocida as test bacteria. The minimum bacteriostatic concentration and minimum bactericidal concentration of the active compounds were determined by the turbidity method. The structure-activity relationships of 1 and 2 were discussed. The results showed that 1, 2 and their pseudoalcoholates were found to be potent inhibitors to S. aureus, E. coli and A. hydrophila, while the other derivatives were found to be inactive. The pseudoalcoholates might be the prodrugs of 1 and 2. The iminium bond in the molecules of 1 or 2 was the determinant for antibacterial activity, and the substituents at the 7 and 8 positions influenced the antibacterial activities of 1 and 2 against different bacteria.

[Study on antibacterial active components from Viola yedoensis].

OBJECTIVE: Study on the antibacterial activity of Viola yedoensis and the antibacterial active compounds. METHOD: The chemical compositions were isolated by means of solvent extraction, column chromatography on silica gel, sephadex LH-20 and crystallization. The antibacterial activities were tested by Neo-Sensitab disk-diffusion method, nephelometric analysis and plating method. RESULT: One new compound (4) along with three known compounds were isolated from this plant for the first time and were identified as aesculetin (1), 6,7-dimethoxycoumarin (2), scopoletin (3) and 5-methoxy-7-hydroxymethylcoumarin (4), respectively. All the compounds showed antibacterial and antibactericidal activities at varying degree on Streptococcus Aureas, S. agalactiae, S. uberis, S. dysgalactiae, E. coli and Salmonella, of which 1 was most active with 0.031- 0.313 g x L(-1) of minimal inhibitory concentrations (MIC) and 0.313 - 0.625 g x L(-1) of minimal bactericidal concentrations (MBC). CONCLUSION: Viola yedoensis has a broad spectrum of antibacterial activity on animal pathogenic bacteria, and coumarins may be the main antibacterial activity ingredients.

(E)-3-[2,5-Dioxo-3-(propan-2-yl-idene)pyrrolidin-1-yl]acrylic acid.

The title compound, C(10)H(11)NO(4), was extracted from a culture broth of Penicillium verruculosum YL-52. The mol-ecular structure is essentially planar, with an r.m.s. deviation of 0.01342 (2) Šfor the non-H atoms. In the crystal structure, adjacent mol-ecules are connected into a centrosymmetric dimer through a pair of O-H⋯O hydrogen bonds. The dimers are further extended into a chain by weak C-H⋯O hydrogen bonds.