Discovery of Dehydroabietylamine Derivatives as Antibacterial and Antifungal Agents.

A diverse array of biologically active derivatives was derived by modifying the chemically active sites of dehydroabietylamine. Herein, we describe the synthesis of a new series of C-19-arylated dehydroabietylamine derivatives using a palladium-catalyzed C(sp3)-H activation reaction. Five analogues (3b, 3d, 3h, 3n, and 4a) exhibited antibacterial activity against Escherichia coli. Compound 4a exhibited strong inhibitory activity against DNA Topo II and Topo IV. Molecular docking modeling indicated that it can bind effectively to the target through interactions with amino acid residues. The synthesized compounds were tested in vitro for their antifungal activity against six common phytopathogenic fungi. The mechanism of action of compound 4c against Rhizoctorzia solani was investigated, revealing that it disrupts the morphology of the mycelium and enhances cell membrane permeability.

Palmitic acid induces GSDMD-mediated pyroptosis in periodontal ligament cells via the NF-κB pathway.

OBJECTIVE: Obesity can affect periodontal tissues and exacerbate periodontitis. Pyroptosis, a newly identified type of inflammatory cell death, is involved in the development of periodontal inflammation. The saturated fatty acid palmitic acid (PA) is elevated in obese patients. The effect of PA on pyroptosis in periodontal ligament cells (PDLCs) and its underlying mechanisms remain unknown. MATERIALS AND METHODS: Human PDLCs were isolated from healthy individuals and cultured for experiments. The effects of PA on PDLC pyroptosis and the underlying mechanisms were examined by transmission electron microscopy, quantitative real-time PCR and western blotting. RESULTS: The morphology of PDLCs in the PA group indicated pyroptotic characteristics, including swollen cells, plasma membrane rupture and changes in subcellular organelles. PA induced inflammatory responses in PDLCs, as indicated by an increase in IL-1ß in the cell culture supernatant. Furthermore, we found that the pyroptosis-related proteins caspase-1, caspase-4 and GSDMD were involved in PA-induced cell death. GSDMD and caspase-4 inhibitors alleviated pyroptotic death of PDLCs. Moreover, PA promoted NF-κB P65 phosphorylation. A NF-κB inhibitor decreased IL-1ß expression and partly rescued cell death induced by PA. CONCLUSION: PA activated the NF-κB pathway and induced the inflammatory response in PDLCs. Caspase-4/GSDMD mediated PDLC pyroptosis induced by PA.

Design, Synthesis, Antifungal Activity, and Molecular Docking of Streptochlorin Derivatives Containing the Nitrile Group.

Based on the structures of natural products streptochlorin and pimprinine derived from marine or soil microorganisms, a series of streptochlorin derivatives containing the nitrile group were designed and synthesized through acylation and oxidative annulation. Evaluation for antifungal activity showed that compound 3a could be regarded as the most promising candidate-it demonstrated over 85% growth inhibition against Botrytis cinerea, Gibberella zeae, and Colletotrichum lagenarium, as well as a broad antifungal spectrum in primary screening at the concentration of 50 µg/mL. The SAR study revealed that non-substituent or alkyl substituent at the 2-position of oxazole ring were favorable for antifungal activity, while aryl and monosubstituted aryl were detrimental to activity. Molecular docking models indicated that 3a formed hydrogen bonds and hydrophobic interactions with Leucyl-tRNA Synthetase, offering a perspective for the possible mechanism of action for antifungal activity of the target compounds.

[Research advances in genetic polymorphisms in Kawasaki disease]. / å·å´Žç— åŸºå› å¤šæ€æ€§çš„ç ”ç©¶è¿›å±•.

Kawasaki disease (KD) is a systemic inflammatory vascular disorder that predominantly affects children and is the leading cause of acquired heart disease in children. Although the etiology of this disease remains unclear, genome-wide association and genome-wide linkage studies have shown that some susceptible genes and chromosomal regions are associated with the development and progression of KD. With the advancement of high-throughput DNA sequencing techniques, more and more genomic information related to KD is being discovered. Understanding the genes involved in the pathogenesis of KD may provide novel insights into the diagnosis and treatment of KD. By analyzing related articles and summarizing related research advances, this article mainly discusses the T cell activation-enhancing genes that have been confirmed to be closely associated with the development and progression of KD and reveals their association with the pathogenesis of KD and coronary artery lesions.

Discovery of Novel Pimprinine and Streptochlorin Derivatives as Potential Antifungal Agents.

Pimprinine and streptochlorin are indole alkaloids derived from marine or soil microorganisms. In our previous study, they were promising lead compounds due to their potent bioactivity in preventing many phytopathogens, but further structural modifications are required to improve their antifungal activity. In this study, pimprinine and streptochlorin were used as parent structures with the combination strategy of their structural features. Three series of target compounds were designed and synthesized. Subsequent evaluation for antifungal activity against six common phytopathogenic fungi showed that some of thee compounds possessed excellent effects, and this is highlighted by compounds 4a and 5a, displaying 99.9% growth inhibition against Gibberella zeae and Alternaria Leaf Spot under 50 µg/mL, respectively. EC50 values indicated that compounds 4a, 5a, 8c, and 8d were even more active than Azoxystrobin and Boscalid. SAR analysis revealed the relationship between 5-(3'-indolyl)oxazole scaffold and antifungal activity, which provides useful insight into the development of new target molecules. Molecular docking models indicate that compound 4a binds with leucyl-tRNA synthetase in a similar mode as AN2690, offering a perspective on the mode of action for the study of its antifungal activity. These results suggest that compounds 4a and 5a could be regarded as novel and promising antifungal agents against phytopathogens due to their valuable potency.

Novel Coumarin 7-Carboxamide/Sulfonamide Derivatives as Potential Fungicidal Agents: Design, Synthesis, and Biological Evaluation.

Coumarin compounds have a variety of biological activities such as anti-tumor, anti-coagulation, anti-HIV, anti-fungal, and insecticidal. Amide and sulfonamide compounds have been used as fungicides for half a century, and dozens of varieties have been developed so far. This study focused on the introduction of carboxamide and sulfonamide moieties in a coumarin core to discover novel derivatives. Based on this strategy, we synthesized two series of novel carboxamide and sulfonamide substituted coumarin derivatives, and their fungicidal activity was also investigated. Some designed compounds possessed potential activities against six phytopathogenic fungi in the primary assays, highlighted by compound 6r. Compound 6r exhibited stronger fungicidal activity against Botrytis cinerea (EC50 = 20.52 µg/mL) and will be the lead structure for further study.

[Clinical details in the diagnosis of Kawasaki disease]. / å·å´Žç— è¯Šæ–­è¿‡ç¨‹ä¸­éœ€è¦æ³¨æ„çš„ä¸´åºŠç»†èŠ‚.

Kawasaki disease (KD) is one of the leading causes of acquired heart diseases in children aged under 5 years. The clinical manifestations of KD include fever, changes in the extremities, rash or redness at the site of bacille Calmette-Guérin vaccination, bilateral bulbar conjunctival hyperemia, changes in lips and mouth, nonsuppurative cervical lymphadenopathy, and other systemic manifestations. There are difficulties in the diagnosis of KD due to its asynchronous clinical manifestations. With reference to the latest case reports and research advances in KD, this article summarizes the clinical details in the diagnosis of KD, so as to improve the level of clinical diagnosis of KD.

Gulosibacter sediminis sp. nov., isolated from Indian Ocean marine sediment.

A novel Gram-stain-positive, catalase-positive, oxidase-negative, aerobic, non-motile, rod-shaped bacterium, designated strain YIM M12148T, was isolated from a marine sediment sample collected from the Indian Ocean. The strain grew optimally at 28 °C, pH 8.0 and in the presence of 1-3 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain YIM M12148T belongs to the genus Gulosibacter, with the highest sequence similarity to Gulosibacter faecalis NBRC 15706T (96.12 %). The cell-wall sugars of strain YIM M12148T were rhamnose, ribose, glucose and mannose. The predominant isoprenoid quinones were MK-8 and MK-9. The polar lipids consisted of major amounts of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unknown phospholipid and one unknown lipid. Major fatty acids (>5 % of the total) of the novel isolate were anteiso-C15 : 0, iso-C15 : 0, iso-C13 : 0 and anteiso-C13 : 0. The genomic DNA G+C content of strain YIM M12148T was 67.15 mol%. On the basis of genotypic and phenotypic data, it is apparent that strain YIM M12148T represents a novel species of the genus Gulosibacter, for which the name Gulosibacter sediminis sp. nov. is proposed. The type strain is YIM M12148T (=KCTC 29660T=DSM 29154T).

Diversity-oriented synthesis and antifungal activities of novel pimprinine derivative bearing a 1,3,4-oxadiazole-5-thioether moiety.

Based on the strategy of diversity-oriented synthesis and the structures of natural product pimprinine and streptochlorin, two series of novel pimprinine derivatives containing 1,3,4-oxadiazole-5-thioether moieties were efficiently synthesized under the optimized reaction conditions. Biological assays conducted at Syngenta showed the designed derivatives displayed an altered pattern of biological activity, of which 5h was identified as the most promising compound with strong activity against Pythium dissimile and also a broad antifungal spectrum in primary screening. Further structural optimization of pimprinine and streptochlorin derivatives is well under way, aiming to discover synthetic analogues with improved antifungal activity. Two series of novel pimprinine derivatives containing 1,3,4-oxadiazole-5-thioether moieties were efficiently synthesized through diversity-oriented synthesis strategy under the optimized conditions. Biological assays showed the designed derivatives exhibited potential activity.

Novel Fluorinated 7-Hydroxycoumarin Derivatives Containing an Oxime Ether Moiety: Design, Synthesis, Crystal Structure and Biological Evaluation.

A series of fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety have been designed, synthesized and evaluated for their antifungal activity. All the target compounds were determined by 1H-NMR, 13C-NMR, FTIR and HR-MS spectra. The single-crystal structures of compounds 4e, 4h, 5h and 6c were further confirmed using X-ray diffraction. The antifungal activities against Botrytis cinerea (B. cinerea), Alternariasolani (A. solani), Gibberella zeae (G. zeae), Rhizoctorzia solani (R. solani), Colletotrichum orbiculare (C. orbiculare) and Alternaria alternata (A. alternata) were evaluated in vitro. The preliminary bioassays showed that some of the designed compounds displayed the promising antifungal activities against the above tested fungi. Strikingly, the target compounds 5f and 6h exhibited outstanding antifungal activity against B. cinerea at 100 µg/mL, with the corresponding inhibition rates reached 90.1 and 85.0%, which were better than the positive control Osthole (83.6%) and Azoxystrobin (46.5%). The compound 5f was identified as the promising fungicide candidate against B. cinerea with the EC50 values of 5.75 µg/mL, which was obviously better than Osthole (33.20 µg/mL) and Azoxystrobin (64.95 µg/mL). Meanwhile, the compound 5f showed remarkable antifungal activities against R. solani with the EC50 values of 28.96 µg/mL, which was better than Osthole (67.18 µg/mL) and equivalent to Azoxystrobin (21.34 µg/mL). The results provide a significant foundation for the search of novel fluorinated 7-hydroxycoumarin derivatives with good antifungal activity.

[Clinical effect of tacrolimus in the treatment of myasthenia gravis in children].

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus in the treatment of children with myasthenia gravis (MG). METHODS: A total of 28 children with MG were treated with tacrolimus. MG-Activities of Daily Living (MG-ADL) scale was used to assess clinical outcome and safety after 1, 3, 6, 9, and 12 months of treatment. RESULTS: After tacrolimus treatment, the MG-ADL score at 1, 3, 6, 9 and 12 months was lower than that at baseline (P<0.05), and the MG-ADL score showed a gradually decreasing trend. The response rates to tacrolimus treatment at 1, 3, 6, 9, and 12 months were 59%, 81%, 84%, 88%, and 88% respectively. At 6, 9, 12, and 18 months of treatment, 4, 13, 14, and 15 children respectively were withdrawn from prednisone. No recurrence was observed during treatment. Major adverse reactions/events were asymptomatic reduction in blood magnesium in 5 children and positive urine occult blood in 1 child, which turned negative without special treatment, and tacrolimus was not stopped due to such adverse reactions/events. One child was withdrawn from tacrolimus due to recurrent vomiting. According to CYP3A5 genotypes, all of the patients were divided into two groups: slow metabolic type (n=19) and non-slow metabolic type (fast metabolic type + intermediate type; n=9). The non-slow metabolism group received a higher dose of tacrolimus, but had a lower trough concentration of tacrolimus than the slow metabolism group (P<0.05). The slow metabolism group had a higher response rates to tacrolimus treatment than the non-slow metabolism group (P<0.05). CONCLUSIONS: Tacrolimus appears to be effective and safe in the treatment of children with MG and is thus an option for immunosuppressive therapy. CYP3A5 genotyping has a certain guiding significance for determining the dosage of tacrolimus.

Molecular characterization of a new recombinant brassica yellows virus infecting tobacco in China.

Brassica yellows virus (BrYV), prevalently distributed throughout mainland China and South Korea while triggering serious diseases in cruciferous crops, is proposed to be a new species in the genus Polerovirus within the family Luteoviridae. There are three distinct genotypes (BrYV-A, BrYV-B and BrYV-C) reported in cabbage and radish. Here, we describe a new BrYV isolate infecting tobacco plants in the field, which was named BrYV-NtabQJ. The complete genome sequence of BrYV-NtabQJ is 5741 nt in length, and 89% of the sequence shares higher sequence identities (about 90%) with different BrYV isolates. However, it possesses a quite divergent region within ORF5, which is more close to Beet western yellows virus (BWYV), Beet mild yellowing virus (BMYV) and Beet chlorosis virus (BChV). A significant recombination event was then detected among BrYV-NtabQJ, BrYV-B Beijng isolate (BrYV-BBJ) and BWYV Leonurus sibiricus isolate (BWYV-LS). It is proposed that BrYV-NtabQJ might be an interspecific recombinant between BrYV-BBJ and BWYV-LS, and the recombination might result in the successful aphid transmission of BrYV from cruciferous crops to tobacco. And it also poses new challenges for BrYV diagnosis and the vegetable production.

Design, synthesis and antifungal activities of novel pyrrole- and pyrazole-substituted coumarin derivatives.

We synthesized a series of novel pyrrole- and pyrazole-substituted coumarin derivatives and evaluated their antifungal activity against six phytopathogenic fungi in vitro. The primary assay results demonstrated that some designed compounds displayed potent activities. Among them, compounds 5g, 6a, 6b, 6c, 6d and 6h exhibited more effective control than Osthole against Cucumber anthrax and Alternaria leaf spot. Furthermore, compound 5g displayed stronger antifungal activity against Rhizoctorzia solani (EC50 = 15.4 µg/mL) than positive control Osthole (EC50 = 67.2 µg/mL).

Comparison of the inhibition potential of parthenolide and micheliolide on various UDP-glucuronosyltransferase isoforms.

Parthenolide (PTL) and micheliolide (MCL) are sesquiterpene lactones with similar structures, and both of them have been reported to exhibit multiple biochemical and pharmacological activities. This study aims to investigate the inhibition of these two compounds on the activity of UDP-glucuronosyltransferases (UGTs). In vitro incubation mixture for recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition kinetics (including inhibition type and parameters) were determined, and in silico docking was employed to elucidate the inhibition difference between PTL and MCL on UGT1A1. MCL showed no inhibition toward all the UGT isoforms, and PTL showed strong inhibition toward UGT1A1. The half-maximal inhibitory concentration (IC50) of PTL on the activity of UGT1A1 was determined to be 64.4 µM. Inhibition kinetics determination showed that PTL exerted noncompetitive inhibition toward UGT1A1, and the inhibition kinetic constant (Ki) was determined to be 12.1 µM. In silico docking method has been employed to show that hydrogen bonds between PTL and the activity cavity of UGT1A1 contributed to the stronger inhibition of PTL on the activity of UGT1A1 than MCL. In conclusion, PTL can more easily induce drug-drug interaction (DDI) with clinical drugs mainly undergoing UGT1A1-catalyzed glucuronidation.

Everolimus-inhibited multiple isoforms of UDP-glucuronosyltransferases (UGTs).

1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase-II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). 2. The results showed that 100 µM of everolimus exerted more than 80% inhibition toward UGT1A1, UGT-1A3 and UGT-2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus toward the activity cavity of UGT1A3 and UGT2B7. Inhibition kinetic-type analysis using Lineweaver-Burk plot showed competitive inhibition toward all these UGT isoforms. The inhibition kinetic parameters (Ki) were calculated to be 2.3, 0.07 and 4.4 µM for the inhibition of everolimus toward UGT1A1, UGT-1A3 and UGT-2B7, respectively. 3. In vitro-in vivo extrapolation (IVIVE) showed that [I]/Ki value was calculated to be 0.004, 0.14 and 0.002 for UGT1A1, UGT-1A3 and UGT-2B7, respectively. Therefore, high DDI potential existed between everolimus and clinical drugs mainly undergoing UGT1A3-catalyzed glucuronidation.

The inhibition of UDP-glucuronosyltransferases (UGTs) by tetraiodothyronine (T4) and triiodothyronine (T3).

1. UDP-glucuronosyltransferases (UGTs) are important drug-metabolizing enzymes (DMEs) catalyzing the glucuronidation elimination of various xenobiotics and endogenous substances. Endogenous substances are important regulators for the activity of various UGT isoforms. Triiodothyronine (T3) and thyroxine (T4) are important thyroid hormones essential for normal cellular differentiation and growth. The present study aims to elucidate the inhibition behavior of T3 and T4 on the activity of UGT isoforms. 2. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to screen the inhibition potential of T3 and T4 on the activity of various UGT isoforms. Initial screening results showed that T4 exerted stronger inhibition potential than T3 on the activity of various UGT isoforms at 100 µM. Inhibition kinetics was determined for the inhibition of T4 on the representative UGT isoforms, including UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7. The results showed that T4 competitively inhibited the activity of UGT1A1, -1A3, -1A7, 1A10 and -2B7, and noncompetitively inhibited the activity of UGT1A8. The inhibition kinetic parameters were calculated to be 1.5, 2.4, 11, 9.6, 4.8 and 3.0 µM for UGT1A1, -1A3, -1A7, -1A8, -1A10 and -2B7, respectively. In silico docking method was employed to demonstrate why T4 exerted stronger inhibition than T3 towards UGT1A1. Stronger hydrogen bonds and hydrophobic interaction between T4 and activity cavity of UGT1A1 than T3 contributed to stronger inhibition of T4 towards UGT1A1. 3. In conclusion, more clinical monitoring should be given for the patients with the elevation of T4 level due to stronger inhibition of UGT isoforms-catalyzed metabolism of drugs or endogenous substances by T4.

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives.

Indazole-containing derivatives represent one of the most important heterocycles in drug molecules. Diversely substituted indazole derivatives bear a variety of functional groups and display versatile biological activities; hence, they have gained considerable attention in the field of medicinal chemistry. This review aims to summarize the recent advances in various methods for the synthesis of indazole derivatives. The current developments in the biological activities of indazole-based compounds are also presented.

Role of the lipid-regulated NF-κB/IL-6/STAT3 axis in alpha-naphthyl isothiocyanate-induced liver injury.

Alpha-naphthyl isothiocyanate (ANIT)-induced liver damage is regarded as a useful model to study drug-induced cholestatic hepatitis. Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry (UPLC-ESI-QTOF MS)-based metabolomics revealed clues to the mechanism of ANIT-induced liver injury, which facilitates the elucidation of drug-induced liver toxicity. 1-Stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:0) and 1-oleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:1) were significantly increased in serum from ANIT-treated mice, and this increase resulted from altered expression of genes encoding the lipid metabolism enzymes Chka and Scd1. ANIT also increased NF-κB/IL-6/STAT3 signaling, and in vitro luciferase reporter gene assays revealed that LPC 18:0 and LPC 18:1 can activate NF-κB in a concentration-dependent manner. Activation of PPARα through feeding mice a Wy-14,643-containing diet (0.1%) reduced ANIT-induced liver injury, as indicated by lowered ALT and AST levels, and liver histology. In conclusion, the present study demonstrated a role for the lipid-regulated NF-κB/IL-6/STAT3 axis in ANIT-induced hepatotoxicity, and that PPARα may be a potential therapeutic target for the prevention of drug-induced cholestatic liver injury.