Marbofloxacin combined with heavy rare-earth ions makes better candidates for veterinary drugs: crystal structure and bio-activity studies.

Marbofloxacin (MB) is a newly developed fluoroquinolone antibiotic used especially as a veterinary drug. It may be regarded as the improved version of enrofloxacin owing to its antibacterial activity, enhanced bioavailability, and pharmacokinetic-pharmacodynamic (PK-PD) properties. In this study, nine heavy rare-earth ions (Y, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu) were selected in light of their potential antibacterial activity and satisfactory biosafety to afford the corresponding rare-earth metal complexes of MB: the MB-Ln series. Their chemical structures and coordination patterns were characterized using IR spectroscopy, HRMS, TGA, and X-ray single-crystal diffraction analysis. Our results confirmed that all the MB-Ln complexes yielded the coincident coordination modes with four MB ligands coordinating to the Ln(III) center. In vitro antibacterial screening on five typical bacteria strains revealed that the MB-Ln complexes exhibited antibacterial activities comparable with MB, as indicated by the MIC/MBC values, in which Escherichia coli and Salmonella typhi were the most sensitive ones to MB-Ln. Furthermore, the MB-Ln complexes were found to be much less toxic in vivo than MB, as suggested by the evaluated LD50 (50% lethal dose) values. All the MB-Ln series complexes fell in the LD50 range of 5000-15 000 mg kg-1, while the LD50 value of MB was only 1294 mg kg-1. Furthermore, MB-Lu, as the selected representative of MB-Ln, could effectively inhibit the activity of DNA gyrase, the same as MB, suggesting the primary antibacterial mechanism of the MB-Ln series. The results demonstrated the good prospects and potential of metal-based veterinary drugs with better drug performance.

[Outcomes and measurements of randomized controlled trial for traditional Chinese medicine in treatment of endometriosis].

This study aims to analyze the outcomes and measurements of randomized controlled trial(RCT) for traditional Chinese medicine(TCM) treatment of endometriosis(EM) and provide a basis for the building of the core outcome set(COS) of EM. The RCT for TCM treatment of EM was retrieved from medical literature databases with the time interval from inception to February 3, 2022. The Cochrane risk of bias assessment tool was employed to evaluate the risk of bias of the included RCT, and descriptive analyses of the extracted information were carried out. A total of 519 RCTs were included, with the sample sizes ranging from 28-582 patients and 239 outcome indicators(8 outcome indicators per RCT on average). According to the functional properties, the reported outcome indicators were classified into 7 indicators: clinical efficacy assessment, indicators of clinical symptoms and signs, TCM symptom efficacy indicators, physical and chemical examinations, quality of life, long-term prognosis, and safety events. All the 519 RCTs had problems, such as the lack of differentiation between primary and secondary outcome indicators(1.73% RCTs reported such differen-tiation), poor quality, confused criteria for composite outcome indicators and arbitrary combination of indicators(45 criteria for the single outcome indicator of efficiency), and messy measurements(as many as 18 measurements for TCM symptom score). In addition, as a chronic disease, EM requires long-term management. The outcome indicators vary for the patients in different disease stages, such as EM pain, EM infertility, and post-operative EM, while the specific outcome indicator sets for different EM populations remain to be developed. In addition, the time point of measurement for EM long-term outcomes remains unclear, and the definition of TCM syndromes lacks standards. The RCT for TCM treatment had a variety of problems, such as the lack of differentiation of outcome indicators, confusion in criteria and measurements, lack of specific outcome indicator sets for different EM populations, and unclear time points for long-term outcomes. Therefore, the studies about COS need to be carried out urgently.

The copper(II) complex of dantron showed therapeutic effect on bacterial gill-rot disease in tilapia infected by Flavobacterium columnar.

Dantron (DA), a kind of polyhydric anthraquinone and one of the bio-active ingredient in Rheum officinale was chosen as the ligand to coordinate with the bio-active copper(II) ion to achieve its antibacterial copper(II) complex, DA-Cu. The coordination structure of DA-Cu, both in the crystal state and solution state, was studied by spectroscopy and X-ray single-crystal diffraction analysis. The inhibition zone, MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) values regarding the in vitro antibacterial activity of DA-Cu towards Flavobacterium columnar, which causes the bacterial gill-rot disease on fish, were significant and specific. DA-Cu in vivo acute toxicity on zebrafish and tilapia was evaluated, suggesting that the higher dose of DA-Cu than 0.1 mg/mL might give potential toxicity. The further therapeutic effect of DA-Cu on the tested tilapia challenged by Flavobacterium columnar was also studied, which showed its clear advantage (including the survival rate, relative weight gain rate, and feed conversion ratio) over DA and the positive control, Sanhuang San, at a much lower dosage of 0.025 mg/mL.

A New Calcium(II)-Based Substitute for Enrofloxacin with Improved Medicinal Potential.

Enrofloxacin (EFX) reacting with Ca(II) afforded a new complex, [Ca(EFX)2(H2O)4] (EFX-Ca), which was structurally characterized both in solid and solution chemistry. E. coli and S. typhi were tested to be the most sensitive strains for EFX-Ca. The LD50 value of EFX-Ca in mice was 7736 mg/kg, implying the coordination of EFX to Ca(II) effectively reduced its acute toxicity. EFX-Ca also decreased the plasma-binding rate and enhanced the drug distribution in rats along with longer elimination half-life. EFX-Ca also showed similar low in vivo acute toxicity and higher anti-inflammation induced by H2O2 or CuSO4 in zebrafish, with reactive oxygen species (ROS)-related elimination. The therapeutic effects of EFX-Ca on two types (AA and 817) of E. coli-infected broilers were also better than those of EFX, with cure rates of 78% and 88%, respectively. EFX-Ca showed promise as a bio-safe metal-based veterinary drug with good efficacy and lower toxicity.

The first copper(I) complex of anthrahydrazone with potential ROS scavenging activity showed significant in vitro anticancer activity by inducing apoptosis and autophagy.

Based on the anticancer pharmacophore of anthrahydrazone and quinoline, a new quinolylanthrahydrazone ligand, 9-AQH (anthracene-9-quinolylhydrazone), was synthesized to further afford four metal complexes, [CoII(9-AQH)(NO3)2(H2O)] (1), [NiII(9-AQH)2(H2O)2]·2NO3 (2), [CuI(9-AQH)2]·NO3 (3), [ZnII(9-AQH)2(NO3)]·NO3 (4), determined by X-ray single crystal diffraction analysis. The reaction of Cu(NO3)2 with 9-AQH formed the stable and repeatable copper(I) complex 3. In vitro screening demonstrated only 3 showed significant and broad-spectrum anticancer activity, indicating that Cu(I) played a key role in exerting the anticancer activity. In solution, Cu(I) was not naturally oxidized to Cu(II) suggested by 1H-NMR (Nuclear Magnetic Resonance) and EPR (Electron Paramagnetic Resonance) analysis. The presence of 3 could also catalyze the H2O2 system to give hydroxyl free radicals, suggested by further EPR and electrophoresis assay. At the cellular level, although no obvious Cu(II) signals were detected and the total ROS (Reactive Oxygen Species) scavenging in the tumor cells treated with 3, the potential redox property between Cu(I)/Cu(II), as a key role, should not be denied for the significant anticancer activity of 3, considering the much complicated circumstance and other reductive substances in cells. The anticancer mechanism of 3 on the most sensitive MGC-803 cells pointed to significant cell apoptosis through mitochondrial pathway, rather than cell cycle arrest. While the autophagy observed in tumor cells treated by 3 suggested its complicated anticancer mechanism, and whether there was an intrinsic correlation still needed to be further investigated.

Structural characterization and pharmacological assessment in vitro/in vivo of a new copper(II)-based derivative of enrofloxacin.

Enrofloxacin (EFX) was selected as the medicinal ligand to afford a new copper(ii)-based complex, EFX-Cu, which was structurally characterized by spectroscopic analyses including X-ray single crystal diffraction. It was also stable and could retain the coordination state in aqueous solution. The in vitro antibacterial activity of EFX-Cu against a panel of pathogenic bacteria was about the same as that of EFX, except that it was twice as active against E. coli. The in vivo test on mice gave a LD50 value of 8148 mg kg-1 for EFX-Cu, which was much lower than those for EFX (LD50, 5312 mg kg-1) and its clinically used sodium salt, EFX-Na (LD50, 1421 mg kg-1). In addition, no obvious lesions in the organs of the dead mice were found by histopathological examination. Pharmacokinetic studies on rats suggested similar pharmacokinetics between EFX-Cu and EFX. On the other hand, EFX-Cu showed higher acute toxicity than EFX-Na in zebrafish, which was inconsistent with that in mice. The ROS-related inflammation and anti-inflammatory assay of EFX-Cu, respectively, in normal cells and zebrafish could be ascribed to its ROS-related redox property. Unfortunately, the final in vivo therapeutic assay in the E. coli-infected mouse model indicated that the therapeutic effect of EFX-Cu, mainly in terms of mortality in mice, was found to be lower than that of EFX-Na at the same dosage (800 mg kg-1, continuous gavage), although the contradictory factors between toxicity and antibacterial activity could not be excluded in this trial.

The copper(II) complexes of new anthrahydrazone ligands: In vitro and in vivo antitumor activity and structure-activity relationship.

Two new copper(II) complexes, 9-PMAH-Cu (1) and 9-FPMAH-Cu (2), of anthrahydrazone were synthesized and structurally characterized, in which 9-FPMAH (9-(4'-trifluoromethyl)-pyrimidine anthrahydrazone) is the 4'-CF3 derivative of 9-PMAH (9-pyrimidine anthrahydrazone). Both complexes 1 and 2 showed similar intercalative binding modes towards DNA and might compete with the typical DNA intercalator, GelRed, in the same binding site. They could also act as topoisomerase (type I) suppressor to effectively inhibit its activity, in which complex 1 was more effective than 2. The in vitro antitumor screening indicated that complex 1 displayed much higher antiproliferative ability than 2 and cisplatin towards all the tested tumor cell lines. On the other hand, complex 1 also showed high cytotoxicity against human normal liver cell line HL-7702, suggesting it is a potential high cytotoxic antitumor candidate. While it was also suggested that the loss of activity of complex 2 might be due to the presence of 4'-CF3 on the pyrimidine ring. Studies on the cellular level showed that complex 1 could arrest the cell cycle of the most sensitive T-24 cells at G2/M phase and induced cell apoptosis. Complex 1 further showed a significant suppression on the tumor growth on the T-24 tumor xenograft mouse model, but not reduced the body weight. Especially, complex 1 could retain its coordination state in H2O even in the presence of HSA. The results suggests that complex 1 is of enough safety to be considered as a promising anticancer candidate by combining the bioactive Cu(II) and the anthrahydrazone pharmacophore.

Structurally Diverse Labdane Diterpenoids from Leonurus japonicus and Their Anti-inflammatory Properties in LPS-Induced RAW264.7 Cells.

A phytochemical study on the aerial parts of Leonurus japonicus led to the isolation and identification of 38 labdane diterpenoids, including 18 new (1, 2, 11, 12, 16-21, 24, 30-34, 37, 38) and 20 known (3-10, 13-15, 22, 23, 25-29, 35, 36) analogues. Their structures were elucidated based on physical data analysis, including 1D and 2D NMR, HRMS, UV, IR, and X-ray diffraction. The structure of the known compound 4 was confirmed by single-crystal X-ray diffraction data. These compounds can be divided into furanolabdane (1-10), tetrahydrofuranolabdane (11-15), lactonelabdane (16-23), labdane (24-29), and seco-labdane (30-38) type diterpenoids. All compounds were screened by lipopolysaccharide (LPS)-induced nitric acid (NO) production in RAW264.7 cells to evaluate anti-inflammatory effects. Compounds 1, 5, 10-13, 16-19, 31-33, and 38 inhibited NO production with IC50 values lower than 50 µM, with compound 30 being the most active, with an IC50 value of 3.9 ± 1.7 µM. Further studies show that compound 30 inhibits pro-inflammatory cytokine production and IKK α/ß phosphorylation and restores the IκB expression levels in the NF-κB signaling pathway.

A new calcium(II) complex of marbofloxacin showing much lower acute toxicity with retained antibacterial activity.

Marbofloxacin (MB) is a newly developed veterinary drug with broad-spectrum antibacterial activity. In this study, a new calcium(II)-based complex of marbofloxacin, MB-Ca, was synthesized and structurally characterized by IR, ESI-MS, UV-Vis and single crystal X-ray diffraction analysis. The characterization of this complex in solution state indicated that the coordinated MB-Ca was partly retained, along with the monomeric and dimeric forms of MB. It also showed satisfactory water solubility (1.89 mg/mL), comparing with MB (2.82 mg/mL) at 35 °C. The in vitro antibacterial activity of MB-Ca was also screened towards a series of typical pathogenic bacteria, and determined by the methods of turbidimetry and disc diffusion. The results indicated it showed comparable antibacterial activity to MB. However, it exhibited higher inhibitive ability in vitro on DNA gyrase than MB alone. Furthermore, MB-Ca showed significantly lower acute toxicity (LD50, 3186 mg/kg) than MB (LD50, 1294 mg/kg) in mice, based on the in vivo acute toxicity test. The histopathological examination on the major organs of the mice by the oral administration of MB-Ca did not show obvious organic lesions, which is similar to those treated by MB. The research results suggest that MB-Ca could be further developed into a new promising metal-based veterinary drug and a better substitute of MB, showing unabated antibacterial activity along with lower toxicity.

[Effects of nitrogen addition on tree root traits.] / æ°®æ·»åŠ å¯¹æ ‘æœ¨æ ¹ç³»ç‰¹æ€§çš„å½±å“.

Atmospheric nitrogen deposition has complex effects on individual plants and terrestrial ecosystems. We synthesized results from 39 published papers (16 papers in English and 23 papers in Chinese) and conducted a meta-analysis to evaluate the general responses of tree root traits to nitrogen addition, and further analyzed the difference of N-induced results between English papers and Chinese papers. Our results showed that N addition significantly increased fine root diameter (+6.7%), fine root N content (+8.9%), and root respiration rate (+17.5%), but did not affect fine root biomass, fine root length, specific root length, fine root C content, and fine root C:N ratio. Different climatic zone and fertilizer types had different effects on the experimental results. In addition, experimental results published in English papers were generally more significant than those in Chinese papers. We summarized the general effects of N addition on tree root systems, and further analyzed the mechanisms underlying the effects of N enrichment on forest ecosystem carbon cycle.

[Soil seed bank and its correlations with aboveground vegetation and environmental factors in water level fluctuating zone of Danjiangkou Reservoir, Central China].

Taking the water level fluctuating zone of the Danjiangkou Reservoir as a case, and by the method of hierarchical cluster analysis, the soil seed banks at 37 sampling plots within the areas of 140-145 m elevation were divided into 6 groups, and the species composition, density, and diversity of the soil seed banks among the groups were compared. The differences between the soil seed banks and the aboveground vegetations were analyzed by S0rensen similarity coefficient, and the correlations among the soil seed banks, aboveground vegetations, and environmental factors were explored by principal component analysis (PCA) and multivariable regression analysis. At the same altitudes of the water level fluctuating zone, the species composition of the soil seed banks had obvious heterogeneity, and the density and diversity indices of the soil seed banks among different groups were great. The similarity coefficient between the soil seed banks and aboveground vegetations was low, and the species number in the soil seed banks was obviously lesser than that in the aboveground vegetations. The density of the soil seed banks was highly positively correlated with the aboveground vegetations coverage and species number and the soil texture, but highly negatively correlated with the soil water-holding capacity and soil porosity.