Novel diaroylhydrazine ligands as iron chelators: coordination chemistry and biological activity

The search for orally effective drugs for the treatment of iron overload disorders is an important goal in improving the health of patients suffering diseases such as β-thalassemia major. Herein, we report the syntheses and characterization of some new members of a series of N-aroyl-N′-picolinoyl hydrazine chelators (the H₂IPH analogs). Both 1:1 and 1:2 Fe^III:L complexes were isolated and the crystal structures of Fe(HPPH)Cl₂, Fe(4BBPH)Cl₂, Fe(HAPH)(APH) and Fe(H3BBPH)(3BBPH) were determined (H₂PPH=N,N′-bis-picolinoyl hydrazine; H₂APH=N-4-aminobenzoyl-N′-picolinoyl hydrazine, H₂3BBPH=N-3-bromobenzoyl-N′-picolinoylhydrazine and H₂4BBPH=N-(4-bromobenzoyl)-N′-(picolinoyl)hydrazine). In each case, a tridentate N,N,O coordination mode of each chelator with Fe was observed. The Fe^III complexes of these ligands have been synthesized and their structural, spectroscopic and electrochemical characterization are reported. Five of these new chelators, namely H₂BPH (N-(benzoyl)-N′-(picolinoyl)hydrazine), H₂TPH (N-(2-thienyl)-N′-(picolinoyl)-hydrazine), H₂PPH, H₂3BBPH and H₂4BBPH, showed high efficacy at mobilizing ⁵⁹Fe from cells and inhibiting ⁵⁹Fe uptake from the serum Fe transport protein, transferrin (Tf). Indeed, their activity was much greater than that found for the chelator in current clinical use, desferrioxamine (DFO), and similar to that observed for the orally active chelator, pyridoxal isonicotinoyl hydrazone (H₂PIH). The ability of the chelators to inhibit ⁵⁹Fe uptake could not be accounted for by direct chelation of ⁵⁹Fe from ⁵⁹Fe–Tf. The most effective chelators also showed low antiproliferative activity which was similar to or less than that observed with DFO, which is important in terms of their potential use as agents to treat Fe-overload disease.     

金线莲挥发油化学成分的研究

采用水蒸气蒸馏法提取花叶开唇兰挥发油,用GC毛细管柱进行分析,归一化法测定其相对含量,并用GC-MS法鉴定化学成分。检出182个成分,鉴定出73个化合物,占挥发油总量的92.64%,主要成分为:正十六烷酸(25.22%)、(Z,Z)-9,12-十八碳二烯酸甲酯(6.47%)、11,14,17-二十碳三烯酸甲酯(4.42%)、(Z,Z)-9,12-十八碳二烯酸(15.35%)和(Z,Z,Z)-9,12,15-十八碳三烯酸甲酯(13.64%)。     

女性生殖道支原体感染现状及耐药性调查分析

目的 了解女性生殖道支原体感染现状及耐药性,采取有效措施降低感染率,同时为临床合理用药提供依据.方法 对415例疑似生殖道感染标本采用珠海迪尔生物有限公司生产的试剂盒进行支原体培养和药敏试验.结果 415例女性生殖道标本中,支原体感染209例,阳性率为50.4％(209/415),其中单纯解脲脲原体(Uu)感染141例,阳性率34.0％(141/415),单纯人型支原体(Mh)感染25例,阳性率6.0％ (25/415),Uu和Mh混合感染43例,阳性率为10.4％ (43/415);药敏试验结果表明:Uu、Uu+ Mh、Mh对强力霉素、交沙霉素、美满霉素、四环素敏感性普遍较高,相反对红霉素、环丙沙星、罗红霉素、氧氟沙星等敏感性较差.结论 女性生殖道支原体感染率较高,已婚育龄妇女应加强妇科检查,做到早检查、早诊断、早治疗.同时,临床医生应结合药敏试验结果合理用药,以降低女性生殖道支原体感染的发生率.     

9-Phenanthrol,a TRPM4 Inhibitor,Protects Isolated Rat Hearts from Ischemia–Reperfusion Injury

Despite efforts to elucidate its pathophysiology, ischemia–reperfusion injury lacks an effective preventative intervention. Because transient receptor potential cation channel subfamily M member 4 (TRPM4) is functionally expressed by many cell types in the cardiovascular system and is involved in the pathogenesis of various cardiovascular diseases, we decided to assess its suitability as a target of therapy. Thus, the aim of this study was to examine the possible cardioprotective effect of 9-phenanthrol, a specific inhibitor of TRPM4. Isolated Langendorff-perfused rat hearts were pretreated with Krebs–Henseleit (K–H) solution (control), 9-phenanthrol, or 5-hydroxydecanoate (5-HD, a blocker of the ATP-sensitive potassium channel) and then subjected to global ischemia followed by reperfusion with the K–H solution. To evaluate the extent of heart damage, lactate dehydrogenase (LDH) activity in the effluent solution was measured, and the size of infarcted area of the heart was measured by 2,3,5-triphenyltetrazolium chloride staining. In controls, cardiac contractility decreased, and LDH activity and the infarcted area size increased. In contrast, in hearts pretreated with 9-phenanthrol, contractile function recovered dramatically, and the infarcted area size significantly decreased. The cardioprotective effects of 9-phenanthrol was not completely blocked by 5-HD. These findings show that 9-phenanthrol exerts a cardioprotective effect against ischemia in the isolated rat heart and suggest that its mechanism of action is largely independent of ATP-sensitive potassium channels.     

Preventive Effect of Halofuginone on Concanavalin A-Induced Liver Fibrosis

Halofuginone (HF) is an active component of extracts derived from the plant alkaloid febrifugine and has shown therapeutic promise in animal models of fibrotic disease. Our main objectives were to clarify the suppressive effect of HF on concanavalin A (ConA)-induced liver fibrosis. ConA injection into the tail vein caused a great increase in the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, while orally administration of HF significantly decreased the levels of the transaminases. In addition, the levels of hyaluronic acid (HA), procollagen III (PCIII) and TGF-β1 in the serum and collagen I, α-SMA, tissue inhibitors of metalloproteinase 2 (TIMP2) and Smad3 in the liver tissue were significantly lowered with the treatment of HF. Histological examination also demonstrated that HF significantly reduced the severity of liver fibrosis. Since ConA-induced liver fibrosis is caused by the repeated activation of T cells, immunomodulatory substances might be responsible for the suppressive effect of HF. We found that the production of nuclear factor (NF)-kB in the serum was increased in ConA-treated group, while decreased significantly with the treatment of HF. The changes of inflammatory cytokines tumor necrosis factor (TNF-α), IL-6 and IL-1β in the serum followed the same rhythm. All together, our findings indicate that orally administration HF (10ppm) would attenuate the liver fibrosis by suppressing the synthesis of collagen I and inflammation-mediated liver injury.     

The impacts of climate change and human activities on biogeochemical cycles on the Qinghai‐Tibetan Plateau

With a pace of about twice the observed rate of global warming, the temperature on the Qinghai‐Tibetan Plateau (Earth's ‘third pole’) has increased by 0.2 °C per decade over the past 50 years, which results in significant permafrost thawing and glacier retreat. Our review suggested that warming enhanced net primary production and soil respiration, decreased methane (CH₄) emissions from wetlands and increased CH₄ consumption of meadows, but might increase CH₄ emissions from lakes. Warming‐induced permafrost thawing and glaciers melting would also result in substantial emission of old carbon dioxide (CO₂) and CH₄. Nitrous oxide (N₂O) emission was not stimulated by warming itself, but might be slightly enhanced by wetting. However, there are many uncertainties in such biogeochemical cycles under climate change. Human activities (e.g. grazing, land cover changes) further modified the biogeochemical cycles and amplified such uncertainties on the plateau. If the projected warming and wetting continues, the future biogeochemical cycles will be more complicated. So facing research in this field is an ongoing challenge of integrating field observations with process‐based ecosystem models to predict the impacts of future climate change and human activities at various temporal and spatial scales. To reduce the uncertainties and to improve the precision of the predictions of the impacts of climate change and human activities on biogeochemical cycles, efforts should focus on conducting more field observation studies, integrating data within improved models, and developing new knowledge about coupling among carbon, nitrogen, and phosphorus biogeochemical cycles as well as about the role of microbes in these cycles.     

Synthesis of novel dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties as potential antibacterial agents

Three novel series of dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties were designed, synthesized and evaluated in terms of their antibacterial and antifungal activities. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains with minimum inhibitory concentration values in the range of 1–64?µg/mL. Compounds 4b and 4c presented the most potent inhibitory activity against Gram-positive bacteria (S. aureus 4220, MRSA 3167, QRSA 3519) and Gram-negative bacteria (E. coli 1924), with minimum inhibitory concentration values of 1 or 2?µg/mL. Compared with previous studies, these compounds exhibited a broad spectrum of inhibitory activity. The cytotoxic activity of the compounds 4a, 4b, 4c and 11n were assessed in L02 cells. In vitro enzyme study implied that compound 4c exerted its antibacterial activity through DHFR inhibition.     

Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors

Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, IIIv was found to have the best in vitro inhibition activity against PTP1B (IC₅₀?=?0.67?±?0.09?µM) and the best selectivity (9-fold) between PTP1B and T-cell protein tyrosine phosphatase (TCPTP). Molecular docking studies demonstrated that compounds IIIm, IIIv and IVg could occupy simultaneously at both the catalytic site and the adjacent pTyr binding site. These results provide novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.