Bisphosphonates are the most commonly prescribed drugs for the treatment of osteoporosis and other bone illnesses. Some of them have also shown antiparasitic activity. In search of improving the pharmacological profile of commercial bisphosphonates, our group had previously developed first row transition metal complexes with N-containing bisphosphonates (NBPs). In this work, we extended our studies to heteroleptic palladium-NBP complexes including DNA intercalating polypyridyl co-ligands (NN) with the aim of obtaining potential multi-target species. Complexes of the formula [Pd(NBP)2(NN)]·2NaCl·xH2O with NBP = alendronate (ale) or pamidronate (pam) and NN = 1,10 phenanthroline (phen) or 2,2'-bipyridine (bpy) were synthesized and fully characterized. All the obtained compounds were much more active in vitro against T. cruzi (amastigote form) than the corresponding NBP ligands. In addition, complexes were nontoxic to mammalian cells up to 50-100 µM. Compounds with phen as ligand were 15 times more active than their bpy analogous. Related to the potential mechanism of action, all complexes were potent inhibitors of two parasitic enzymes of the isoprenoid biosynthetic pathway. No correlation between the anti-T. cruzi activity and the enzymatic inhibition results was observed. On the contrary, the high antiparasitic activity of phen-containing complexes could be related to their ability to interact with DNA in an intercalative-like mode. These rationally designed compounds are good candidates for further studies and good leaders for future drug developments. Four new palladium heteroleptic complexes with N-containing commercial bisphosphonates and DNA intercalating polypyridyl co-ligands were synthesized and fully characterized. All complexes displayed high anti-T. cruzi activity which could be related to the inhibition of the parasitic farnesyl diphosphate synthase enzyme but mainly to their ability to interact DNA.
2019-03-13·Molecules (Basel, Switzerland)3区 · 化学
Protective Effects of Kuding Tea (Ilex kudingcha C. J. Tseng) Polyphenols on UVB-Induced Skin Aging in SKH1 Hairless Mice.
3区 · 化学
作者: Ruokun Yi ; Jing Zhang ; Peng Sun ; Yu Qian ; Xin Zhao
In this study, the protective effects of Kuding tea polyphenols (KTPs) on ultraviolet B (UVB)-induced skin injury of SKH1 hairless mice were studied. The ion precipitation method was used for extraction of polyphenols from Kuding tea. High-performance liquid chromatography showed that KTPs contains chlorogenic acid, cryptochlorogenic acid, isochlorogenic acid B, isochlorogenic acid A, and isochlorogenic acid C. SKH1 hairless mice were induced skin aging using 2.0 mW/s intensity of 90 mJ/cm² UV light once a day for seven weeks. The 2.5% and 5% KTPs solution was smeared on 2 cm² of back skin of skin aging mice twice a day. Mouse experiments showed that KTP strongly increased the serum levels of total superoxide dismutase (T-SOD) and catalase (CAT) and reduced those of malondialdehyde, interleukin 6 (IL-6), IL-1β, and tumor necrosis factor alpha (TNF-α) in mice with UVB-induced skin damage. KTP also increased the levels of type 1 collagen (Col I), hydroxyproline, and hyaluronic acid and reduced those of Col III and hydrogen peroxide in the damaged skin tissues of mice. Pathological observations of tissues stained with H & E, Masson's trichrome, Verhoeff, and toluidine blue showed that KTPs could protect skin cells, collagen, and elastin and decrease the number of mast cells, thus inhibiting skin damage. Quantitative PCR and western blot assays showed that KTP upregulated the mRNA and protein expression of tissue inhibitor of metalloproteinase 1 (TIMP-1), TIMP-2, copper/zinc-SOD, manganese-SOD, CAT, and glutathione peroxidase and downregulated the expression of matrix metalloproteinase 2 (MMP-2) and MMP-9. In addition, the same concentration of KTP had stronger protective effects than vitamin C. The results of this study demonstrate that KTPs have good skin protective effects, as they are able to inhibit UVB-induced skin damage.
2002-09-01·Journal of Surgical Research4区 · 医学
Effect of Lactobacillus casei on a Novel Murine Model of Abdominal Sepsis
Lactobacilli are one of the probiotics and there is strong evidence for the efficacy of lactobacilli administration as a nonspecific immunostimulant in increasing host defense mechanisms. The present study tested the hypothesis that heat-killed Lactobacillus casei (LC9018) has a protective activity against fecal peritonitis.
Cecal ligation and tip resection (CLTR) induced fecal peritonitis was developed as a novel mouse model of abdominal sepsis, and the effects of LC9018 pretreatment on survival after CLTR, of the peritoneal exudate cells before or after CLTR and of bacterial growth in the peritoneal cavity after CLTR were investigated.
Mortality after CLTR varied directly with the length of the opened bowel. To obtain a sublethal experimental group, the length of the opened bowel was fixed at 4 mm, where mortality was 87%, for further experiments. Survival of mice after CLTR was augmented in mice that had been pretreated intraperitoneally (ip) with LC9018 24 h previously. Viable bacterial growth in the peritoneal cavity was markedly inhibited in LC9018-pretreated mice. Peritoneal exudate cell accumulation observed 24 h after ip injection of LC9018 was significantly enhanced, suggesting that augmentation of the resistance of mice to CLTR was caused especially by the induction of polymorphonuclear cells.
CLTR may provide a reproducible and simple murine model of bacterial sepsis and pretreatment with LC9018 developed a protective activity against CLTR surgery.