Oxidative Stress and the Nrf2/PPARγ Axis in the Endometrium: Insights into Female Fertility.

Successful pregnancy depends on precise molecular regulation of uterine physiology, especially during the menstrual cycle. Deregulated oxidative stress (OS), often influenced by inflammatory changes but also by environmental factors, represents a constant threat to this delicate balance. Oxidative stress induces a reciprocally regulated nuclear factor erythroid 2-related factor 2/peroxisome proliferator-activated receptor-gamma (Nrf2/PPARγ) pathway. However, increased PPARγ activity appears to be a double-edged sword in endometrial physiology. Activated PPARγ attenuates inflammation and attenuates OS to restore redox homeostasis. However, it also interferes with physiological processes during the menstrual cycle, such as hormonal signaling and angiogenesis. This review provides an elucidation of the molecular mechanisms that support the interplay between PPARγ and OS. Additionally, it offers fresh perspectives on the Nrf2/PPARγ pathway concerning endometrial receptivity and its potential implications for infertility.

Serum trace element levels and activity of enzymes associated with oxidative stress in endometriosis and endometrial cancer.

Endometriosis and endometrial cancer are closely related to oxidative stress. However, the direct relationship between copper and zinc levels and oxidative stress in the extracellular and intracellular space remains unclear. The presented study is focused on the determination of serum Zn and Cu levels, glutathione concentration and enzyme activity in three groups: patients diagnosed with endometrial cancer (EC), patients diagnosed with endometriosis (EM), and a healthy control group. Spectrophotometric determination of trace elements revealed that levels of zinc and copper were lower in blood plasma of patients with endometriosis as compared with the other groups; however, there were no significant differences in the Cu/Zn ratio. Furthermore, significantly increased blood serum glutathione levels were detected in both EM and EC groups compared with the control group. While the activity of superoxide dismutase (SOD) was similar across the studied groups, we observed differences in the activity of other enzymes associated with oxidative stress, including glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST), between the control group and the EM and EC patients. Additionally, analysis of gene expression based on free circulating mRNA indicated significant differences in the expression of SOD isoenzymes between the patient groups and the control group; expression of GPx isoenzymes was also altered. Obtained results may have potential application in diagnostics as well as monitoring of endometriosis and endometrial cancer.

Low-dimensional compounds containing bioactive ligands. XXII. First crystal structure, cytotoxic activity and DNA and HSA binding of a zirconium(IV) complex with 8-hydroxyquinoline-2-carboxylic acid.

A new zirconium(IV) complex, diaquabis(8-hydroxyquinoline-2-carboxylato-κ3N,O2,O8)zirconium(IV) dimethylformamide disolvate, [Zr(C10H5NO3)2(H2O)2]·2C3H7NO or [Zr(QCa)2(H2O)2]·2DMF (1) (HQCaH is 8-hydroxyquinoline-2-carboxylic acid and DMF is dimethylformamide), was prepared and characterized by elemental analysis, IR spectroscopy and single-crystal X-ray structure analysis. Complex 1 is a mononuclear complex in which the ZrIV atoms sit on the twofold axis and they are octacoordinated by two N and six O atoms of two tridentate anionic QCa2- ligands, and two aqua ligands. Outside the coordination sphere are two DMF molecules bound to the complex unit by hydrogen bonds. The structure and stability of complex 1 in dimethyl sulfoxide were verified by NMR spectroscopy. The cytotoxic properties of 1 and HQCaH were studied in vitro against eight cancer cell lines, and their selectivity was tested on the BJ-5ta noncancerous cell line. Both the complex and HQCaH exhibited low activity, with IC50 > 200 µM. DNA and human serum albumin (HSA) binding studies showed that 1 binds to calf thymus (CT) DNA via intercalation and is able to bind to the tryptophan binding site of HSA (Trp-214).

Zinc(II) niflumato complex effects on MMP activity and gene expression in human endometrial cell lines.

Endometriosis is a chronic inflammatory disease which increasingly affects young women under 35 years of age and leads to subfertility even infertility. Analysis of the cytotoxic effect of zinc(II) niflumato complex with neocuproine ([Zn(neo)(nif)2] or Zn-Nif) on immortalized human endometriotic cell line (12Z) and on control immortalized human endometrial stromal cell line (hTERT) was performed using xCELLigence technology for approximately 72 h following the treatment with Zn-Nif as well as cell viability Trypan Blue Assay. 12Z cell line proliferated more slowly compared to unaffected cells, whereas hTERT cells did not show similar behavior after treatment. The complex probably reduces the effect of pro-inflammatory pathways due to the effect of NSAID, while presence of zinc might reduce the level of ROS and regulate ER2 levels and MMP activity. The observed effects and high selectivity for rapidly proliferating cells with increased inflammatory activity suggest a good prognosis of successful decrease of endometriosis stage with this complex.

Two isostructural Co(II) flufenamato and niflumato complexes with bathocuproine: Analogues with a different cytotoxic activity.

Two novel Co(II) fenamato complexes containing bathocuproine (bcp), namely [Co(bcp)(flu)2] (1) and [Co(bcp)(nif)2] (2) (flu = flufenamato, nif = niflumato) were synthesized and characterized by elemental analysis, single-crystal X-ray structure analysis as well as absorption and fluorescence spectroscopy. Investigation of their molecular structure revealed that both complexes are isostructural and form analogous complex molecules, with a Co(II) atom hexacoordinated by two nitrogen atoms of bcp and four oxygen atoms of two chelate bonded flu (1) and nif (2) ligands in a distorted octahedral arrangement. Surprisingly, the results of cytotoxicity experiments on four cancer cell lines (HeLa, HT-29, PC-3 and MCF-7) have revealed that despite similar structure of the complexes, the nif complex exhibits significantly higher activity, being the most effective against the PC-3 cell line (IC50 (MTT) = 6.11 ±â€¯1.95 µM). Further studies performed on PC-3 cell line have shown that the mechanism of the cytotoxic action of nif complex (2) might involve activation of autophagic processes and apoptosis, while for its flu analogue (1) apoptosis was detected.

Novel zinc complexes of a non-steroidal anti-inflammatory drug, niflumic acid: Structural characterization, human-DNA and albumin binding properties.

Three novel Zn(II) complexes of NSAID niflumic acid (Hnif) were prepared and studied, namely; [Zn(MeOH)4(nif)2] (1), [Zn(cyclam)(nif)2] (2) and [Zn(nif)2(tmen)] (3), where nif is deprotonated niflumic acid, cyclam is 1,4,8,11-Tetraazacyclotetradecane and tmen is N,N,N',N'-Tetramethylethylenediamine. The complexes have been characterized by infrared spectroscopy, elemental and thermal analysis and single-crystal X-ray structure analysis. All three complexes contain two deprotonated niflumato anions monodentately coordinated via carboxylato groups. Furthermore, fluorescence binding studies of the prepared compounds with human genomic DNA-EB (ethidium bromide) were carried out, which suggest that all complexes are able to bind to DNA via intercalation. Moreover, from the obtained results it followed that complexes 2 and 3 bind to DNA from the tissue with aortic aneurysm (aDNA) and control (cDNA) with a different strength. Additionally, complexes 1-3 exhibit good binding affinity to human serum albumin with high binding constant.