Fritz Wieser

PPAR Action in Human Placental Development and Pregnancy and Its Complications

During pregnancy crucial anatomic, physiologic, and metabolic changes challenge the mother and the fetus. The placenta is a remarkable organ that allows the mother and the fetus to adapt to the new metabolic, immunologic, and angiogenic environment imposed by gestation. One of the physiologic systems that appears to have evolved to sustain this metabolic regulation is mediated by peroxisome proliferator-activated receptors (PPARs). In clinical pregnancy-specific disorders, including preeclampsia, gestational diabetes, and intrauterine growth restriction, aberrant regulation of components of the PPAR system parallels dysregulation of metabolism, inflammation and angiogenesis. This review summarizes current knowledge on the role of PPARs in regulating human trophoblast invasion, early placental development, and also in the physiology of clinical pregnancy and its complications. As increasingly indicated in the literature, pregnancy disorders, such as preeclampsia and gestational diabetes, represent potential targets for treatment with PPAR ligands. With the advent of more specific PPAR agonists that exhibit efficacy in ameliorating metabolic, inflammatory, and angiogenic disturbances, further studies of their application in pregnancy-related diseases are warranted.

Advances in the genetics of endometriosis

Endometriosis is a gynecological disease characterized by implantation of endometrial tissue outside of the uterus. Early familial aggregation and twin studies noted a higher risk of endometriosis among relatives. Studies on the roles of the environment, genetics and aberrant regulation in the endometrium and endometriotic lesions of women with endometriosis suggest that endometriosis arises from the interplay between genetic variants and environmental factors. Elucidating the hereditary component has proven difficult because multiple genes seem to produce a susceptibility to developing endometriosis. Molecular techniques, including linkage and genome-wide analysis, have identified candidate genes located near known loci related to development and regulation of the female reproductive tract. As new candidate genes are discovered and hereditary pathways identified using technologies such as genome-wide analysis, the possibility of prevention and treatment becomes more tangible for millions of women affected by endometriosis. Here, we discuss the advances of genetic research in endometriosis and describe technologies that have contributed to the current understanding of the genetic variability in endometriosis, variability that includes regulatory polymorphisms in key genes.

A Botanical Extract from Channel Flow Inhibits Cell Proliferation, Induces Apoptosis, and Suppresses CCL5 in Human Endometriotic Stromal Cells

Abstract Growing evidence suggests that medicinal herbs have direct actions on endometrial cells. By screening multiple herbs using an in vitro model of endometriosis, we found that a commonly used herbal formula exerted considerable antiproliferative effects. Our purpose was to investigate the effects of this antiendometriosis herbal mixture on cell proliferation, apoptosis, and CCL5 expression and secretion in endometriotic stromal cells in vitro. Isolated normal endometrial, eutopic, and ectopic endometriotic stromal cells were cultured under established conditions. Cell proliferation, apoptosis, and CCL5 gene expression protein secretion was evaluated after incubation with different concentrations of an antiendometriosis herbal mixture extract. Cell proliferation was assessed by cell counting, 3H-thymidine incorporation, and MTS assays. Apoptosis was determined by blotting using anti-cleaved caspase 3 antibodies and by a TUNEL assay. CCL5 gene expression and protein secretion were determined by transient transfection of gene promoter reporters and ELISAs in cell supernatants. Extracts of a traditional herbal mixture dose-dependently decreased cell proliferation in normal, eutopic, and ectopic endometriotic stromal cells. 3H-Thymidine uptake and MTS confirmed these findings. The herbal extracts induced apoptosis, as evidenced by activation of caspase 3 and the presence of TUNEL-positive cells after treatment. The herbal extracts also suppressed CCL5 gene transcription and protein secretion in endometriotic stromal cells, even when corrected for cell number. Extracts from a medicinal herbal mixture have direct effects on cell proliferation, apoptosis, and CCL5 production in endometriotic stromal cells. Our findings support the further investigation of novel, potentially safe and well-tolerated botanical products as future endometriosis treatments.

Effects of Phorbol Dibutyrate on Cell Proliferation, Apoptosis, and Tumor Necrosis Factor-alpha Expression in Human Endometrial Adenocarcinoma Cells

Objectives: Recent evidence suggested that protein kinase C (PKC), a major cell cycle regulator in endometrial models, mimics progesterone withdrawal by inducing downstream signals. In the current study we examined the hypothesis that the PKC activator phorbol 12,13 dibutyrate (PDB) would inhibit cell proliferation and induce apoptosis in two endometrial adenocarcinoma cell (EAC) lines, HEC-1B and Ishikawa cells. We further examined whether the induction of tumor necrosis factor-alpha (TNF-alpha) might mediate these effects. Methods: EAC lines were cultured under standard and serum-free conditions to study the effects of PDB on cell kinetics. Cell proltferation was determined by cell count using a hemacytometer and by incorporation of 3H thymidine into 100% trichloracetic acid-precipitable DNA. Apoptosis was determined by measuring cytoplasmic histone-associated DNA fragments. Conditioned media concentrations of TNF-alpha were measured by a commercially available enzyme-linked immunosorbent assay (ELISA). EACs were transfected with a-125-bp TNF-alpha promoter luciferase construct and treated with PDB to evaluate transcriptional activation. Results: Activation of the PKC system with PDB (10 nM) decreased cell proliferation and mitogenesis in EACs. PDB induced apoptosis in both EAC lines. EACs exhibit basal TNF-alpha gene expression and protein secretion and these were increased potently by PDB. However, neutralization of TNF-alpha by addition of anti-TNF-alpha antibodies did not prevent the suppression of mitogenesis, induction of apoptosis, or activation of TNF-alpha gene expression by PDB. Conclusion: Activation of the PKC system leads to inhibition of cell proliferation, induction of apoptosis, and TNF-alpha expression in EACs. However, apoptosis in this setting does not appear to require TNF-alpha action. EACs provide an informative model to investigate aspects of endometrial epithelial remodeling that may occur under physiologic conditions of progesterone withdrawal.

Genetik der Endometriose

ZusammenfassungDie Endometriose ist eine benigne, östrogenabhängige, vererbbare Erkrankung, wobei jedoch der genaue Vererbungsmodus unklar ist. Das erhöhte Risiko für Endometriose in der Verwandtschaft (5–8% bei Verwandten 1.xa0Grades) weist auf einen polygenen Mechanismus hin. Das polygene Modell ist dadurch definiert, dass die Entstehung einer Erkrankung durch einen kumulativen Effekt von mehreren Genen beeinflusst wird. Für das polygene Modell sprechen das Vorkommen von schwereren Formen und das Vorkommen in jüngeren Jahren im Rahmen der familiär gehäuft auftretenden Endometriose. Hinzu kommt, dass die Endometriose durch Umweltfaktoren beeinflusst wird. Somit besteht ein polygener und multifaktorieller Entstehungsmechanismus. Die Möglichkeit der Identifizierung von Genen und Genprodukten mittels innovativer genetischer Untersuchungsmethoden erleichtert nicht nur das Verständnis der Pathogenese der Endometriose, sondern könnte eine bessere Diagnose und/oder Therapie der Endometriose und gezielte präventive Maßnahmen ermöglichen.AbstractEndometriosis is a multifactorial disease affecting up to 2–15% of women of reproductive age. This condition is characterized by the presence and growth of endometrial cells outside the uterus. Susceptibility to endometriosis depends on complex interactions of immunologic, hormonal, environmental, and genetic factors. Endometriosis is a genetic disease, although the mode of inheritance is not exactly clear. It does not appear to be inherited as a Mendelian trait but it does cluster in families. The 5 to 8% risk for first-degree relatives is more reminiscent of polygenic/multifactorial tendencies than of a single mutant gene. The fact that endometriosis is more severe and shows early-onset in familial compared to sporadic cases suggests a polygenic mode of inheritance. Other factors, however can explain familial clustering, such as exposure to environmental or infectious agents. If achievable, the identification of genes involved in the pathophysiology of endometriosis using innovative technologies such as genomics and proteomics could allow individualization of therapies as well as primary and secondary prevention strategies for endometriosis, aimed at high-risk populations.

Endoscopic laser ablation of ureteral endometriosis

A 37-year-old female with a known history of endometriosis presented with progressive dysmenorrhea and dyspareunia, and complaints of hematuria. After cystoscopy and bilateral retrograde pyelography was performed, distal stenosis in the right ureter without ureteral obstruction and renal impairment was diagnosed. Abdominal hysterectomy and excision of peritoneal endometriotic lesions on the surface of the right ureter and bladder wall was done preserving the ovaries. The intrinsic endometriotic lesion in the right ureter was detected ureteroscopically and histologically and treated successfully by holmium laser ablation avoiding ureteral resection and re-implantation.