Salvia miltiorrhiza Bunge as a Potential Natural Compound against COVID-19.

Salvia miltiorrhiza Bunge, commonly called danshen, is widely used in traditional Chinese medicine for its cardiovascular and neuroprotective effects, which include antioxidative, anti-inflammatory, and antifibrotic properties. The purpose of this study was to evaluate the preclinical potential of S. miltiorrhiza extracts for the treatment of COVID-19. First, the impact of the extract on the binding between SARS-CoV-2 and the cellular ACE2 receptors was assessed using atomic force microscopy (AFM), showing a significant reduction in binding by the extract at concentrations in the µg/mL range. Second, the interference of this extract with the inflammatory response of blood mononuclear cells (PBMCs) was determined, demonstrating potent inhibitory properties in the same concentration range on pro-inflammatory cytokine release and interference with the activation of NFκB signaling. Together, these in vitro data demonstrate the potential of S. miltiorrhiza against COVID-19, consisting first of the blockade of the binding of SARS-CoV-2 to the ACE2 receptor and the mitigation of the inflammatory response from leukocytes by interfering with NFκB signaling. This dataset prompts the launch of a clinical trial to address in vivo the clinical benefits of this promising agent.

Differential expression of steroidogenic enzymes according to endometriosis type.

OBJECTIVE: To evaluate, in peritoneal, ovarian, and rectovaginal endometriotic lesions, expression of steroidogenic enzymes involved in the activation and inactivation of estrogens: 17ß-hydroxysteroid dehydrogenase type 1 (HSD17B1) and 2 (HSD17B2), estrone sulfotransferase (EST), and steroid sulfatase (STS). SETTING: Academic gynecology research unit. DESIGN: Retrospective study. PATIENT(S): Disease-free (n = 41) patients and patients with endometriosis (n = 79) were included for quantitative polymerase chain reaction (q-PCR) (15 disease-free, 33 endometriosis) and immunohistochemistry (26 disease-free, 46 endometriosis) studies. INTERVENTION(S): Q-PCR and immunohistochemistry. MAIN OUTCOME MEASURE(S): Evaluation of mRNA and protein expression. RESULT(S): Glandular HSD17B1, HSD17B2, and STS protein expression were demonstrated. HSD17B2 mRNA values were higher in the secretory phase of the menstrual cycle in the endometrium of disease-free women, but not in the eutopic endometrium of patients with endometriosis. HSD17B1 mRNA was equally expressed in the various tissues investigated, and EST mRNA was expressed at low levels in the different lesion types. HSD17B2 mRNA expression was decreased in ovarian and rectovaginal endometriosis compared with eutopic endometrium, while STS mRNA was increased in rectovaginal lesions compared with ovarian lesions. Ratios between pro- and antiestrogenic enzymes (STS/EST and HSD17B1/HSD17B2) were more in favor of estrogens in ovarian and rectovaginal endometriosis. CONCLUSION(S): In endometriosis development, local activation of estrogens appears to be important. STS and HSD17B1 inhibitors may therefore prove useful to treat the disease.

Nerve fiber density in deep nodular endometriotic lesions induced in a baboon experimental model.

OBJECTIVE: To study the occurrence of nerve fibers in deep nodular endometriotic lesions after nodules were induced in baboons and nerve fiber densities measured 6 months after the grafting procedure. DESIGN: Experimental animal study. SETTING: Academic gynecology research unit. ANIMALS: Ten baboons (Papio anubis). INTERVENTION(S): Recovery of induced endometriotic nodules and eutopic endometrium. MAIN OUTCOME MEASURE(S): Protein gene product (PGP) 9.5 and nerve growth factor (NGF) immunohistochemistries were performed to evaluate nerve fiber density and NGF expression in induced endometriotic lesions and eutopic endometrium. RESULT(S): Eutopic (basalis) endometrium, myometrium, and invasive and noninvasive nodular lesions were analyzed separately. The highest nerve fiber densities were observed in normal myometrium and in the basal layer of eutopic endometrium. No significant differences were observed between the two lesion types. However, the NGF staining intensity score was found to be higher in glands of deep invasive lesions than in glands of eutopic baboon endometrium. CONCLUSION(S): This is the first study to show the presence of nerve fibers in eutopic baboon endometrium and induced deep endometriotic nodules. Long-term studies are now warranted to determine if nerves still grow in invasive and noninvasive lesions >6 months after grafting, and to evaluate the role of the lesion environment.

Induction of endometriotic nodules in an experimental baboon model mimicking human deep nodular lesions.

OBJECTIVE: To establish an experimental model for the study of deep nodular endometriosis. DESIGN: Induction of nodular endometriosis in baboons by grafting different uterine specimens to the peritoneal cavity. SETTING: Research and university facilities. ANIMAL(S): Ten baboons, to develop a model of induced deep nodular endometriosis. INTERVENTION(S): Biopsies of endometrium, and endometrium plus the junctional zone (JZ), full uterine thickness, and myometrium grafted to the peritoneum. MAIN OUTCOME MEASURE(S): Macroscopic descriptions recorded for observed induced lesions; staining with hematoxylin and eosin for histological evaluation and specific antibodies (CK22, CD10) for immunohistochemical studies; and analysis of surface area and volume of lesions, glandular density, and invasion of surrounding organs. RESULT(S): The incidence of induced nodular endometriosis was 100%, but the extent depended on the tissue grafted. Lesions induced after grafting specimens containing the JZ were statistically significantly larger than those not containing the JZ. Surrounding organ invasion was reported in more than 40% of lesions after grafting specimens containing the JZ. CONCLUSION(S): The first experimental model of nodular endometriosis allows investigation of deeper nodular lesions as well as invasion phenomena associated with nodular lesions.

Nuclear factor-kappaB: a main regulator of inflammation and cell survival in endometriosis pathophysiology.

OBJECTIVE: To update, analyze, and summarize the literature concerning nuclear factor-kappaB (NF-κB) participation in endometriosis pathophysiology. DESIGN: Review. RESULT(S): Nuclear factor-kappaB is physiologically activated in the human endometrium, showing variable activity. A cyclic p65-DNA binding pattern was shown in the endometrium of healthy women. This cyclic pattern was altered in the endometrium of patients with endometriosis. Nuclear factor-kappaB is basally activated in peritoneal endometriotic lesions, showing higher p65 activity in red endometriotic lesions than in black lesions. In vivo and in vitro studies show up-regulation of inflammation and cell proliferation and down-regulation of apoptosis by NF-κB activity. Iron overload has been shown in the pelvic cavity of endometriosis patients, and iron overload and oxidative stress activate NF-κB in macrophages, which have been shown to participate in the endometriosis-associated inflammatory reaction. CONCLUSION(S): Nuclear factor-kappaB activation dysregulation in the endometrium of endometriosis patients may explain some endometrial biological alterations associated with endometriosis. The scientific evidence strongly suggests that NF-κB activity in endometriotic cells stimulates inflammation and cell proliferation and inhibits apoptosis, favoring the development and maintenance of endometriosis. Iron overload in the pelvic cavity of endometriosis patients could be a main factor enhancing oxidative stress and activating NF-κB in a chronic manner, contributing to endometriosis establishment and growth.

Peritoneal endometriosis is an inflammatory disease.

Peritoneal endometriosis is a chronic inflammatory disease characterized by increased numbers of peritoneal macrophages and their secreted products. Inflammation plays a major role in pain and infertility associated with endometriosis, but is also extensively involved in the molecular processes that lead to peritoneal lesion development. Peritoneal oxidative stress is currently thought to be a major constituent of the endometriosis-associated inflammatory response. Excessive production of reactive oxygen species, secondary to peritoneal influx of pro-oxidants such as heme and iron during retrograde menstruation, may induce cellular damage and increased proinflammatory gene expression through nuclear factor-kappa B activation. In particular, prostaglandin biosynthetic enzyme expression is regulated by this transcriptional factor, and increased peritoneal prostaglandin concentrations have been demonstrated in endometriosis. In the light of available data collected from patient biopsies, as well as in vitro and in vivo studies, the respective involvement and potential molecular interactions of iron, nuclear factor-kappa B and prostaglandins in the pathogenesis of endometriosis are explored and discussed. The key role of peritoneal macrophages is emphasized and potential therapeutic targets are examined.

Endometriomas as a possible cause of reduced ovarian reserve in women with endometriosis.

OBJECTIVE: To evaluate the adverse effects of endometriomas on ovarian reserve. DESIGN: Analysis of prospectively collected biopsy samples. SETTING: Gynecology research unit in a university hospital. PATIENT(S): Women younger than age 35 years with endometriomas. INTERVENTION(S): Biopsy of normal cortex from ovaries affected by endometriomas (≤4 cm) and contralateral ovaries without cysts. MAIN OUTCOME MEASURE(S): Presence of cortex-specific stroma, observation of superficial endometriosis, follicular density, and presence of fibrosis. RESULT(S): Twenty samples of cortical tissue from ovaries with endometriomas and 11 from contralateral ovaries without cysts were analyzed. Follicular density was significantly lower in cortex from ovaries with endometriomas than in cortex from contralateral ovaries without cysts (mean ± SD = 6.3 ± 4.1/mm(3) vs 25.1 ± 15.0/mm(3)). Eleven (55%) cortical samples from ovaries with endometriomas showed fibrosis and concomitant loss of cortex-specific stroma, not observed in contralateral normal ovaries. Multivariate analysis revealed that the presence of endometrioma and fibrosis were significantly and independently associated with follicular density. CONCLUSION(S): Endometriotic cyst formation and associated structural tissue alterations in apparently normal ovarian cortex may be a cause of reduced ovarian reserve. Early diagnosis and intervention may be beneficial in women with endometriomas to protect their ovarian function.

In vivo biocompatibility of three potential intraperitoneal implants.

The intraperitoneal biocompatibility of PDMS, polyHEMA and pEVA was investigated in rats, rabbits and rhesus monkeys. No inflammation was evidenced by hematological analyses and measurement of inflammatory markers throughout the experiment and by post-mortem examination of the pelvic cavity. After 3 or 6 months, histological analysis revealed fibrous tissue encapsulating PDMS and PEVA implants in all species and polyHEMA implants in rabbits and monkeys. Calcium deposits were observed inside polyHEMA implants. The intraperitoneal biocompatibility of all 3 polymers makes them suitable for the design of drug delivery systems, which may be of great interest for pathologies confined to the pelvic cavity.

Is the baboon model appropriate for endometriosis studies?

OBJECTIVE: To determinethe prevalence of spontaneous endometriosis andthe incidence of induced endometriosis after endocervical canal resection in baboons. DESIGN: Induction and follow-up of endometriosis in baboons, which is one of the primate species that develop spontaneous endometriosis. Forty-one baboons were checked for the presence of spontaneous endometriosis. We then attempted to induce endometriosis in 30 of them by endocervical canal resection. SETTING: Institute of Primate Research, Nairobi, Kenya, and Catholic University of Louvain, Brussels, Belgium. ANIMAL(S): Forty-one baboons were checked for spontaneous endometriosis and 30 of them were used to develop a model of induced endometriosis. INTERVENTION(S): A total of 41 baboons underwent diagnostic laparoscopy for 10 months. In a first step, 30 of this number subsequently underwent endocervical canal resection. In a second step, 20 of the 30 underwent uterine horn resection. MAIN OUTCOME MEASURE(S): Follow-up by laparoscopy. RESULT(S): Two of the 41 baboons were diagnosed with spontaneous endometriosis (4.8%). Twelve months after the surgical procedure to induce endometriosis, 8 of 29 animals presented with endometriotic lesions diagnosed by using laparoscopy and confirmed by histologic examination. The incidence of induced endometriosis in our model was thus 27.6%. In 2 baboons, endometriosis disappeared over time, resulting in a final rate of 20.7% (6/29). CONCLUSION(S): The rate of spontaneous endometriosis is very low (4.8%). Endometriosis can be induced (with a rate of just 27.6%) by endocervical canal resection to stimulate retrograde menstruation.

Insights into iron and nuclear factor-kappa B (NF-kappaB) involvement in chronic inflammatory processes in peritoneal endometriosis.

Endometriosis is a chronic pelvic inflammatory process. Local inflammation is known to play a role in pain and infertility associated with the disease, and may be extensively involved in molecular and cellular processes leading to endometriosis development. In this review, we focus on two inflammatory mediators clearly implicated in the pathogenesis of endometriosis, iron and NF-kappaB, and their potential association. Iron is essential for all living organisms, but excess iron results in toxicity and is linked to pathological disorders. In endometriosis patients, iron overload has been demonstrated in the different compartments of the peritoneal cavity (peritoneal fluid, endometriotic lesions, peritoneum and macrophages). This iron overload affects numerous mechanisms involved in endometriosis development. Moreover, iron can generate free radical species able to react with a wide range of cellular constituents, inducing cellular damage. Overproduction of reactive oxygen species also impairs cellular function by altering gene expression via regulation of redox-sensitive transcription factors such as NF-kappaB, which is clearly implicated in endometriosis. Indeed, NF-kappaB is activated in endometriotic lesions and peritoneal macrophages of endometriosis patients, which stimulates synthesis of proinflammatory cytokines, generating a positive feedback loop in the NF-kappaB pathway. NF-kappaB-mediated gene transcription promotes a variety of processes, including endometriotic lesion establishment, maintenance and development. In conclusion, iron and NF-kappaB appear to be linked and both are clearly involved in endometriosis development, making these pathways an attractive target for future treatment and prevention of this disease.

Involvement of the nuclear factor-κB pathway in the pathogenesis of endometriosis.

OBJECTIVE: To evaluate the role of nuclear factor-κB (NF-κB) in the pathogenesis of endometriosis. DESIGN: A literature search was conducted in PubMed to identify all relevant citations. RESULT(S): Our findings highlight the important role of NF-κB in the pathophysiology of endometriosis. In vitro and in vivo studies show that NF-κB-mediated gene transcription promotes inflammation, invasion, angiogenesis, and cell proliferation and inhibits apoptosis of endometriotic cells. Constitutive activation of NF-κB has been demonstrated in endometriotic lesions and peritoneal macrophages of endometriosis patients. Agents blocking NF-κB are effective inhibitors of endometriosis development and some drugs with known NF-κB inhibitory properties have proved efficient at reducing endometriosis-associated symptoms in women. Iron overload activates NF-κB in macrophages. NF-κB activation in macrophages and ectopic endometrial cells stimulates synthesis of proinflammatory cytokines, generating a positive feedback loop in the NF-κB pathway and promoting endometriotic lesion establishment, maintenance and development. CONCLUSION(S): NF-κB transcriptional activity modulates key cell processes contributing to the initiation and progression of endometriosis. Because endometriosis is a multifactorial disease, inhibiting NF-κB appears to be a promising strategy for future therapies targeting different cell functions involved in endometriosis development, such as cell adhesion, invasion, angiogenesis, inflammation, proliferation, and apoptosis. Upcoming research will elucidate these hypotheses.

Differential expression of genes from the homeobox A cluster in deep endometriotic nodules and peritoneal lesions.

OBJECTIVE: To compare expression of homeobox A (HOXA) genes involved in the differentiation of the female reproductive tract in deep endometriotic nodules and peritoneal lesions. DESIGN: Prospective experimental study. SETTING: Academic gynecology research unit. PATIENT(S): Thirty patients undergoing laparoscopy. INTERVENTION(S): During laparoscopy, deep endometriotic nodules (n=30) and peritoneal lesions (n=11) were recovered. Eutopic endometrium and vaginal tissue (n=30) were collected for control purposes. MAIN OUTCOME MEASURE(S): Quantification of HOXA-9, HOXA-10, HOXA-11, and HOXA-13 in deep nodules, peritoneal lesions, and control samples by real-time reverse-transcription polymerase chain reaction, and localization of HOXA-10 and HOXA-13 proteins by immunohistochemistry. RESULT(S): The HOXA-13 transcripts were detected in 29 out of 30 nodules, and their expression was significantly higher than in vaginal tissue, but they were barely detectable in endometrium and peritoneal lesions. Expression of HOXA-10 and HOXA-11 transcripts in deep nodules was similar to eutopic endometrium, and HOXA-10 expression was significantly lower in peritoneal endometriotic lesions. The HOXA-10 immunostaining was mainly localized in the stroma of deep endometriotic nodules, HOXA-13 in glandular structures and stroma, and neither of these proteins were detected in fibromuscular areas. CONCLUSION(S): Marked expression of HOXA-10 and HOXA-13 in the endometrium-like tissue of nodules but low expression in peritoneal endometriotic lesions supports the theory of differential origin of these two types of endometriosis.

Evaluation of estrogen treatment in an immunodeficient mouse endometriosis model.

BACKGROUND/AIMS: Endometriosis is known to be an estrogen-dependent disease. However, only a few studies have analyzed the effect of estrogen treatment in mice xenotransplanted with human endometrium. The objective of this study was to adapt a previously developed heterologous murine model to the study of estrogens and test the impact of estrone treatment on endometriosis development. METHODS: Human proliferative endometrium was xenotransplanted into the peritoneal cavity of castrated immunodeficient mice. These mice were treated with estrogens by means of subcutaneous estrone-releasing pellets. The effect of estrone on estradiol level, uterine histology and endometriosis development was evaluated after 21 days. RESULTS: Bioactivity of estrone pellets and their metabolization into estradiol were demonstrated. However, there was no impact on endometriosis development (no difference in lesion number, weight, size or fluorescence). This lack of response was not due to absence of estrogen receptor expression, since strong expression was found in all lesions harvested. Surprisingly, castrated nontreated mice presented with lesions showing high proliferative activity, similar to lesions found in treated mice (around 30%). CONCLUSION: The high proliferation observed in lesions recovered from ovariectomized nontreated mice questions the utility of using estrogens in heterologous murine models.

Review: luminescence as a tool to assess pelvic endometriosis development in murine models.

Classic murine endometriosis models may be insufficient to evaluate the effect of therapeutic agents on endometriosis development, because the process of identification and measurement of induced lesions is often impeded, as implants are small and embedded in murine tissue. In this context, as summarized in the current review, luminescence techniques have proved useful for identifying and visualizing or quantifying endometriotic transplants. They are also a valuable tool for endometrial cell tracking in live animals, yielding further information by adding spatial and temporal dimensions to biological processes in vivo. Such approaches involve transplanting luminescently labeled murine or human endometrium into animals. Two main strategies are applied to label endometrium before injection: use of genetically modified tissue or tissue labeled with a fluorescent dye. Each model has its advantages and disadvantages, the choice of model depends on the study objectives/design (long- or short-term studies, homologous or heterologous model).

Iron storage is significantly increased in peritoneal macrophages of endometriosis patients and correlates with iron overload in peritoneal fluid.

OBJECTIVE: To further investigate peritoneal iron disruption in endometriosis by studying iron storage in peritoneal macrophages of patients with endometriosis compared with controls. DESIGN: Cross-sectional study. SETTING: Academic gynecology research unit in a university hospital. PATIENT(S): Fifty patients undergoing laparoscopy. INTERVENTION(S): Collection of peritoneal fluid samples (N = 50) from patients with (n = 27) and without (n = 23) endometriosis undergoing laparoscopy. MAIN OUTCOME MEASURE(S): Quantification of peritoneal macrophage ferritin by immunocytochemical staining and immunodensitometry and measurement of peritoneal iron, transferrin, ferritin, and prohepcidin concentrations. RESULT(S): The optical density of peritoneal macrophage ferritin staining was statistically significantly higher in endometriosis patients than in controls. Higher iron concentrations, transferrin saturations, and ferritin concentrations were also detected in case of endometriosis. A statistically significant positive correlation was found between the optical density of macrophage ferritin staining and peritoneal iron concentrations in endometriosis and control patients. CONCLUSION(S): Iron storage is statistically significantly increased in peritoneal macrophages of patients with endometriosis and correlates with iron overload in peritoneal fluid. The potential implications of iron accumulation in peritoneal macrophages in case of endometriosis are discussed.

Unsuccessful induction of endometriosis in female rhesus macaques (Macaca mulatta).

BACKGROUND/AIMS: The aim of this study was to induce endometriosis in female rhesus macaques (Macaca mulatta) for research purposes. METHODS: Three female monkeys from 4 to 4.5 years of age underwent three consecutive attempts at endometriosis induction over an 8-month period: (i) the first attempt involved intravaginal sampling of endometrial tissue and transplantation into the intrapelvic cavity; (ii) the second entailed surgical removal of endometrium after hysterotomy and intra-abdominal placement, and (iii) the third used endometrial mucosa obtained by scraping the uterus after hysterectomy, placed in a surgical pouch created in the retrovesical space (Retzius). In each case, the pelvic cavity was closely inspected after 7, 9, and 6 weeks respectively for the presence of endometriotic lesions, and peritoneal biopsies were performed. RESULTS: Neither macroscopic observation nor histological analysis revealed any endometriotic lesions. CONCLUSION: This failure to induce endometriosis in female rhesus macaques suggests that this species is not the most efficient experimental model among primates to investigate endometriosis development or treatment.

Antiangiogenic and vascular-disrupting agents in endometriosis: pitfalls and promises.

It is widely known that angiogenesis plays a key role in endometriotic lesion formation and development. Antiangiogenic treatments aimed at inhibiting new vessel formation have proven efficient in experimental models. However, as antiangiogenic strategies do not target pre-existing pericyte-protected vessels, they require chronic administration and are likely to be beneficial for early-stage disease only or to prevent recurrence after surgery. Moreover, they may have detrimental effects on reproductive function. Vascular-disrupting agents (VDAs) have emerged as a promising new tool for the treatment of tumors. VDAs target established blood vessels, resulting in tumor ischemia and necrosis. These agents may therefore be more efficient against advanced disease. Two major types of VDAs are being developed for cancer: ligand-directed VDAs using antibodies, peptides and growth factors to deliver toxic effectors to tumor endothelium; and small-molecule VDAs exploiting physiological differences between tumor and normal endothelium to induce acute vascular shutdown. The ongoing evolution in genomics and proteomics is revolutionizing the discovery of novel endothelial markers. Several studies suggest that the vasculature of endometriotic lesions may have particular pathophysiological properties, which could be exploited for the development of selective VDAs. The aim of this review is to explore the merits and limitations of vascular therapy for the treatment of endometriosis.

Expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in human endometrial stromal and epithelial cells is regulated by interferon-gamma but not iron.

BACKGROUND/AIMS: Endometrial cells are chronically exposed to iron due to cyclic menstrual bleeding. Iron induces expression of adhesion molecules in endothelial cells. The purpose of this study was to investigate iron incorporation by human endometrial cells and to test whether iron may stimulate expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1. METHODS: Endometrial stromal and epithelial cells were cultured in medium alone or supplemented with INF-gamma or transferrin (Tf). Iron incorporation by cells was quantified by densitometry of ferritin immunostaining. ICAM-1 and VCAM-1 expression were evaluated at the transcriptional level by real-time RT-PCR. Membrane-bound and soluble protein levels of ICAM-1 were measured by quantitative immunohistochemistry and ELISA, respectively. RESULTS: Tf induced a significant increase in ferritin immunostaining in both endometrial cell types. Endometrial cells treated with INF-gamma expressed more ICAM-1 and VCAM-1 than untreated cells. By contrast, Tf treatment did not alter ICAM-1 and VCAM-1 expression in cultured endometrial cells. CONCLUSIONS: Endometrial cells are able to incorporate iron from Tf and to metabolize it to ferritin. Iron, unlike interferon-gamma, does not appear to be involved in the regulation of ICAM-1 and VCAM-1 expression in cultured endometrial cells.

Agents blocking the nuclear factor-kappaB pathway are effective inhibitors of endometriosis in an in vivo experimental model.

BACKGROUND: In vitro studies suggest that the transcription factor nuclear factor-kappa B (NF-kappaB) is implicated in the transduction of proinflammatory signals in endometriosis. The aim of this study was to investigate the involvement of NF-kappaB and the processes regulated by NF-kappaB in the initial development of endometriotic lesionsin vivo. METHODS: Endometriosis was induced in nude mice by intraperitoneal injection of fluorescent-labeled menstrual endometrium. Two NF-kappaB inhibitors (BAY 11-7085 and SN-50) were injected intraperitoneally on days 0, 2 and 4 after endometriosis induction, and endometriotic lesions were recovered on day 5. Number, mass, fluorimetry and surface (morphometry) of endometriotic lesions were quantified. NF-kappaB activation, intercellular adhesion molecule (ICAM)-1 expression, cell proliferation and apoptosis were evaluated by immunohistochemical analyses and the TUNEL method. RESULTS: Both NF-kappaB inhibitors induced a significant reduction in lesion development compared to control mice. NF-kappaB activation and ICAM-1 expression of endometriotic lesions were significantly reduced in treated mice, and cell proliferation was significantly reduced in BAY 11-7085-treated mice. Both inhibitors produced a significant increase in apoptosis of endometriotic lesions, as assessed by active caspase-3 immunostaining and the TUNEL method. CONCLUSION: This study demonstrates, for the first time, that the NF-kappaB pathway is implicated in the development of endometriotic lesions in vivo and that NF-kappaB inhibition reduces ICAM-1 expression and cell proliferation, but increases apoptosis of endometriotic lesions, diminishing the initial development of endometriosis in an animal model.

Increased activation of nuclear factor-kappa B (NF-kappaB) in isolated peritoneal macrophages of patients with endometriosis.

Endometriosis is characterized by pelvic inflammation that shows an increased number of activated peritoneal macrophages and their secreted products such as cytokines, growth factors, and angiogenic factors. Our results show that activation of nuclear factor-kappa B (NF-kappaB), a pro-inflammatory transcription factor, is statistically significantly increased in peritoneal macrophages from patients with endometriosis when compared with controls.