Similarities and differences between embryonic implantation and CTC invasion: Exploring the roles of abortifacients in cancer metastasis chemoprevention.

Mifepristone (RU486) is a chemical contraceptive marketed in more than 55 countries and used by hundreds of millions of women worldwide. Current studies reported its uses by both genders for a safe and long-term psychotic depression and particularly for traditional cancer chemotherapy. Here, we investigated the multidisciplinary data from recent large epidemiological chemoprevention studies for long-term use of oral contraceptives to reduce cancer risk, and from the unsuccessful clinical trials of mifepristone used as a post-metastatic anticancer drug, and elucidated the similarities and differences in cellular and molecular processes between embryonic implantation to endometrium and adhesion/invasion of circulating tumor cells (CTCs) to vascular endothelium. The deep analyses provide a stronger scientific basis for repurposing abortifacients for safe and effective cancer metastatic chemoprevention. Initiation of such cancer drug development strategy represents a paradigm shift from traditional post-metastasis treatments to novel pre-metastasis chemoprevention.

Azadirachta indica A. Juss (neem) as a contraceptive: An evidence-based review on its pharmacological efficiency.

BACKGROUND: Azadirachta indica A. Juss. is an Indian medicinal plant with innumerable pharmacological properties. Studies have proven that the phytochemicals from neem possess remarkable contraceptive abilities with limited knowledge on its mechanism of action. PURPOSE: The present review aims to summarize the efficiency of A. indica treatment as a contraceptive. METHODS: The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were used. Published scientific articles on antifertility, antispermatogenic, antiovulation, hormone altering, contraceptive, and abortifacient activities of A. indica were collected from reputed Journals from 1980 to 2020 using electronic databases. Specific keywords search was completed to collect numerous articles with unique experiment design and significant results. This was followed by the selection of the requisite articles based on the criteria designed by the authors. Data extraction was based on the common research elements included in the articles. RESULTS: A total of 27 studies were considered for reviewing, which included key pharmacological investigations. In the beginning, authors evaluated a number of publications on the contraceptive properties of A. indica, in which it was revealed that most of the publications were made between 2005 and 2009. All the collected articles were categorised and reviewed as antifertility, antispermatogenic, antiovulation, hormone altering, contraceptive, and abortifacient. Authors also assessed studies based on the plant parts used for pharmacological evaluations including leaves, seeds, stem-bark, and flowers. The article was primarily divided into different sections based on the previous works of authors on phytochemistry and pharmacological review articles. CONCLUSION: Although A. indica is not reported with the complete alleviation of reproductive system in both male and female animal models, studies have proven its efficacy as a contraceptive. Extracts and phytochemicals from neem neither reduced the libido nor retarded the growth of secondary sexual characters, thus indicating only a temporary and reversible contraceptive activity. However, there is a dearth for clinical studies to prove the efficacy of A. indica as a herbal contraceptive.

Is it safe to consume traditional medicinal plants during pregnancy?

The popularity of natural medicine is growing worldwide. Unlike conventional licensed medicines, herbal medicine practices are usually not supported by effectiveness, efficacy, or safety studies, which raise concerns about potential risks involved in their usage, particularly in high-risk patients such as pregnant women where teratogenicity is a concern. Despite a lack of science-based evidence, the use of herbal products for the management of pregnancy-associated challenges is common, due to the common notion that they are free of toxic effects and adverse reactions because they are "natural." The lack of concern about utilizing herbal remedies during pregnancy is strengthened by the lack of regulation in most countries for their marketing. However, plant-based remedies are not free of adverse reactions. Medicinal plants and herbal remedies contain substances that can be toxic to the human body and the fetus. Potential effects of indiscriminate use of medicinal plants are embryotoxicity, teratogenic, and abortifacient effects. Some plant constituents can cross the placenta and reach the fetus. Phytochemicals and their metabolites are known to induce stimulation of uterine contraction and hormone imbalance that could result in abortion. The alterations to the hormonal profile can affect conception, induce teratogenic activity, and halt the pregnancy or produce a congenital malformation. Due to the wide range of modes of action of phytochemicals, some medicinal plants may be safe to use during certain trimesters of pregnancy and harmful at other stages. This manuscript reviews available scientific information concerning potential health hazards associated with the consumption of herbal medicines during pregnancy, highlighting those herbs that should be avoided due to their potential abortifacient and/or teratogenic activity. We focused on plants that were tested by preclinical studies, and studies of these plants are summarized. Common therapeutic use of these herbs, estimated effects, toxicological effects, and animal studies of these plants is summarized. The literature reviewed suggests that consumption of the following medicinal plants should be avoided during pregnancy: Abrus precatorius, Achyranthes aspera, Ailanthus excelsa, Aloe vera, Aristolochia indica, Areca catechu, Bambusa vulgaris, Cassia occidentalis, Cicer arietinum, Cimicifuga racemose, Dolichandrone falcate, Ginkgo biloba, Hydrastis canadensis, Indigofera trifoliate, Lavandula latifolia, Maytenus ilicifolia, Momordica cymbalaria, Moringa oleifera, Musa rosacea, Oxalis corniculate, Phytolacca dodecandra, Plumeria rubra, Ricinus communis, Ruta graveolens, Stachys lavandulifolia, Senna alata, Trigonella foenum-graecum, Vitus agnus-castus, and Valeriana officinalis.

Abortifacient metapristone (RU486 derivative) interrupts CXCL12/CXCR4 axis for ovarian metastatic chemoprevention.

Recent global epidemiological studies revealed the lower ovarian cancer death from long-term use of oral contraceptives. However, the underlying mechanism of action is not clear. Here, we use the abortifacient metapristone (RU486 derivative) to test the hypothesis that the contraceptives might interrupt CXCL12/CXCR4 chemokine axis to inhibit ovarian cancer metastasis. Metapristone at concentrations (

The paradigm-shifting idea and its practice: from traditional abortion Chinese medicine Murraya paniculata to safe and effective cancer metastatic chemopreventives.

Recent large epidemiological studies demonstrated benefit of oral contraceptives in reducing cancer risk, and our analysis also showed molecular and cellular similarities between embryo implantation and CTCs adhesion-invasion to endothelium. We here hypothesize that abortion traditional Chinese medicine (TCM) may serve well for pre-metastatic chemoprevention. To test the hypothesis, we selected the safe and well-known abortifacient TCM Murraya paniculata and identified a most-promising extracted fraction G (containing flavonoids and coumarins) from its many raw ethanol/dichloromethane extracts by using the bioactivity-guided fast screen assay. G showed free radical scavenging effect, and specifically inhibited both embryo implantation to human endometrial bed and cancer HT29 cells to human endothelium in a concentration-dependent manner (1-30 µg/mL) without significant cytotoxicity demonstrated by its high adhesion inhibition ratio. The inhibition may result from its down-regulation on expression of integrin ß1 and α6, and CD44 on HT29 cells, as well as E-selectin on endothelial cells. Furthermore, G inhibited invasion and migration of HT29 cells. Pretreatment followed by one-month oral administration of G to the immunocompetent mice inoculated with mouse melanoma cells produced significant inhibition on lung metastasis without marked side effects. Collectively, this paradigm-shifting study provides, for the first time, a new strategy to discover safe and effective pre-metastatic chemopreventives from abortion TCM.

A comparison of the metabolism of the abortifacient compounds from Ponderosa pine needles in conditioned versus naive cattle.

Isocupressic acid (ICA) is the abortifacient compound in ponderosa pine (Pinus ponderosa L.) needles, which can cause late-term abortions in cattle (Bos taurus). However, cattle rapidly metabolize ICA to agathic acid (AGA) and subsequent metabolites. When pine needles are dosed orally to cattle, no ICA is detected in their serum, whereas AGA is readily detected. Recent research has demonstrated that AGA is also an abortifacient compound in cattle. The observation has been made that when cattle are dosed with labdane acids for an extended time, the concentration of AGA in serum increases for 1 to 2 d but then decreases to baseline after 5 to 6 d even though they are still being dosed twice daily. Therefore, in this study we investigated whether cattle conditioned to pine needles metabolize ICA, and its metabolites, faster than naïve cattle. Agathic acid was readily detected in the serum of naïve cattle fed ponderosa pine needles, whereas very little AGA was detected in the serum of cattle conditioned to pine needles. We also compared the metabolism of ICA in vitro using rumen cultures from pine-needle-conditioned and naïve cattle. In the rumen cultures from conditioned cattle, AGA concentrations were dramatically less than rumen cultures from naïve cattle. Thus, an adaptation occurs to cattle conditioned to pine needles such that the metabolism AGA by the rumen microflora is altered.

Equine amnionitis and fetal loss: mare abortion following experimental exposure to Processionary caterpillars (Ochrogaster lunifer).

REASONS FOR PERFORMING STUDY: In Australia, there have been recent reports of unusual abortions in mid- to late-gestation mares. These were clinically distinct from other recognised causes of pregnancy loss and the term 'equine amnionitis and fetal loss' (EAFL) was adopted to describe this syndrome. Initial investigations concluded that possible causal factors included the presence on affected stud farms of Processionary caterpillars (Ochrogaster lunifer). OBJECTIVES: To determine if exposure of pregnant mares to Processionary caterpillars or their shed exoskeletons can induce EAFL. METHODS: Processionary caterpillars and their shed exoskeletons were collected and stored frozen. Mid-gestation mares were dosed with a slurry of caterpillars or shed exoskeleton by nasogastric intubation. Their clinical responses and times to abortion were recorded. All aborted fetuses were autopsied and samples taken for bacteriological and virological culture and histopathology. RESULTS: Intubating mares in mid-pregnancy with preparations of either whole Processionary caterpillars or shed caterpillar exoskeletons induced abortion with few impending clinical signs. The gross pathological and bacteriological findings of the aborted fetuses were similar to those observed in field cases of EAFL. POTENTIAL RELEVANCE: Possible exposure to Processionary caterpillars should be considered when examining cases of fetal loss in the mare. The present results provide a starting point to further explore the aetiology and pathogenesis of EAFL.

[Phenolic acids from Arnebia euchroma mifepristone in anti-early pregnancy of SD rattus norvegicus].

OBJECTIVE: Observing the effect of phenolic acids from Arnebia euchroma assist mifepristone in anti-early pregnancy of SD rattus norvegicus. METHOD: Feed the SD rattus norvegicus with phenolic acids from A. euchroma during the 7 th to 9 th day, and then we observe the restaining rate of pregnancy. At the same time, we determine the progesterone level in blood serum in the ways of radioimmunoassay. RESULT: 720 g x kg(-1) enolic aids from A. euchroma can markedly increase the restaining rate of pregnancy (P < 0.05) than that only mifepristone dose (8.0 g x kg(-1)). In addition, the number of everage still bith increase, however, to the pogesterone level in blood serum. It has little effect. CONCLUSION: The effect of phenolic acids from A. euchroma assist mifepristone in anti-early pregnancy of SD rattus norvegicus is clear, and it dosen't work in the ways of decreasing the pogesterone level.

2,4,6-Trisubstituted pyrimidine derivatives as pregnancy interceptive agents.

A series of 2,4,6-trisubstituted pyrimidine derivatives was synthesized and evaluated for their in vivo pregnancy interceptive activity in hamsters. Out of the 17 compounds synthesized three compounds showed 100% activity at a dose of 10mg/kg.

Medical abortion in the first trimester.

Pregnancy can be terminated safely by inducing abortion medically at any stage of gestation. Antagonists such as mifepristone block the action of progesterone and hence result in uterine contractions and increase the sensitivity of the uterus to prostaglandins. In the last 15 years the combination of a single dose of mifepristone (600 mg) followed 48 hours later with a suitable prostaglandin (1 mg gemeprost vaginal pessary or 400 microg oral misoprostol) has been licensed in most countries in Europe and the USA for induction of abortion in the early weeks of pregnancy. The safety and efficacy of these methods is comparable to vacuum aspiration at the same gestation. The complete abortion rate is related to the type and dose of prostaglandin, the route of administration as well as the gestation and parity. Published data suggest that the dose of mifepristone can be reduced from 600 mg to 200 mg without loss of efficacy. Although misoprostol tablets are formulated for oral use, extensive clinical experience has demonstrated vaginal administration is more effective and is associated with fewer side-effects. Successful abortion using medical methods requires a well organized service which includes referral without delay and a robust system of follow up to identify failures. The failure rate as reflected by the number of women who require surgical intervention falls with increasing experience. In those countries where medical abortion has been freely available for about 10 years, such as France, Scotland and Sweden, about 60-70% of eligible women elect for this method.

Antifertility activity of Ricinus communis seed in female guinea pigs.

OBJECTIVE: To investigate the anti-fertility effect of Ricinus communis seed extract. DESIGN: Laboratory-based experiment. SETTING: Laboratory of the Department of Pharmacology, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia in 1996. RESULTS: The seed extract was found to possess anti-implantation and abortifacient effects. It was also observed that the seed extract prolonged the oestrus cycle of guinea pigs. The dioestrus phase was significantly prolonged as well. After stopping administering the extract, however, the normal dioestrus phase and oestrus cycle started to resume. The seed extract also reduced the weight of the uterus without affecting that of the ovaries significantly. CONCLUSION: Ricinus communis possesses an anti-fertility effect in female guinea pigs, which might be extrapolated in human beings. These findings might support the accredited claim of its traditional use to avoid unwanted pregnancies. Further studies, however, should be pursued.

Medical methods for termination of pregnancy. Report of a WHO Scientific Group.

Recent estimates indicate that as many as 53 million pregnancies are terminated by induced abortion each year. One-third of these abortions are performed in unsafe conditions, resulting in some 50,000-100,000 deaths each year, and many more women have complications which may have long-term consequences for their health. This report of a WHO Scientific Group reviews medical methods for the termination of first- and second-trimester pregnancy, including studies on the agents that induce abortion, their mode of action, and their efficacy compared with surgical methods. It examines the factors that cause women to seek abortion services, as well as those that affect complications, their prevention and the acceptability of different methods. The report makes a number of recommendations on the service environment required to employ medical methods and for further research in the field of medical termination of pregnancy.

The toxic and abortifacient effects of ponderosa pine.

Ponderosa pine needles cause abortion and a poorly described toxicosis when eaten by cattle. In previous trials, the abortifacient compound of pine needles was identified as isocupressic acid. At abortifacient doses, isocupressic acid caused no other toxicosis. However, other pine needle fractions, similar in composition to several commercially available rosin products, caused no abortion but were very toxic. The purpose of this study was to describe the toxicoses of ponderosa pine, compare its toxicity with other rosin and related pine products, and identify the toxin. Four groups of three pregnant beef cows each were treated with either ponderosa pine tips, rosin gum, dehydroabietic acid, or ground alfalfa. The cows treated with pine tips aborted, had retained placentas with endometritis, and developed both renal and neurologic lesions. The cattle treated with rosin gum or dehydroabietic acid did not abort but developed similar signs and lesions of intoxication. Clinical signs of intoxication included anorexia, mild rumen acidosis, dyspnea, paresis progressing to paralysis, and death. Clinical biochemical results, suggestive of renal, hepatic, and muscular disease, included azotemia, hypercreatinemia, hyperphosphatemia, proteinuria, and marked elevations of various serum enzymes. Histologically, all poisoned animals had nephrosis, vacuolation of basal ganglia neuropil with patchy perivascular and myelinic edema, and skeletal myonecrosis. The alfalfa-treated controls were normal. These findings suggest that ponderosa pine needles and tips are both abortifacient and toxic. Because the lesions caused by pine tips, rosin gum, and dehydroabietic acid are similar, toxicosis is most likely due to the diterpene abietane acids, common in all three.

[Studies on the antifertility constituents of Marsdenia oreophila].

A new pregnane glycoside, marsdeoreophiside B was isolated from the stems of Marsdenia oreophila (Asclepiadeaece). The structure was elucidated by means of chemical and spectrometric analysis as 12-O-cinnamyldihydrosarcostin-3-O-beta-D-glucopyranosyl (1-->4)-O-3-O-methyl-6-deoxy-beta-D-allopyranosyl(1-->4)-O-beta-D- oleandropyranosyl (1-->4)-O-beta-D-cymaropyranoside. It showed significant antifertility activity in rats.

Possible antifertility agents belonging to substituted indoles.

Of the 21 compounds evaluated for antiimplantation and abortifacient activities, compounds (A1, A2, A4 and B1) and compounds (C1, C2, D1 and D3) were found to exhibit 40% and 30% antiimplantation activity, respectively, in female rats when given orally on days 1-5 postcoitum. The remaining 13 compounds were found to be inactive. All of the 21 compounds were also tested for the abortifacient activity, but all were found to be inactive.

Isolation of a ribosome-inactivating and abortifacient protein from seeds of Luffa acutangula.

A glycoprotein with a molecular weight of 28,000 as estimated by SDS-polyacrylamide gel electrophoresis was isolated from seeds of Luffa acutangula using a procedure that involved acetone precipitation, ion exchange chromatography on CM Sepharose CL-6B and gel filtration on Sephadex G-50. In immunodiffusion studies it was found to be immunologically distinct from abortifacient proteins isolated from other members of the Cucurbitaceae family including Momordica charantia, Momordica cochinchinensis, Trichosanthes kirilowii and Trichosanthes cucumeroides. There were some differences in amino acid composition among the proteins although there was a gross similarity. The protein from L. acutangula was capable of inducing mid-term abortion in mice and inhibiting protein synthesis in a cell-free system.