Jeanne Stutzmann

Resveratrol analog (Z)-3,5,4′-trimethoxystilbene is a potent anti-mitotic drug inhibiting tubulin polymerization

Resveratrol (3,5,4′‐trihydroxystilbene) a natural polyphenol present in medicinal plants, grapes and wines, has potent chemopreventive properties on intestinal carcinogenesis. A methylated derivative (Z‐3,5,4′‐trimethoxystilbene: R3) was synthesized. R3 at 0.3 μM exerted a 80% growth inhibition of human colon cancer Caco‐2 cells and arrested growth completely at 0.4 μM (R3 was 100‐fold more active than resveratrol). The cis conformation of R3 was also 100‐fold more potent than the trans isomer. R3 (0.3 μM) caused cell cycle arrest at the G2/M phase transition. The drug inhibited tubulin polymerization in a dose‐dependent manner (IC50= 4 μM), and it reduced also by 2‐fold ornithine decarboxylase and s‐adenosylmethionine decarboxylase activities. This caused the depletion of the polyamines, putrescine and spermidine, which are growth factors for cancer cells. R3 inhibited partially colchicine binding to its binding site on tubulin, indicating that R3 either partially overlaps with colchicine binding or that R3 binds to a specific site of tubulin that is not identical with the colchicine binding site modifying colchicine binding by allosteric influences. The resveratrol derivative (Z)‐3,5,4′‐trimethoxystilbene (R3) is an interesting anti‐mitotic drug that exerts cytotoxic effects by depleting the intracellular pool of polyamines and by altering microtubule polymerization. Such a drug may be useful for the treatment of neoplastic diseases.

Adhesion complexes implicated in intestinal epithelial cell-matrix interactions

This article review summarizes data on cell‐substratum adhesion complexes involved in the regulation of cellular functions in the intestine. We first focus on the molecular composition of the two main adhesion structures—the β1 integrin‐adhesion complex and the hemidesmosome—found in vivo and in two human intestinal cell lines. We also report the key findings on the cellular behavior and response to the extracellular matrix that involve integrins, the main transmembrane anchors of these complexes. How the dynamics of cell/extracellular matrix interactions contribute to cell migration, proliferation, differentiation, and tumorigenicity is discussed in the light of the data provided by the human intestinal cells. Microsc. Res. Tech. 51:179–190, 2000.

Time-Dependent Effects of a Functional'-Type Orthopedic Appliance on the Rat Mandible Growth

The modus operandi and the time-dependent variations in the effects of the LSU-activator, an orthopedic appliance currently used in human orthodontic therapy, was experimentally analyzed in growing rats. This appliance causes a forward positioning of the lower jaw and a restriction of mandibular motility. After a 4-week treatment, the following changes were observed: (i) the growth rate of the condylar cartilage was accelerated, this growth-promoting effect being more pronounced when the LSU-activator was worn during the animals rest span. (ii) the direction of condylar growth became more backward-oriented; no significant difference between day and night treatment, i.e. during the rest and activity spans could be detected; (iii) the supplementary lengthening of the mandible was greater in rats treated during rest than in rats treated during waking and (iv) the number of serial sarcomeres in the lateral pterygoid muscle was smaller. This growth retardation of the muscle was greater in rest-time than in waking-time treated individuals. The LSU-type activators action implies a two-step effect: during the time of wearing the appliance, the more forward positioning of the mandible causes a reduced growth of the lateral pterygoid muscle; during the time the LSU-type activator is not worn, the mandible is functioning in a more forward position such a way that it stimulates the growth rate of the condylar cartilage and the subperiosteal ossification of the posterior border of the ramus. It is therefore essential, for a few hours every day, that the mandible be allowed to move freely from the appliance in a more forward position.

Experimental models of acute and chronic liver failure in nude mice to study hepatocyte transplantation.

Although hepatocyte transplantation is a promising therapy for acute liver failure in human, there is still a lack of animal models suffering from hepatic injury in which the benefits of hepatocyte transplantation could be evaluated solely, without the bias caused by immunosuppression. As a consequence, the aim of the study was first to develop reproducible models of partial hepatectomy and of thioacetamide (TA)- or Jo2-induced acute liver failure in nude mice. Chronic liver disease was also investigated by repeated injections of sublethal doses of thioacetamide. Survival rates, routine histologic observations, alanin aminotransferase sera content, Ki67, and caspase 3 immunodetection were investigated both after 40% partial hepatectomy and after toxic-induced damages. Liver injuries were more severe and/or precocious in nude mice than in Balb/c mice for a given treatment with a maximum of acute injury obtained 24 h after single toxic injection, and were found to be transitory and reversible within 10 days. Toxics induced apoptosis followed by necrosis, confirming recent published data. Onset of fibrosis leading to reproducible chronic cirrhosis in nude mice correlated with increasing number of Ki67-positive cells, indicating that high levels of cell proliferation occurred. Chronic cirrhosis progressively reversed to fibrosis when the treatment ceased. Preliminary results demonstrated that engrafted xenogeneic hepatocytes could be detected in the host liver by anti-MHC class I immunohistochemistry. Fractions enriched in 2n or 4n hepatocytes by cell sorting using a flow cytometer were equivalent to the unpurified fraction in terms of engraftment in control nude mice or in nude mice subjected to PH. However, in mice suffering from liver injury 24 h after Jo2 or TA treatment, the engraftment of 2n hepatocytes was about twice that of an unpurified hepatocyte population or of a population enriched in 4n hepatocytes.

Turn‐over of human alveolar bone removed either in the day or in the night

Abstract Human Alveolar bone was removed in the same individual during bilateral mandibular first premolar extraction, the first one between 1000 and 1230, and the second one between 2200 and 0030 , or vice versa. The statistical analysis (Student t‐test for matched pairs) shows : 1. the mitotic index was higher in the specimens taken between 1000 and 1230, while 3H‐thymidine labelled cells index as estimated in a 1‐hour organ culture, was higher in the specimens taken between 2200 and 0030. 2. Alkaline phosphatase activity (a parameter of bone formation) as well as s‐glucuronidase and acid phenylphosphatase activities (parameters of bone resorption rate), were higher in the specimens taken between 2200 and 0030. These findings reflect the existence of nyctohemeral fluctuations in human bone turn‐over.

Seasonal variations of the human alveolar bone turn‐over. A quantitative evaluation in organ culture

Abstract Alveolar bone removed from eleven to thirteen year‐old boys, was placed into organ culture. The analysis of the results shows that the formation rate (as estimated by 45Ca uptake and alkaline phenylphosphatase activity) and the resorption rate (as estimated by s‐glucuronidase and acid phenylphosphatase activities) were both greater to a highly significant degree in the 80 cases where alveolar bone was removed between April the 1st and July the 1st than in the 80 cases taken between October the 15th and January the 15th.

Ultradian mitotic rhythms in culture of human sarcomatous bone cells originating from the patient before and after chemotherapy

Bone sarcomatous cells derived from human malignant tumors were cultured. The mitotic index was recorded for 39 hr. When the cultured cells originated from patients with cancer disease before any chemotherapy, ultradian mitotic rhythms of a 6-9-hr period were detected, but in many cases only after a sensitive statistical analysis was performed. When the cultured cells originated from cancer patients undergoing chemotherapy, the mitotic index was decreased, and the amplitudes of the 6-9-hr component oscillations of the mitotic index were highly significantly increased. Damping and fading out of an ultradian mitotic rhythmicity was a bad prognostic portent in bone cancer. With reference to chemotherapy, the restored and amplified ultradian rhythmicity disclosed an appreciable antitumor effect and better survival prospects for the patient.