Role of Kupffer cells in thioacetamide-induced cell cycle dysfunction.

It is well known that gadolinium chloride (GD) attenuates drug-induced hepatotoxicity by selectively inactivating Kupffer cells. In the present study the effect of GD in reference to cell cycle and postnecrotic liver regeneration induced by thioacetamide (TA) in rats was studied. Two months male rats, intraveously pretreated with a single dose of GD (0.1 mmol/Kg), were intraperitoneally injected with TA (6.6 mmol/Kg). Samples of blood and liver were obtained from rats at 0, 12, 24, 48, 72 and 96 h following TA intoxication. Parameters related to liver damage were determined in blood. In order to evaluate the mechanisms involved in the post-necrotic regenerative state, the levels of cyclin D and cyclin E as well as protein p27 and Proliferating Cell Nuclear Antigen (PCNA) were determined in liver extracts because of their roles in the control of cell cycle check-points. The results showed that GD significantly reduced the extent of necrosis. Noticeable changes were detected in the levels of cyclin D1, cyclin E, p27 and PCNA when compared to those induced by thioacetamide. Thus GD pre-treatment reduced TA-induced liver injury and accelerated the postnecrotic liver regeneration. These results demonstrate that Kupffer cells are involved in TA-induced liver and also in the postnecrotic proliferative liver states.

Glycyrrhizin attenuates endotoxin- induced acute liver injury after partial hepatectomy in rats

Massive hepatectomy associated with infection induces liver dysfunction, or even multiple organ failure and death. Glycyrrhizin has been shown to exhibit anti-oxidant and anti-inflammatory activities. The aim of the present study was to investigate whether glycyrrhizin could attenuate endotoxin-induced acute liver injury after partial hepatectomy. Male Wistar rats (6 to 8 weeks old, weighing 200-250 g) were randomly assigned to three groups of 24 rats each: sham, saline and glycyrrhizin. Rats were injected intravenously with lipopolysaccharide (LPS) 24 h after 70 percent hepatectomy. Glycyrrhizin, pre-administered three times with 24 h intervals 48 h before hepatectomy, prolonged the survival of rats submitted to partial hepatectomy and LPS injection, compared with saline controls. Glycyrrhizin was shown to attenuate histological hepatic changes and significantly reduced serum levels of aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase, at all the indicated times (6 rats from each were sacrificed 1, 3, 6, and 9 h after LPS injection), compared with saline controls. Glycyrrhizin also significantly inhibited hepatocyte apoptosis by down-regulating the expression of caspase-3 and inhibiting the release of cytochrome C from mitochondria into the cytoplasm. The anti-inflammatory activity of glycyrrhizin may rely on the inhibition of release of tumor necrosis factor-a, myeloperoxidase activity, and translocation of nuclear factor-kappa B into the nuclei. Glycyrrhizin also up-regulated the expression of proliferating cell nuclear antigen, implying that it might be able to promote regeneration of livers harmed by LPS. In summary, glycyrrhizin may represent a potent drug protecting the liver against endotoxin-induced injury, especially after massive hepatectomy.

Glycyrrhizin attenuates endotoxin- induced acute liver injury after partial hepatectomy in rats.

Massive hepatectomy associated with infection induces liver dysfunction, or even multiple organ failure and death. Glycyrrhizin has been shown to exhibit anti-oxidant and anti-inflammatory activities. The aim of the present study was to investigate whether glycyrrhizin could attenuate endotoxin-induced acute liver injury after partial hepatectomy. Male Wistar rats (6 to 8 weeks old, weighing 200-250 g) were randomly assigned to three groups of 24 rats each: sham, saline and glycyrrhizin. Rats were injected intravenously with lipopolysaccharide (LPS) 24 h after 70% hepatectomy. Glycyrrhizin, pre-administered three times with 24 h intervals 48 h before hepatectomy, prolonged the survival of rats submitted to partial hepatectomy and LPS injection, compared with saline controls. Glycyrrhizin was shown to attenuate histological hepatic changes and significantly reduced serum levels of aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase, at all the indicated times (6 rats from each were sacrificed 1, 3, 6, and 9 h after LPS injection), compared with saline controls. Glycyrrhizin also significantly inhibited hepatocyte apoptosis by down-regulating the expression of caspase-3 and inhibiting the release of cytochrome C from mitochondria into the cytoplasm. The anti-inflammatory activity of glycyrrhizin may rely on the inhibition of release of tumor necrosis factor-a, myeloperoxidase activity, and translocation of nuclear factor-kappa B into the nuclei. Glycyrrhizin also up-regulated the expression of proliferating cell nuclear antigen, implying that it might be able to promote regeneration of livers harmed by LPS. In summary, glycyrrhizin may represent a potent drug protecting the liver against endotoxin-induced injury, especially after massive hepatectomy.

The role of ACTH in the pathogenesis of polycystic ovarian syndrome in rats: hormonal profiles and ovarian morphology.

Numerous hypotheses have been proposed about the pathogenesis of the polycystic ovarian syndrome (PCOS). However, hormonal control of persistent follicles has not been established. The objective of the present study was to compare the follicular structure and hormonal profiles of rats treated with the adrenocorticotrophic hormone (ACTH) with two experimental models of PCOS. ACTH-treated animals were compared with those exposed to continuous light, those treated with estradiol valerate, and with control (in proestrous and diestrous). Serum hormone levels, histomorphometrical changes, and immunoexpression of vimentin, cytokeratins, cadherins, and proliferating cell nuclear antigen (PCNA) were examined. Treatment with ACTH resulted in an elevation of corticosterone secretion with LH reduction but without changes in ovarian morphology. Although stress (or ACTH) stimulation may be only one of pathophysiological mechanisms involved in follicular cyst pathogenesis in other species, we do not have important evidence to suppose that this would happen in rats.

MIBI scintigraphy, indicators of cell proliferation and histology of parathyroid glands in uraemic patients.

BACKGROUND: Although scintigraphy with (99m)Tc-sestamibi (MIBI) has been used to localize parathyroid glands prior to surgery for hyperparathyroidism, using it to evaluate parathyroid function remains controversial. The purpose of this study was to evaluate the possible association of MIBI uptake with gland weight, histological pattern and proliferative activity of parathyroid cells. METHODS: We studied 18 patients with secondary hyperparathyroidism (SHP); mean age 38+/-3 years, 55% female, mean time on haemodialysis 7.7+/-0.9 years. All patients had parathyroidectomy (PTx). The weights of the removed glands were estimated, and parathyroid hyperplasia was classified as diffuse (n = 28) or nodular (n = 29). The expression of proliferative cell nuclear antigen (PCNA) was evaluated by immunohistochemistry. Before PTx, all patients underwent MIBI evaluation and were categorized using a 0-3 uptake scoring system. Low uptake (scores of 0 and 1) was seen in 39 glands and high uptake (scores of 2 and 3) in 18. RESULTS: Estimated gland weights, percentage of nodular hyperplasia and PCNA expression were greater in glands with high MIBI scores than in those with low scores (P<0.01). In glands with nodular hyperplasia, PCNA expression was higher (318+/-66 cells/mm2) than in those with diffuse hyperplasia (104+/-16 cells/mm2; P<0.001). CONCLUSIONS: High MIBI scores were associated with high estimated gland weight, degree of cell proliferation and presence of nodular hyperplasia. MIBI scintigraphy is useful in clinical practice for localizing parathyroid glands, and it could guide the management of SHP by indicating the degree of its severity.

Proliferating cell nuclear antigen immunoreaction in adrenal tumors.

AIMS AND BACKGROUND: We studied, retrospectively, 33 cases of adrenal tumors of children at the Pediatric Endocrinology Unit, Children's Institute, São Paulo State University Medical School, from 1975 to 1993. All patients had at least 2 years of follow-up with a few exceptions. METHODS: Clinical follow-up data were correlated with histopathologic review, laboratory data and cell kinetic evaluation (based on detection of proliferating cell nuclear antigens). RESULTS: With one exception, all the patients had presented signs of androgen production and had high levels of dehydro-epiandrosterone-sulfate. Tumor weight evaluation represented a good parameter of neoplasm evolution: of 19 cases weighing less than 250 g, 17 had no evidence of disease after surgery, and 2 had an unfavorable prognosis. Of 14 cases weighing more than 250 g, only 1 had no evidence of disease and 13 had an unfavorable evolution. CONCLUSIONS: Proliferating cell nuclear antigen (PCNA) was not helpful to evaluate adrenal neoplasm evolution: our study did not show any correlation between PCNA score and prognosis.