A postulated role for 16 alpha-hydroxydehydroepiandrosterone in the prevention of respiratory distress syndrome

The concentrations of 16-hydroxylated steroids, especially 16 alpha-hydroxydehydroepiandrosterone (16 alpha-hydroxyDHEA) in amniotic fluid and infants' blood are elevated many fold at normal birth time as compared with mid-term concentrations and those found in prematurely born infants. It is logical to postulate that 16 alpha-hydroxyDHEA may be the natural inducer of lung maturation and preventor of respiratory distress syndrome. Because the infant born at normal gestational terminus has a very high concentration of blood 16 alpha-hydroxyDHEA, treating premature infants with amounts of this steroid to provide blood concentrations that are normal in full-term infants should be a well-tolerated procedure and should avoid the developmental problems associated with glucocorticoid treatments.     

A postulated role of garlic organosulfur compounds in prevention of valproic acid hepatotoxicity

Valproic acid (2-propyl-pentanoic acid, VPA) is well established as a first-line and widely used antiepileptic agent. VPA is well tolerated in most patients and has an impressive safety profile. VPA induced hepatotoxicity is rare, but often there is fatal complication of this drug and it is more frequent in children under 2 years of age and in those taking multiple drugs. Several findings showed that oxidative stress induced by reactive oxygen species (ROS) over production and/or compromised antioxidant capacity play an important role in the development of hepatotoxicity in VPA treated patients. Reduced glutathione (GSH) and its related enzymes are important cellular defense against oxidative stress in which VPA induced oxidative stress impairs their function in hepatocytes. Consequently any mechanism which removes ROS or prevents hepatic GSH depletion or induce activation and production of GSH dependent enzymes may provide protection for hepatotoxicity in VPA-treated patient. As garlic organosulfur compounds enhance cellular antioxidant activity by free radical scavenging and augmentation of endogenous antioxidants via prevention of GSH depletion and alteration of GSH dependent enzymes activity and/or their gene expression, we propose the hypothesis that garlic organosulfur compounds can prevent valproic acid hepatotoxicity.     

Inosine biosynthesis in transfer RNA: A postulated role in immune regulation

A hypothesis is put forth describing a role in immune regulation for inosine biosynthesis in the anticodon of tRNA. The enzymatic insertion of hypoxanthine into the tRNA wobble base position is predicted to be a control point for the translation of proteins and peptides required for normal immune function. The substrate for inosine biosynthesis in tRNA, hypoxanthine, is an intermediate in the purine catabolic pathway, and defects in this pathway are associated with inherited immunodeficiency diseases. Therefore, a role for aberrant inosine biosynthesis in tRNA is postulated in causing the immunodeficient conditions, and it may be a relevant molecular defect in leukemia as well.     

A postulated role of p130 in telomere maintenance by human papillomavirus oncoprotein E7

High-risk human papillomaviruses (HR-HPVs) infections is highly associated with the development of cervical cancer. It is now recognized that telomere length maintenance or extension is indispensable for carcinogenesis. The early oncoproteins E6 and E7 are the main malignant transformation factors of HR-HPVs and they maintain telomeres by different mechanisms, of which E6 protein activating telomerase is well documented. Reports showed that E7 protein utilized an alternative lengthen of telomere (ALT) mechanism to restore telomere length, yet the underlying molecular basis remains largely unknown. We propose that degradation of tumor suppressor pRb family member p130 plays an essential role in E7-regulated telomere extension by ALT. ALT is a mechanism based on homologous recombination (HR) between telomere sister chromatids, and a number of proteins involved in the HR pathway, such as MRN [MRE11 (meiotic recombination 11)-Rad50-NBS1 (Nijmegen breakage syndrome 1)] complex are required for the ALT pathway. Rb family member p130 could inhibit ALT by interacting with Rad50, while HPV E7 could activate ALT by degrading p130. We will make E7 mutants which are defective in p130 degradation to test whether these cells have a limited life span. Besides, immunofluorescence assay will show an ALT-related promyelocytic leukemia (PML) body (APBs) in E7-expressing cells. Although cervical cancer usually has high telomerase activities since the expressing of HPV E6, the anti-telomerase therapy will be unavailable for cervical cancer since it may activate E7-induced ALT. Our hypothesis not only enrich the knowledge of the regulation of ALT, but also indicate that p130 may serve as a potential suppressor of ALT, and gene therapy of p130 may be used in cervical cancers.     

A physiologic role for testosterone in limiting estrogenic stimulation of the breast

OBJECTIVE: The normal ovary produces abundant testosterone in addition to estradiol (E(2)) and progesterone, but usually only the latter two hormones are "replaced" in the treatment of ovarian failure and menopause. Some clinical and genetic evidence suggests, however, that endogenous androgens normally inhibit estrogen-induced mammary epithelial proliferation (MEP) and thereby may protect against breast cancer. DESIGN: To investigate the role of endogenous androgen in regulating mammary epithelial proliferation, normal-cycling rhesus monkeys were treated with flutamide, an androgen receptor antagonist. To evaluate the effect of physiological testosterone (T) supplementation of estrogen replacement therapy, ovariectomized monkeys were treated with E(2), E(2) plus progesterone, E(2) plus T, or vehicle. RESULTS: We show that androgen receptor blockade in normal female monkeys results in a more than twofold increase in MEP, indicating that endogenous androgens normally inhibit MEP. Moreover, we show that addition of a small, physiological dose of T to standard estrogen therapy almost completely attenuates estrogen-induced increases in MEP in the ovariectomized monkey, suggesting that the increased breast cancer risk associated with estrogen treatment could be reduced by T supplementation. Testosterone reduces mammary epithelial estrogen receptor (ER) alpha and increases ERbeta expression, resulting in a marked reversal of the ERalpha/beta ratio found in the estrogen-treated monkey. Moreover, T treatment is associated with a significant reduction in mammary epithelial MYC expression, suggesting that T's antiestrogenic effects at the mammary gland involve alterations in ER signaling to MYC. CONCLUSIONS: These findings suggest that treatment with a balanced formulation including all ovarian hormones may prevent or reduce estrogenic cancer risk in the treatment of girls and women with ovarian failure.     

A morphologic basis postulated for valproic acid's embryotoxic action in rats.

A tentative 3 phase sequence of pathogenesis is proposed for the embryotoxic action of valproic acid (800 mg/kg) administered orally to rats on day 13 of pregnancy. This is based on histopathological changes in the extraembryonic and embryonic tissues which occurred in the absence of any biologically significant effect on maternal homeostasis. Major events in the first, decidual (or maternal) phase are cells lining the maternal sinusoids in the decidua basalis are necrosed, desquamated, and washed away by the arterial circulation through the afferent channels. The necrosed cells, with their walls still intact, occlude the lumen of these arterial channels at the point of their entry into the giant cell-trophospongial zone. The channel occlusions cause ischemia and homeostasis of the maternal circulation in the labyrinth by reducing the rate of inflow of maternal blood. The embolic occlusion of maternal arterial channels apparently results in a long-term reduction in the number and size of maternal channels that supply arterial blood to the labyrinth. In the second or placental phase, the parenchyma of the labyrinth and connective tissue in the chorionic plate and umbilical cord, which have been deprived of nutrition and oxygen by the ischemia and stasis of maternal blood in the labyrinth, undergo degenerative changes. In the third or embryonic phase, a pleiotropic karyorrhexis in the embryo, initiated as early as 4 h postdosing, appeared aggravated, presumably by the preceding labyrinthine degeneration of the placental phase. The valproic acid-induced embryotoxicity thus seemed to result from a combination of maternal, placental, and embryonic changes.     

A postulated role for human papillomavirus (HPV) in the transformation and proliferation of oral squamous cell carcinoma (OSCC)

Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy and is a major cause of cancer morbidity and mortality worldwide. A strong association of oral cancer with high-risk HPVs infection underlines the importance of the virus in the pathogenesis of these squamous cell carcinomas. We postulate that HPV may contribute to the carcinogenesis of oral epithelial and function to stimulate transformation and proliferation of OSCC. The appropriate method, which may involve immunoprevention, immunotherapy, or immunomodulatory, needs to be developed. Not only humoral immunity, but also cellular immunity must be part of this process.     

Relative lack of toxicity of transplatin compared with cisplatin in rodents.

The differential toxicity of the cis- and trans-isomers of diamminedichloroplatinum (II) (cisplatin and transplatin) was investigated in rats and guinea pigs. In both species, repeated daily administration of 1 to 2 mg per kg cisplatin produced severe histological and/or functional damage to renal and gastro-intestinal systems and resulted in death of the animals. Quantification of tissue platinum by atomic absorption spectroscopy demonstrated accumulation of large amounts of platinum in the kidney of the animals, with lesser amounts in the liver and gastro-intestinal tract. Transplatin, administered at total doses two- to four-fold that of cisplatin, was essentially non-toxic by histological and functional assessment. However, the amounts of tissue platinum measured in transplatin-treated animals were no smaller than those measured in cisplatin-treated animals; indeed, platinum concentrations in kidneys of transplatin-treated rats were more than 2.5 times those in cisplatin-treated rats. Thus tissue platinum content did not correlate with organ damage. These data suggest that mechanism(s) involving steric interactions of platinum species, perhaps with cellular macromolecules such as DNA or RNA, may be important in the differential toxicity of these two compounds.     

Nutritional prevention of pre-eclampsia — A special role for 1 series prostaglandin precursors?

PGE1 appears to act as a physiological regulator of uteroplacental blood flow. Its vasodilatory, anti-vasopressor, and platelet stabilizing effects could be expected to counteract the placental ischemia, hypertension and excessive coagulation that are seen in pre-eclampsia. Supplementation with efficient essential fatty acid precursors of PGE1 reduces platelet aggregation, has been used with success in the treatment of hypertension and arterial vasospasm, and might offer a nutritional means of reducing the incidence and severity of pre-eclampsia. Assurance of adequate general nutrition also appears to be of importance in this regard.     

A target role for mast cell in the prevention and therapy of hepatic fibrosis

Hepatic fibrosis is a common pathological process of chronic hepatic disease. Despite the extensive studies, the pathophysiological mechanisms in hepatic fibrosis remain unclear. Mast cell has a variety of physiological and pathological functions through the production of heparin, histamine, neutrophil chemoattractants, immunoregulatory cytokines, and mast cell-specific serine proteases tryptase and chymase. The survival and proliferation of mast cell are dependent upon stem cell factor. More recently, the data have suggested that mast cell has been associated with hepatic fibrosis in many chronic liver diseases. However, to what extent the mast cell effects the hepatic fibrosis remains to be clarified. Several therapeutic approaches to inhibit mast cell activation have already demonstrated some clinical utility in tissue fibrosis or inflammatory diseases such as the use of mast cell stabilizers, inhibitors of tryptase or chymase, blockade of stem cell factor and anti-IgE therapy. The article introduces the hypothesis that mast cell has a central role when it is affected by its activation state in the progression of hepatic fibrosis, thus new therapeutic strategies for treatment of hepatic fibrosis are suggested by this hypothesis. Considering the important role of mast cell and the development of these tangible therapeutic approaches in hepatic fibrosis will enable us to target any types of chronic liver diseases, which appears to be a more reasonable or a promising strategy.     

Prevention of gonadal toxicity and preservation of gonadal function and fertility in young women with systemic lupus erythematosus treated by cyclophosphamide: the PREGO-Study

BACKGROUND: With dramatically improved survival rates of SLE patients, comorbidity and long-term damage such as premature ovarian failure (POF) gain increasing importance. In the Erlangen cohort, 14% of cyclophosphamide treated patients younger than 41 years have POF, which is a common consequence of cyclophosphamide treatment. PATIENTS AND METHODS: We tested the concentrations of FSH and LH, before, during and after cyclophosphamide treatment in 63 premenopausal women with SLE without ovarian protection and initiated the PREGO-Study (Prospective randomized study on protection against gonadal toxicity) in patients with SLE. RESULTS: In lupus patients treated with cyclophosphamide, 60% suffered from POF and hypergonadotropic amenorrhea. Whereas the POF rate was <50% in women below 30 years, it was 60% between 30 and 40 years. The cumulative dosage of cyclophosphamide also strongly influenced POF rate. CONCLUSIONS: Our present results, with a high POF rate in Cyclophosphamide treated SLE patients demonstrate the urgent need for ovarian protection in this patient group. Besides POF these women are at high risk for premature atherosclerosis which is the major cause of death in lupus. Following preliminary encouraging experience in women with lymphoma, in whom the temporary induction of a prepubertal hormonal milieu during chemotherapy, has significantly decreased the risk of POF, we have initiated the PREGO-Study, comparing randomised monthly injection versus no injection of gonadotropin-releasing hormone analogue (GnRH-a) to young SLE patients during cyclophosphamide therapy.     

顺铂诱导肾小管上皮细胞毒性及Bcl-2对抗细胞凋亡作用机理研究

目的探讨顺铂诱导肾小管上皮细胞(RPTC)凋亡的作用机制和BCL-2基因抑制顺铂诱导细胞凋亡的作用途径。方法应用不同亚细胞结构分布的BCL-2基因体外转染RPTC,激光共焦显微技术和免疫荧光技术分析BCL-2(X)基因表达产物在RPTC线粒体和内质网上的分布定位,采用Hoechst33258染色并进行细胞凋亡计数。结果不同畸变的BCL-2(BCL-acta,BCL-cb5)分别定位于RPTC的线粒体、内质网,BCL-nt同时定位于上述两种细胞器。BCL-cb5组可见更多BAX被激活,同时可见较多碎裂细胞核。定位于线粒体上的BCL-acta明显抑制顺铂对RPTC诱导的细胞凋亡(P<0.05)。结论BCL-2抑制顺铂诱导RPTC凋亡主要是通过线粒体途径起作用。