Toxicologic Pathology
1533-1601
0192-6233
Mỹ
Cơ quản chủ quản: SAGE Publications Inc.
Lĩnh vực:
Cell BiologyPathology and Forensic MedicineToxicologyMolecular Biology
Các bài báo tiêu biểu
Apoptose: Tổng Quan về Chết Tế Bào Chương Trình Hóa Quá trình chết tế bào chương trình hóa, hay còn gọi là apoptosis, được đặc trưng bởi những đặc điểm hình thái cụ thể và các cơ chế sinh hóa phụ thuộc năng lượng. Apoptose được coi là một thành phần thiết yếu của nhiều quá trình bao gồm sự thay thế tế bào bình thường, sự phát triển và chức năng đúng đắn của hệ miễn dịch, sự teo tại chỗ phụ thuộc hormone, phát triển phôi và sự chết tế bào do hóa chất. Việc apoptosis không ổn định (quá ít hoặc quá nhiều) là yếu tố trong nhiều tình trạng của con người bao gồm các bệnh thoái hóa thần kinh, tổn thương thiếu máu cục bộ, rối loạn tự miễn và nhiều loại ung thư. Khả năng điều chỉnh sự sống hay chết của một tế bào đã được công nhận có tiềm năng điều trị to lớn, do vậy, nghiên cứu vẫn tiếp tục tập trung vào việc làm rõ và phân tích cơ chế chu trình tế bào và các con đường tín hiệu điều khiển sự ngừng chu trình và apoptosis. Vì lý do đó, lĩnh vực nghiên cứu apoptosis đang tiến lên với tốc độ đáng kể. Mặc dù nhiều protein apoptosis chủ chốt đã được xác định, nhưng các cơ chế phân tử của sự hoạt động hay không hoạt động của những protein này vẫn cần được làm sáng tỏ. Mục tiêu của bài tổng quan này là cung cấp cái nhìn tổng quát hiện nay về quá trình apoptosis bao gồm hình thái, sinh hóa, vai trò của apoptosis trong sức khỏe và bệnh tật, các phương pháp phát hiện, cũng như thảo luận về các dạng alternative apoptosis có thể có.
Tập 35 Số 4 - Trang 495-516 - 2007
#Chết tế bào chương trình hóa #apoptosis #cơ chế sinh hóa #tế bào miễn dịch #thoái hóa thần kinh #bệnh tật #điều trị #protein apoptosis.
Drug Nanoparticles: Formulating Poorly Water-Soluble Compounds More than 40% of compounds identified through combinatorial screening programs are poorly soluble in water. These molecules are difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues. Formulating these compounds as pure drug nanoparticles is one of the newer drug-delivery strategies applied to this class of molecules. Nanoparticle dispersions are stable and have a mean diameter of less than 1 micron. The formulations consist of water, drug, and one or more generally regarded as safe excipients. These liquid dispersions exhibit an acceptable shelf-life and can be postprocessed into various types of solid dosage forms. Drug nanoparticles have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routes of administration can be identified with milligram quantities of drug substance, providing the discovery scientist with an alternate avenue for screening and identifying superior analogs. For the toxicologist, the approach provides a means for dose escalation using a formulation that is commercially viable. In the past few years, formulating poorly water-soluble compounds using a nanoparticulate approach has evolved from a conception to a realization whose versatility and applicability are just beginning to be realized.
Tập 36 Số 1 - Trang 43-48 - 2008
Brain Inflammation and Alzheimer's-Like Pathology in Individuals Exposed to Severe Air Pollution Air pollution is a complex mixture of gases (e.g., ozone), particulate matter, and organic compounds present in outdoor and indoor air. Dogs exposed to severe air pollution exhibit chronic inflammation and acceleration of Alzheimer's-like pathology, suggesting that the brain is adversely affected by pollutants. We investigated whether residency in cities with high levels of air pollution is associated with human brain inflammation. Expression of cyclooxygenase-2 (COX2), an inflammatory mediator, and accumulation of the 42-amino acid form of β-amyloid (A β42), a cause of neuronal dysfunction, were measured in autopsy brain tissues of cognitively and neurologically intact lifelong residents of cities having low (n:9) or high (n:10) levels of air pollution. Genomic DNA apurinic/apyrimidinic sites, nuclear factor- κB activation and apolipoprotein E genotype were also evaluated. Residents of cities with severe air pollution had significantly higher COX2 expression in frontal cortex and hippocampus and greater neuronal and astrocytic accumulation of A β42 compared to residents in low air pollution cities. Increased COX2 expression and A β42 accumulation were also observed in the olfactory bulb. These findings suggest that exposure to severe airpollution is associated with brain inflammation and A β 42 accumulation, two causes of neuronal dysfunction that precede the appearance of neuritic plaques and neurofibrillary tangles, hallmarks of Alzheimer's disease.
Tập 32 Số 6 - Trang 650-658 - 2004
Evaluation of Organ Weights for Rodent and Non-Rodent Toxicity Studies: A Review of Regulatory Guidelines and a Survey of Current Practices The Society of Toxicologic Pathology convened a working group to evaluate current practices regarding organ weights in toxicology studies. A survey was distributed to pharmaceutical, veterinary, chemical, food/nutritional and consumer product companies in Europe, North America, and Japan. Responses were compiled to identify organs routinely weighed for various study types in rodent and non-rodent species, compare methods of organ weighing, provide perspectives on the value of organ weights and identify the scientist(s) responsible for organ weight data interpretation. Data were evaluated as a whole as well as by industry type and geographic location. Regulatory guidance documents describing organ weighing practices are generally available, however, they differ somewhat dependent on industry type and regulatory agency. While questionnaire respondents unanimously stated that organ weights were a good screening tool to identify treatment-related effects, opinions varied as to which organ weights are most valuable. The liver, kidneys, and testes were commonly weighed and most often considered useful by most respondents. Other organs thatbreak were commonly weighed included brain, adrenal glands, ovaries, thyroid glands, uterus, heart, and spleen. Lungs, lymph nodes, and other sex organs were weighed infrequently in routine studies, but were often weighed in specialized studies such as inhalation, immunotoxicity, and reproduction studies. Organ-to-body weight ratios were commonly calculated and were considered more useful when body weights were affected. Organ to brain weight ratios were calculated by most North American companies, but rarely according to respondents representing veterinary product or European companies. Statistical analyses were generally performed by most respondents. Pathologists performed interpretation of organ weight data for the majority of the industries.
Tập 35 Số 5 - Trang 742-750 - 2007
Caloric Restriction and Aging: Studies in Mice and Monkeys It is widely accepted that caloric restriction (CR) without malnutrition delays the onset of aging and extends lifespan in diverse animal models including yeast, worms, flies, and laboratory rodents. The mechanism underlying this phenomenon is still unknown. We have hypothesized that a reprogramming of energy metabolism is a key event in the mechanism of CR (Anderson and Weindruch 2007). Data will be presented from studies of mice on CR, the results of which lend support to this hypothesis. Effects of long-term CR (but not short-term CR) on gene expression in white adipose tissue (WAT) are overt. In mice and monkeys, a chronic 30% reduction in energy intake yields a decrease in adiposity of approximately 70%. In mouse epididymal WAT, long-term CR causes overt shifts in the gene expression profile: CR increases the expression of genes involved in energy metabolism (Higami et al. 2004), and it down-regulates the expression of more than 50 pro-inflammatory genes (Higami et al. 2006). Whether aging retardation occurs in primates on CR is unknown. We have been investigating this issue in rhesus monkeys subjected to CR since 1989 and will discuss the current status of this project. A new finding from this project is that CR reduces the rate of age-associated muscle loss (sarcopenia) in monkeys (Colman et al. 2008).
Tập 37 Số 1 - Trang 47-51 - 2009
Recommended Approaches for the Evaluation of Testicular and Epididymal Toxicity
Tập 30 Số 4 - Trang 507-520 - 2002
Preclinical Safety Evaluation of rhuMAbVEGF, an Antiangiogenic Humanized Monoclonal Antibody Recombinant humanized antivascular endothelial growth factor (rhuMAbVEGF) is a monoclonal IgG, antibody that is being developed as an antiangiogenic agent for use in treating a variety of solid tumors. Preclinical safety studies included an immunohistochemical tissue cross-reactivity study, in vitro hemolytic potential and blood compatibility studies, and multiple dose toxicity studies. Toxicity studies were conducted in cynomolgus monkey because rhuMAbVEGF is pharmacologically active in this species and does not bind rat or mouse vascular endothelial growth factor (VEGF). Following twice weekly administration of rhuMAbVEGF for 4 or 13 wk, young adult cynomolgus monkeys exhibited physeal dysplasia characterized by a dose-related increase in hypertrophied chondrocytes, subchondral bony plate formation, and inhibition of vascular invasion of the growth plate. In addition, decreased ovarian and uterine weights and an absence of corpora lutea were observed in females receiving 10 and 50 mg/kg/dose in the 13-wk study. Both the physeal and ovarian changes were reversible with cessation of treatment. No other treatment-related effects were observed following rhuMAbVEGF administration at doses up to 50 mg/kg. These findings indicate that VEGF is required for longitudinal bone growth and corpora lutea formation and that rhuMAbVEGF can reversibly inhibit physiologic neovascularization at these sites.
Tập 27 Số 1 - Trang 78-86 - 1999
Estrogen and Xenoestrogens in Breast Cancer There is growing concern that estrogenic environmental compounds that act as endocrine-disrupting chemicals might potentially have adverse effects on hormone-sensitive organs such as the breast. This concern is further fueled by evidence indicating that natural estrogens, specifically 17β-estradiol, are important factors in the initiation and progression of breast cancer. We have developed an in vitro—in vivo model in which we have demonstrated the carcinogenicity of E2 in human breast epithelial cells MCF-10F. Hypermethylation of NRG1, STXBP6, BMP6, CSS3, SPRY1, and SNIP were found at different progression stages in this model. The use of this powerful and unique model has provided a tool for exploring whether bisphenol A and butyl benzyl phthalate have relevance in the initiation of breast cancer. These studies provide firsthand evidence that the natural estrogen 17β-estradiol and xenoestrogenic substances like bisphenol A are able to induce neoplastic transformation in human breast epithelial cells.
Tập 38 Số 1 - Trang 110-122 - 2010
An Overview of Current Cytochrome P450 Technology for Assessing the Safety and Efficacy of New Materials Studies of xenobiotic biotransformation by in vitro techniques are destined to play an increasingly important role in assessing the safety and efficacy of drugs and other new chemical entities. The first part of this article summarizes some of the in vitro techniques that have been developed to evaluate xenobiotics as inducers of liver microsomal cytochrome P450. The second part provides an overview of reaction phenotyping, an in vitro technology for determining which human P450 enzyme or enzymes are involved in the biotransformation of xenobiotics.
Tập 24 Số 1 - Trang 45-57 - 1996