Publisher Summary The classification of cell death can be based on morphological or biochemical criteria or on the circumstances of its occurrence. Currently, irreversible structural alteration provides the only unequivocal evidence of death; biochemical indicators of cell death that are universally applicable have to be precisely defined and studies of cell function or of reproductive capacity do not necessarily differentiate between death and dormant states from which recovery may be possible. It has also proved feasible to categorize most if not all dying cells into one or the other of two discrete and distinctive patterns of morphological change, which have, generally, been found to occur under disparate but individually characteristic circumstances. One of these patterns is the swelling proceeding to rupture of plasma and organelle membranes and dissolution of organized structure—termed “coagulative necrosis.” It results from injury by agents, such as toxins and ischemia, affects cells in groups rather than singly, and evokes exudative inflammation when it develops in vivo. The other morphological pattern is characterized by condensation of the cell with maintenance of organelle integrity and the formation of surface protuberances that separate as membrane-bounded globules; in tissues, these are phagocytosed and digested by resident cells, there being no associated inflammation.

Cell death : the significance of apoptosis

Publisher Summary This chapter explores that the changes that take place in the protein molecules during denaturation constitute one of the most interesting and complex classes of reactions that can be found either in nature or in the laboratory These reactions are important because of the information they can provide about the more intimate details of protein structure and function They are also significant because they challenge the chemist with a difficult area for the application of chemical principles The chapter reviews that the denaturation is a process in which the spatial arrangement of the polypeptide chains within the molecule is changed from that typical of the native protein to a more disordered arrangement The chapter also discusses the classification of protein structures: primary, secondary, and tertiary structures The primary structure is that expressed by the structural chemical formula and depends entirely on the chemical valence bonds that the classical organic chemist would write down for the protein molecule The secondary structure is the configuration of the polypeptide chain that results from the satisfaction of the hydrogen bonding potential between the peptide N-H and C=O groups The tertiary structure is the pattern according to which the secondary structures are packed together within the native protein molecule The term “denaturation” as used in this chapter is indented to include changes in both the secondary and tertiary structures

Some factors in the interpretation of protein denaturation.

The rat estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study we investigated the messenger RNA expression of both ER subtypes in rat tissues by RT-PCR and compared the ligand binding specificity of the ER subtypes. Saturation ligand binding analysis of in vitro synthesized human ER alpha and rat ER beta protein revealed a single binding component for 16 alpha-iodo-17 beta-estradiol with high affinity [dissociation constant (Kd) = 0.1 nM for ER alpha protein and 0.4 nM for ER beta protein]. Most estrogenic substances or estrogenic antagonists compete with 16 alpha-[125I]iodo-17 beta-estradiol for binding to both ER subtypes in a very similar preference and degree; that is, diethylstilbestrol > hexestrol > dienestrol > 4-OH-tamoxifen > 17 beta-estradiol > coumestrol, ICI-164384 > estrone, 17 alpha-estradiol > nafoxidine, moxestrol > clomifene > estriol, 4-OH-estradiol > tamoxifen, 2-OH-estradiol, 5-androstene-3 beta, 17 beta-diol, genistein for the ER alpha protein and dienestrol > 4-OH-tamoxifen > diethylstilbestrol > hexestrol > coumestrol, ICI-164384 > 17 beta-estradiol > estrone, genistein > estriol > nafoxidine, 5-androstene-3 beta, 17 beta-diol > 17 alpha-estradiol, clomifene, 2-OH-estradiol > 4-OH-estradiol, tamoxifen, moxestrol for the ER beta protein. The rat tissue distribution and/or the relative level of ER alpha and ER beta expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ER alpha and prostate, ovary, lung, bladder, brain, uterus, and testis for ER beta. The described differences between the ER subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues.

Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta

Protein extracts derived from bone can initiate the process that begins with cartilage formation and ends in de novo bone formation. The critical components of this extract, termed bone morphogenetic protein (BMP), that direct cartilage and bone formation as well as the constitutive elements supplied by the animal during this process have long remained unclear. Amino acid sequence has been derived from a highly purified preparation of BMP from bovine bone. Now, human complementary DNA clones corresponding to three polypeptides present in this BMP preparation have been isolated, and expression of the recombinant human proteins have been obtained. Each of the three (BMP-1, BMP-2A, and BMP-3) appears to be independently capable of inducing the formation of cartilage in vivo. Two of the encoded proteins (BMP-2A and BMP-3) are new members of the TGF-beta supergene family, while the third, BMP-1, appears to be a novel regulatory molecule.

https://science.sciencemag.org/content/sci/242/4885/1528.full.pdf

Novel regulators of bone formation: molecular clones and activities.

Thereisgrowinginterestinthepossiblehealththreatposedbyendocrine-disruptingchemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor , retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness. (Endocrine Reviews 30: 293–342, 2009)

/pdf/endocrine-disrupting-chemicals-an-endocrine-society-3fgbtp8gql.pdf

Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement

SummaryAllogeneic transplants of demineralized powdered bone or whole teeth in different shapes transformed fibroblasts to cartilage and bone. Coarse powders of bone elicited significantly higher yields of transformation products than fine powder did; criteria of transformation included histologic findings, alkaline phosphatase activity, 35S and 32P incorporation. The temporal sequence of fibro-blast-chondroblast-osteoblast transformation was profoundly influenced by the geometry of the transformant. The incursion of capillaries among the transformed cells resulted in chondrolysis.

Influence of geometry of transplanted tooth and bone on transformation of fibroblasts.

Aromatic influences on the yields of mammary cancers following administration of 7,12-dimethylbenz(a)anthracene.

In the hypophysectomized albino rat which is protected from contact with steroids in the ration and environment the uterus and vagina are highly atrophic but are sensitive indicators of activity of substances which promote their growth. Both the pituitary growth hormone and certain steroids have the common property of inducing growth of these tissues. The vaginal epithelium consists of 2 layers of cells which differ profoundly in their growth in response to steroids, depending on the molecular structure of these compounds. The differential response to modifications of chemical structures of steroids permits evaluation of the importance of the intramolecular components for the process of growth. The number and site of functional groups, the geometry of the molecule and the state of oxidation are of high importance in determining physiologic activity of steroids in the androstane series; these features are less specific in the estrane series. Side groups at positions C3 and C17 are of importance in the promotion of growth by steroids in the androstane series, but these active centers are not equivalent in their physiological influence. As a generalization, hydrogenation of the oxygen function at C17 (but not at C3) and dehydrogenation at critical areas of the ring structure increase the quantitative efficacy of steroids in promoting growth. The position of double bonds and the state of oxidation at both C3 and C17 determine the qualitative type of growth—cellular pattern, which a compound in the androstane series induces in the vaginal epithelium.

https://rupress.org/jem/article-pdf/100/3/225/1078294/225.pdf

Chemical structure of steroids in relation to promotion of growth of the vagina and uterus of the hypophysectomized rat

Under simple conditions, an intravenous injection (pulse dose) of large but tolerable amounts of certain polynuclear aromatic hydrocarbons evokes mammary cancer in every rat,' whereas leukemia arises rarely. In the present work, it was found that by rearrangement of the experimental conditions, leukosis and leukemia were induced in high yield but with small incidence of cancer of the breast. In rat, a pulse dose of 7,12-dimethylbenz(a)anthracene damages only those cells which synthesize DNA,2 whereas cells which proliferate by meiosis are not injured.3 4 A single pulse dose of 7,12-DMBA effectively induces mammary cancer under stated conditions. By definition, an effective amount of 7,12DMBA is that quantity which induces mammary cancer in every rat but is not lethal to any animal. Three equal fractions of the largest tolerable and effective amount given at intervals of 3 days called forth more cancers than the total amount injected on one occasion;5 each of the fractions itself evoked cancers in every animal. The leukemogenic action of hydrocarbons was discovered by Morton and Mider' by repeatedly painting the skin of mice with 3-methylcholanthrene. The incidence7 of leukemia was 99 per cent with mean latent period of 86 days; in the predominant type of leukemia there was enlargement of thymus, liver, spleen, and lymph nodes. In the rat, prolonged feeding of aromatic hydrocarbons elicited leukemia in rather low yields. The incidence of leukemia evoked by various hydrocarbons in feeding experiments was 3-MC (ref. 8), 14 per cent; 7,12-DMBA (ref. 9), 47 per cent; 2-acetylaminophenanthrene (ref. 10), 48 per cent. Experimental.-Normal rats of Long-Evans strain, bred at random, were used exclusively. They were provided a commercial ration and water ad libitum and kept in air-conditioned rooms at 250 ± 1. A lipide emulsion\" of 7,12-DMBA (0.5% w/w) was injected in a caudal vein. No single injection exceeded 6 mg of 7,12-DMBA. The day of the first pulse dose is designated day 0. The rats were weighed thrice weekly. Leucocyte count, differential cell count, and hemoglobin were determined in heparinized venous blood. Components of the buffy coat were measured in a slender glass capillary tube (75 mm in length; 0.3 mm internal diameter; wall thickness 0.2 mm) which was filled with blood and centrifuged at 12,000 rpm for 5 min; the thickness of the layers of the buffy coat was measured immediately by microscopy using an ocular micrometer; the results are expressed in percentage of the length of this microhematocrit. Surgical operations were performed under ether anesthesia. Prior to the first pulse dose of 7,12-DMBA, in some experiments, spleen was exteriorized to a subcutaneous position, leaving its vascular pedicle intact. Biopsy of liver was done through an abdominal incision, 1 cm in length, and a wedge (ca. 50 mg) of the periphery of the organ was excised for histologic study.

https://www.pnas.org/content/pnas/55/1/74.full.pdf

Induction of leukemia in rat by pulse doses of 7,12-dimethylbenz(a)anthracene.

The purposes of surgery of the human adrenal glands are to remove neoplasms of these structures or to abolish functional activities which are deleterious to the organism; both conditions may be coeval. The principle of abolition of dangerous physiological functions of the adrenals, of course, is the opposite to stimulation of these glands by a corticotrophic agent, for example, corticotrophin (ACTH). There are several clear indications for the removal of nonneoplastic adrenals at present; no doubt more will be found, and the subject will assume greater importance. Frequently disease conditions caused by adrenal hyperfunction or those mediated through normal activity of these glands can be cured or alleviated by surgical procedures, with impressive results. Adrenal surgery is now in a fast-moving evolutionary stage. Recently there have been four major developments in this area. These are (a) methods of maintenance of life in the absence of the adrenal glands or in

Charles Huggins

Papers

Influence of geometry of transplanted tooth and bone on transformation of fibroblasts.

Aromatic influences on the yields of mammary cancers following administration of 7,12-dimethylbenz(a)anthracene.

Chemical structure of steroids in relation to promotion of growth of the vagina and uterus of the hypophysectomized rat

Induction of leukemia in rat by pulse doses of 7,12-dimethylbenz(a)anthracene.

Surgery of the adrenals.