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

This article describes the induction the induction and suppression of breast cancer in albino rats; the study was conducted to permit the analysis of the mechanisms of the causes and extinction of cancer 2 of the central problems in cancer research. A single feeding of 20 mg of 712 dimethylbenz(a)anthracene (712-DMBA) dissolved in sesame oil developed mammary cancer in all of over 700 healthy female rats of the Sprague-Dawley strain. The mammary cancer evoked by the aromatic hydrocarbons were all rather similar in cytologic appearance and all had the cellular pattern of papillary adenocarcinoma. Experiments also showed that while 712-DMBA and 2-aminophenanthrene were strong carcinogens benz(a)anthracene and phenanthrene did not evoke mammary cancer. It appears that the methyl and amnio groups convert the otherwise inactive parent molecular species to powerful carcinogens. 3 factors seem to determine mammary carcinogenicity in polynuclear aromatic hydrocarbons: 1) the electron transfer 2) the geometric factor and 3) the molecular thickness. Regression of mammary cancer has been induced by 2 types of alteration of the endocrine status the withdrawal of the hormones essential for the life and growth of the cancer usually done through ovariectomy on the administration of appropriate hormones. In an experiment female rats previously induced with mammary cancer through administration of 712-DMBA were given for 30 days 20 mcg of estradiol-17 and 4 mg of progesterone. In a group of 100 rats treated this way 52 were free from cancer at necropsy whereas their control companions succumbed to cancer. This experiment was repeated under more rigorous conditions with rats with large mammary cancers; the results were equally successful.

http://science.sciencemag.org/content/sci/137/3526/257.full.pdf

Induction and Extinction of Mammary Cancer: A striking effect of hydrocarbons permits analysis of mechanisms of causes and cure of breast cancer

Summary Simultaneous bilateral adrenalectomy in man can now be done with comparative safety (29 consecutive cases without fatality.) The adrenalless man on adequate hormonal substitution therapy presents the metabolic picture of excellent health, although adrenal insufficiency can develop rapidly when hormonal replacement is inadequate to meet the demands of the organism. In four cases of advanced cancer of the prostate which became reactivated after previous antiandrogen control, some or all of the following effects were observed: relief of intractable bone pain, gain in body weight, reduction of considerably increased acid phosphatase levels and of the least percentage of thermocoagulable proteins, together with an increase of total protein content of serum, increased hemoglobin and erythrocyte content of whole blood, and shrinkage of the primary tumor. Two cases of prostatic cancer did not improve to any significant degree after adrenalectomy. The period of observation of these cases has been 4–9 months. Of six cases of advanced mammary cancer with metastases, two cases were improved, one patient was moderately benefited, and there was no demonstrable evidence of regression in three cases. In four advanced neoplasms, other than prostatic or mammary, adrenalectomy caused no detectable regression of the tumor.

/pdf/inhibition-of-human-mammary-and-prostatic-cancers-by-28t97qi9mk.pdf

Charles Huggins

Papers

Induction and Extinction of Mammary Cancer: A striking effect of hydrocarbons permits analysis of mechanisms of causes and cure of breast cancer

Inhibition of Human Mammary and Prostatic Cancers by Adrenalectomy

Bilateral Adrenalectomy in Prostatic Cancer: Clinical Features and Urinary Excretion of 17-Ketosteroids and Estrogen.

CHROMOGENIC SUBSTRATES IV. ACYL ESTERS OF p-NITROPHENOL AS SUBSTRATES FOR THE COLORIMETRIC DETERMINATION OF ESTERASE

Sodium phenolphthalein phosphate as a substrate for phosphatase tests