THE USE OF IN VIVO VAGINAL TTC REDUCTION OF SPAYED MICE FOR THE STUDY OF MODE OF ACTION OF ANTI-ESTROGENS

Porphyrinogenic compounds are known to induce porphyria-mediated hepatocellular injury and subsequent regenerative proliferation in rodents, ultimately leading to hepatocellular tumor induction. However, an appropriate in vivo experimental model to evaluate an effect of porphyrinogenic compounds on human liver has not been fully established. Recently, the chimeric mouse with humanized liver (PXB mice) became widely used as a humanized model in which human hepatocytes are transplanted. In the present study, we examined the utility of PXB mice as an in vivo experimental model to evaluate the key events of the porphyria-mediated cytotoxicity mode of action (MOA) in humans. The treatment of PXB mice with 5-aminolevulinic acid, a representative porphyrinogenic compound, for 28 days caused protoporphyrin IX accumulation, followed by hepatocyte necrosis, increased mitosis, and an increase in replicative DNA synthesis in human hepatocytes, indicative of cellular injury and regenerative proliferation, similar to findings in patients with porphyria or experimental porphyria models and corresponding to the key events of the MOA for porphyria-mediated hepatocellular carcinogenesis. We conclude that the PXB mouse is a useful model to evaluate the key events of the porphyria-mediated cytotoxicity MOA in humans and suggest the utility of PXB mice for clarifying the human relevancy of findings in mice.

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Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells

Journal of Hematology & Oncology ◽

10.1186/s13045-020-01016-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yahui Ding ◽

Xiaoping Chen ◽

Can Liu ◽

Weizhi Ge ◽

Qin Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Small Molecule ◽

Mode Of Action ◽

Rna Silencing ◽

Breast Cancer Cells ◽

Triple Negative ◽

Parent Compound ◽

Aggressive Breast Cancer

Abstract Background TNBC is the most aggressive breast cancer with higher recurrence and mortality rate than other types of breast cancer. There is an urgent need for identification of therapeutic agents with unique mode of action for overcoming current challenges in TNBC treatment. Methods Different inhibitors were used to study the cell death manner of DMOCPTL. RNA silencing was used to evaluate the functions of GPX4 in ferroptosis and apoptosis of TNBC cells and functions of EGR1 in apoptosis. Immunohistochemical assay of tissue microarray were used for investigating correlation of GPX4 and EGR1 with TNBC. Computer-aided docking and small molecule probe were used for study the binding of DMOCPTL with GPX4. Results DMOCPTL, a derivative of natural product parthenolide, exhibited about 15-fold improvement comparing to that of the parent compound PTL for TNBC cells. The cell death manner assay showed that the anti-TNBC effect of DMOCPTL mainly by inducing ferroptosis and apoptosis through ubiquitination of GPX4. The probe of DMOCPTL assay indicated that DMOCPTL induced GPX4 ubiquitination by directly binding to GPX4 protein. To the best of our knowledge, this is the first report of inducing ferroptosis through ubiquitination of GPX4. Moreover, the mechanism of GPX4 regulation of apoptosis is still obscure. Here, we firstly reveal that GPX4 regulated mitochondria-mediated apoptosis through regulation of EGR1 in TNBC cells. Compound 13, the prodrug of DMOCPTL, effectively inhibited the growth of breast tumor and prolonged the lifespan of mice in vivo, and no obvious toxicity was observed. Conclusions These findings firstly revealed novel manner to induce ferroptosis through ubiquitination of GPX4 and provided mechanism for GPX4 inducing mitochondria-mediated apoptosis through up-regulation of EGR1 in TNBC cells. Moreover, compound 13 deserves further studies as a lead compound with novel mode of action for ultimate discovery of effective anti-TNBC drug.

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lncRNAs in development and disease: from functions to mechanisms

Open Biology ◽

10.1098/rsob.170121 ◽

2017 ◽

Vol 7 (7) ◽

pp. 170121 ◽

Cited By ~ 73

Author(s):

M. Joaquina Delás ◽

Gregory J. Hannon

Keyword(s):

Differential Expression ◽

Cell Fate ◽

Mode Of Action ◽

Non Coding Rnas

Differential expression of long non-coding RNAs (lncRNAs) during differentiation and their misregulation in cancer highlight their potential as cell fate regulators. While some example lncRNAs have been characterized in great detail, the functional in vivo relevance of others has been called into question. Finding functional lncRNAs will most probably require a combination of complementary approaches that will greatly vary depending on their mode of action. In this review, we discuss the different tools available to dissect genetically lncRNA requirements and how each is best suited to studies in particular contexts. Moreover, we review different strategies used to select candidate lncRNAs and give an overview of lncRNAs described to regulate development and cancer through different mechanisms.

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Vasopressin as a neuroendocrine regulator of anterior pituitary hormone secretion

Acta Endocrinologica ◽

10.1530/acta.0.1290489 ◽

1993 ◽

Vol 129 (6) ◽

pp. 489-496 ◽

Cited By ~ 33

Author(s):

Andreas Kjær

Keyword(s):

Arginine Vasopressin ◽

Mode Of Action ◽

Anterior Pituitary ◽

Hormone Secretion ◽

Pituitary Hormones ◽

Pituitary Hormone ◽

Anterior Pituitary Hormones ◽

Anterior Pituitary Hormone

Secretion of the anterior pituitary hormones adrenocorticotropin (ACTH), β-endorphin and prolactin (PRL) is complex and involves a variety of factors. This review focuses on the involvement of arginine-vasopressin (AVP) in neuroendocrine regulation of these anterior pituitary hormones with special reference to receptor involvement, mode of action and origin of AVP. Arginine-vasopressin may act via at least two types of receptors: V1− and V2−receptors, where the pituitary V1−receptor is designated V1b. The mode of action of AVP may be mediating, i.e. anterior pituitary hormone secretion is transmitted via release of AVP, or the mode of action may be permissive, i.e. the presence of AVP at a low and constant level is required for anterior pituitary hormones to be stimulated. Under in vivo conditions, the AVP-induced release of ACTH and β-endorphin is mainly mediated via activation of hypothalamic V1− receptors, which subsequently leads to the release of corticotropin-releasing hormone. Under in vitro conditions, the AVP-stimulated release of ACTH and β-endorphin is mediated via pituitary V1b− receptors. The mode of action of AVP in the ACTH and β-endorphin response to stress and to histamine, which is involved in stress-induced secretion of anterior pituitary hormones, is mediating (utilizing V1− receptors) as well as permissive (utilizing mainly V1− but also V2−receptors). The AVP-induced release of PRL under in vivo conditions is conveyed mainly via activation of V1−receptors but V2−receptors and probably additional receptor(s) may also play a role. In stress- and histamine induced PRL secretion the role of AVP is both mediating (utilizing V1 −receptors) and permissive (utilizing both V1− and V2− receptors). Arginine-vasopressin may be a candidate for the PRL-releasing factor recently identified in the posterior pituitary gland. Arginine-vasopressin of both magno- and parvocellular origin may be involved in the regulation of anterior pituitary hormone secretion and may reach the corticotrophs and the lactotrophs via three main routes: the peripheral circulation, the long pituitary portal vessels or the short pituitary portal vessels.

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Research Topic: On the Mode of Action of Barbituates In Vivo

Res Medica ◽

10.2218/resmedica.v6i1.834 ◽

2014 ◽

Vol 6 (1) ◽

Author(s):

John Wallwork

Keyword(s):

Mode Of Action ◽

Research Topic

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Zinc oxide microrods and nanorods: different antibacterial activity and their mode of action against Gram-positive bacteria

RSC Advances ◽

10.1039/c4ra08462d ◽

2014 ◽

Vol 4 (99) ◽

pp. 56031-56040 ◽

Cited By ~ 42

Author(s):

Ilaria Rago ◽

Chandrakanth Reddy Chandraiahgari ◽

Maria P. Bracciale ◽

Giovanni De Bellis ◽

Elena Zanni ◽

...

Keyword(s):

Zinc Oxide ◽

Antibacterial Activity ◽

Mode Of Action ◽

Gram Positive ◽

Gram Positive Bacteria

ZnO micro and nanorods, produced through simple and inexpensive techniques, resulted to be strong antimicrobials against Gram-positive bacteria, in vitro as well as in vivo, by altering cell outer structures like membrane and exopolysaccharides.

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Mechanism of Action of Progestins in the Treatment of Hormone-dependent Breast Cancer.

Tumori Journal ◽

10.1177/030089167506100601 ◽

1975 ◽

Vol 61 (6) ◽

pp. 501-508 ◽

Cited By ~ 5

Author(s):

Francesco Di Carlo ◽

Giovanni Pacilio ◽

Giuseppe Conti

Keyword(s):

Breast Cancer ◽

Estrogen Receptors ◽

Mechanism Of Action ◽

Mode Of Action ◽

Binding Capacity ◽

Specific Receptors ◽

High Concentrations ◽

Good Agreement

The in vitro interference of some gestagens with the binding of 3H-17 β-oestradiol to cytosol specific receptors was investigated with a view to elucidating the mechanism of action of progestins in the treatment of human hormone-dependent breast cancer. A decrease (up to 85 %) of oestradiol binding capacity was observed with high concentrations of progesterone, clogestone and medrogestone. These findings are in good agreement with those previously obtained by the same progestins in our laboratory on rat uterine estrogen receptors in vitro or in vivo. These results provide support for the hypothesis that the mode of action of progestins in the therapy of mammary and perhaps uterine carcinomas is to some extent related to the inhibition of oestradiol binding to cytosol specific receptors.

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Coral snake venoms: mode of action and pathophysiology of experimental envenomation

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46651987000300001 ◽

1987 ◽

Vol 29 (3) ◽

pp. 119-126 ◽

Cited By ~ 58

Author(s):

Oswald Vital Brazil

Keyword(s):

Mode Of Action ◽

Acetylcholine Release ◽

Motor Nerve ◽

Low Grade ◽

Coral Snake ◽

Snake Venoms ◽

Phospholipases A2 ◽

Muscle Fiber Membrane ◽

Phospholipase A2 Activity

Coral snakes, the New World Elapidae, are included in the genera Micniroides and Micrurus. The genus Mlcrurus comprises nearly all coral snake species and those which are responsible for human snake-bite accidents. The following generalizations concerning the effects induced by their venoms, and their venom-properties can be made. Coral snake venoms are neurotoxic, producing loss of muscle strenght and death by respiratory paralysis. Local edema and necrosis are not induced nor blood coagulation or hemorrhages. Proteolysis activity is absent or of very low grade. They display phospholipase A2 activity. Nephrotoxic effects are not evoked. The main toxins from elapid venoms are postsynaptic and presynaptic neurotoxins and cardiotoxins. Phospholipases A2 endowed with myonecrotic or cardiotoxin-like properties are important toxic components from some elapid venoms. The mode of action of Micrurus frontalis, M. lemniscatus, M. corallinus and M. fulvius venoms has been investigated in isolated muscle preparations and is here discussed. It is shown that while M. frontalis and M. lemniscatus venoms must contain only neurotoxins that act at the cholinergic end-plate receptor (postsynaptic neurotoxins), M. corallinus venom also inhibits evoked acetylcholine release by the motor nerve endings (presynaptic neurotoxin-like effect) and M. fulvius induces muscle fiber membrane depolarization (cardiotoxin-like effect). The effects produced by M. corallinus and M. fulvius venoms in vivo in dogs and M. frontalis venom in dogs and monkeys are also reported.

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Gene Expression Profiles in Rat Liver Slices Exposed to Hepatocarcinogenic Enzyme Inducers, Peroxisome Proliferators, and 17α-Ethinylestradiol

International Journal of Toxicology ◽

10.1080/10915810600846963 ◽

2006 ◽

Vol 25 (5) ◽

pp. 379-395 ◽

Cited By ~ 6

Author(s):

Gisela Werle-Schneider ◽

Andreas Wölfelschneider ◽

Marie Charlotte von Brevern ◽

Julia Scheel ◽

Thorsten Storck ◽

...

Keyword(s):

Gene Expression ◽

Rat Liver ◽

Mode Of Action ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Peroxisome Proliferators ◽

Liver Slices ◽

Enzyme Inducers

Transcription profiling is used as an in vivo method for predicting the mode-of-action class of nongenotoxic carcinogens. To set up a reliable in vitro short-term test system DNA microarray technology was combined with rat liver slices. Seven compounds known to act as tumor promoters were selected, which included the enzyme inducers phenobarbital, α-hexachlorocyclohexane, and cyproterone acetate; the peroxisome proliferators WY-14,643, dehydroepiandrosterone, and ciprofibrate; and the hormone 17 α-ethinylestradiol. Rat liver slices were exposed to various concentrations of the compounds for 24 h. Toxicology-focused TOXaminer™ DNA microarrays containing approximately 1500 genes were used for generating gene expression profiles for each of the test compound. Hierarchical cluster analysis revealed that (i) gene expression profiles generated in rat liver slices in vitro were specific allowing classification of compounds with similar mode of action and (ii) expression profiles of rat liver slices exposed in vitro correlate with those induced after in vivo treatment (reported previously). Enzyme inducers and peroxisome proliferators formed two separate clusters, confirming that they act through different mechanisms. Expression profiles of the hormone 17 α-ethinylestradiol were not similar to any of the other compounds. In conclusion, gene expression profiles induced by compounds that act via similar mechanisms showed common effects on transcription upon treatment in vivo and in rat liver slices in vitro.

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