Sites of action for neurotoxic pesticides

ABSTRACT The effect of testosterone and 5α-dihydrotestosterone on protein and nucleic acid content as well as on the activities of some enzymes has been studied in the ventral prostate and the seminal vesicles of immature castrated rats. Both androgens were given intraperitoneally in doses of 1 mg daily for one or three days the rats were sacrificed one day after the last injection. In the prostate it was found that 5α-dihydrotestosterone had a greater effect on DNA increase, i. e. cell proliferation than testosterone, whereas cell metabolism was stimulated by the two androgens to nearly the same extent. In the seminal vesicles a single dose led to the same results as had been obtained in the prostate, i. e. a greater cell proliferative action of 5α-dihydrotestosterone and an equal stimulation of cell metabolism by testosterone and 5α-dihydrotestosterone was also observed. When three doses of the two androgens were given, cell proliferation as well as cell metabolism in the seminal vesicles were significantly more increased after 5α-dihydrotestosterone than after testosterone. The difference of action after systemic administration of the two androgens is explained by their different accumulation and by their different peripheral metabolism in the target tissues. From the partly independent effects of various androgens on cell proliferation and cell metabolism the conclusion may be drawn that there exist at least two intracellular sites of action.

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An Insight in Pathophysiological Mechanism of Alzheimer’s Disease and its Management using Plant Natural Products

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200730155928 ◽

2020 ◽

Vol 20 ◽

Author(s):

Zeba Firdaus ◽

Tryambak Deo Singh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Products ◽

Side Effects ◽

Neuronal Degeneration ◽

Acetylcholinesterase Inhibitor ◽

Pathophysiological Mechanism ◽

Limited Effectiveness ◽

Drug Development Research ◽

Sites Of Action

: Alzheimer’s disease (AD) is an age-associated nervous system disorder and a leading cause of dementia worldwide. Clinically it is described by cognitive impairment, and pathophysiologically by deposition of amyloid plaques and neurofibrillary tangles in the brain and neurodegeneration. This article reviews the pathophysiology, course of neuronal degeneration, and the various possible hypothesis of AD progression. These hypotheses include amyloid cascade, tau hyperphosphorylation, cholinergic disruption, metal dysregulation, vascular dysfunction, oxidative stress, and neuroinflammation. There is an exponential increase in the occurrence of the AD in recent few years that indicate an urgent need to develop some effective treatment. Currently, only 2 classes of drugs are available for AD treatment namely acetylcholinesterase inhibitor and NMDA receptor antagonist. Since AD is a complex neurological disorder and these drugs use a single target approach, alternatives are needed due to limited effectiveness and unpleasant side-effects of these drugs. Currently, plants have been used for drug development research especially because of their multiple sites of action and fewer side effects. Uses of some herbs and phytoconstituents for the management of neuronal disorders like AD have been documented in this article. Phytochemical screening of these plants shows the presence of many beneficial constituents like flavonoids, triterpenes, alkaloids, sterols, polyphenols, and tannins. These compounds show a wide array of pharmacological activities such as anti-amyloidogenic, anticholinesterase, and antioxidant. This article summarizes the present understanding of AD progression and gathers biochemical evidence from various works on natural products that can be useful in the management of this disease.

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Studies on the mechanism of acute inhibition of thyroglobulin hydrolysis by iodine

Acta Endocrinologica ◽

10.1530/acta.0.1080511 ◽

1985 ◽

Vol 108 (4) ◽

pp. 511-517 ◽

Cited By ~ 12

Author(s):

Nandalal Bagchi ◽

Birdie Shivers ◽

Thomas R. Brown

Keyword(s):

Time Course ◽

Period 2 ◽

Iodotyrosine Deiodinase ◽

Rate Of Hydrolysis ◽

Underlying Mechanisms ◽

Excess Iodide ◽

Sites Of Action ◽

Hydrolysis Of

Abstract. Iodine in excess is known to acutely inhibit thyroidal secretion. In the present study we have characterized the time course of the iodine effect in vitro and investigated the underlying mechanisms. Labelled thyroid glands were cultured in vitro in medium containing mononitrotyrosine, an inhibitor of iodotyrosine deiodinase. The rate of hydrolysis of labelled thyroglobulin was measured as the proportion of labelled iodotyrosines and iodothyronines recovered at the end of culture and was used as an index of thyroidal secretion. Thyrotrophin (TSH) administered in vivo acutely stimulated the rate of thyroglobulin hydrolysis. Addition of Nal to the culture medium acutely inhibited both basal and TSH-stimulated thyroglobulin hydrolysis. The effect of iodide was demonstrable after 2 h, maximal after 6 h and was not reversible upon removal of iodide. Iodide abolished the dibutyryl cAMP induced stimulation of thyroglobulin hydrolysis. Iodide required organic binding of iodine for its effect but new protein or RNA synthesis was not necessary. The inhibitory effects of iodide and lysosomotrophic agents such as NH4C1 and chloroquin on thyroglobulin hydrolysis were additive suggesting different sites of action. Iodide added in vitro altered the distribution of label in prelabelled thyroglobulin in a way that suggested increased coupling in the thyroglobulin molecule. These data indicate that 1) the iodide effect occurs progressively over a 6 h period, 2) continued presence of iodide is not necessary once the inhibition is established, 3) iodide exerts its action primarily at a post cAMP, prelysosomal site and 4) the effect requires organic binding of iodine, but not new RNA or protein synthesis. Our data are consistent with the hypothesis that excess iodide acutely inhibits thyroglobulin hydrolysis by increasing the resistance of thyroglobulin to proteolytic degradation through increased iodination and coupling.

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Perspective: Nonreproductive Sites of Action of Reproductive Hormones*

Endocrinology ◽

10.1210/endo.142.6.8221 ◽

2001 ◽

Vol 142 (6) ◽

pp. 2200-2204 ◽

Cited By ~ 33

Author(s):

S. C. Manolagas ◽

S. Kousteni

Keyword(s):

Reproductive Hormones ◽

Sites Of Action

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Ion channels and G protein-coupled receptors as targets for invertebrate pest control: from past challenges to practical insecticides

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbab089 ◽

2021 ◽

Author(s):

Yoshihisa Ozoe

Keyword(s):

Ion Channels ◽

G Protein ◽

Pest Control ◽

Gaba Receptors ◽

Chloride Channels ◽

Structural Changes ◽

G Protein Coupled Receptors ◽

Octopamine Receptors ◽

Sites Of Action ◽

G Protein Coupled

Abstract In the late 1970s, we discovered that toxic bicyclic phosphates inhibit the generation of miniature inhibitory junction potentials, implying their antagonism of γ-aminobutyric acid (GABA) receptors (GABARs; GABA-gated chloride channels). This unique mode of action provided a strong incentive for our research on GABARs in later years. Furthermore, minor structural changes conferred insect GABAR selectivity to this class of compounds, convincing us of the possibility of GABARs as targets for insecticides. Forty years later, third-generation insecticides acting as allosteric modulator antagonists at a distinctive site of action in insect GABARs were developed. G protein-coupled receptors (GPCRs) are also promising targets for pest control. We characterized phenolamine receptors functionally and pharmacologically. Of the tested receptors, β-adrenergic-like octopamine receptors were revealed to be the most sensitive to the acaricide/insecticide amitraz. Given the presence of multiple sites of action, ion channels and GPCRs remain potential targets for invertebrate pest control.

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