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Fulltext Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists

Paudel P, Park SE, Seong SH, Fauzi FM, Jung HA, Choi JS

J Integr Neurosci, 2023 Jan 05;22(1):10.
PMID: 36722239 DOI: 10.31083/j.jin2201010

BACKGROUND: Cholecystokinin (CCK) is one of the most abundant peptides in the central nervous system and is believed to function as a neurotransmitter as well as a gut hormone with an inverse correlation of its level to anxiety and depression. Therefore, CCK receptors (CCKRs) could be a relevant target for novel antidepressant therapy.
METHODS: In silico target prediction was first employed to predict the probability of the bromophenols interacting with key protein targets based on a model trained on known bioactivity data and chemical similarity considerations. Next, we tested the functional effect of natural bromophenols from Symphyocladia latiuscula on the CCK2 receptor followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein.
RESULTS: Results of cell-based functional G-protein coupled receptor (GPCR) assays demonstrate that bromophenols 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) are full CCK2 antagonists. Molecular docking simulation of 1‒3 with CCK2 demonstrated strong binding by means of interaction with prime interacting residues: Arg356, Asn353, Val349, His376, Phe227, and Pro210. Simulation results predicted good binding scores and interactions with prime residues, such as the reference antagonist YM022.
CONCLUSIONS: The results of this study suggest bromophenols 1-3 are CCK2R antagonists that could be novel therapeutic agents for CCK2R-related diseases, especially anxiety and depression.

Matched MeSH terms: Receptor, Cholecystokinin B*
Fulltext Effect of Sequence of Fruit Intake in a Meal on Satiety

Abdul Hakim BN, Yahya HM, Shahar S, Abdul Manaf Z, Damanhuri H

Int J Environ Res Public Health, 2019 11 13;16(22).
PMID: 31766283 DOI: 10.3390/ijerph16224464

Little is known about the effects of manipulating sequence of fruit consumption during a meal in suppressing an individual's appetite. Therefore, we investigate the effects of the sequence of fruit intake on satiety and blood glucose in a group of 17 healthy, young male adults. This intervention study repeatedly measured the effects of fruit intake (120 g red apple) before and after a meal and control (no fruit). Ad libitum test meal was weighed before and after a meal. Subjective appetite rating and appetite-related hormones were assessed at regular time intervals. The satiety score was significantly higher for fruit intake before a meal followed by after a meal and control (p < 0.05). Eating fruit before a meal reduced 18.5% (166 kcal) subsequent energy intake compared to control (p < 0.05). Fruit intake before a meal had a significantly higher incremental area under the curve (iAUC) of Glucagon-like peptide 1 (GLP-1), compared to after a meal (p < 0.05). There were no differences in plasma changes of ghrelin, Cholecystokinin 8 (CCK8), or blood glucose in all sessions. Consuming fruit before a meal potentially enhanced satiety. Further research is required to confirm both short- and long-term effects of the sequence of fruit intake on appetite regulation in a wider population.

Matched MeSH terms: Cholecystokinin/blood
Fulltext Cholecystokinin hyperresponsiveness in functional dyspepsia

Chua AS, Keeling PW

World J Gastroenterol, 2006 May 07;12(17):2688-93.
PMID: 16718754 DOI: 10.3748/wjg.v12.i17.2688

Functional dyspepsia (FD) is a common disorder of yet uncertain etiology. Dyspeptic symptoms are usually meal related and suggest an association to gastrointestinal (GI) sensorimotor dysfunction. Cholecystokinin (CCK) is an established brain-gut peptide that plays an important regulatory role in gastrointestinal function. It inhibits gastric motility and emptying via a capsaicin sensitive vagal pathway. The effects on emptying are via its action on the proximal stomach and pylorus. CCK is also involved in the regulation of food intake. It is released in the gut in response to a meal and acts via vagal afferents to induce satiety. Furthermore CCK has also been shown to be involved in the pathogenesis of panic disorder, anxiety and pain. Other neurotransmitters such as serotonin and noradrenaline may be implicated with CCK in the coordination of GI activity. In addition, intravenous administration of CCK has been observed to reproduce the symptoms in FD and this effect can be blocked both by atropine and loxiglumide (CCK-A antagonist). It is possible that an altered response to CCK may be responsible for the commonly observed gastric sensorimotor dysfunction, which may then be associated with the genesis of dyspeptic symptoms.

Matched MeSH terms: Cholecystokinin/antagonists & inhibitors; Cholecystokinin/physiology*
Fulltext Central pathways integrating metabolism and reproduction in teleosts

Shahjahan M, Kitahashi T, Parhar IS

Front Endocrinol (Lausanne), 2014;5:36.
PMID: 24723910 DOI: 10.3389/fendo.2014.00036

Energy balance plays an important role in the control of reproduction. However, the cellular and molecular mechanisms connecting the two systems are not well understood especially in teleosts. The hypothalamus plays a crucial role in the regulation of both energy balance and reproduction, and contains a number of neuropeptides, including gonadotropin-releasing hormone (GnRH), orexin, neuropeptide-Y, ghrelin, pituitary adenylate cyclase-activating polypeptide, α-melanocyte stimulating hormone, melanin-concentrating hormone, cholecystokinin, 26RFamide, nesfatin, kisspeptin, and gonadotropin-inhibitory hormone. These neuropeptides are involved in the control of energy balance and reproduction either directly or indirectly. On the other hand, synthesis and release of these hypothalamic neuropeptides are regulated by metabolic signals from the gut and the adipose tissue. Furthermore, neurons producing these neuropeptides interact with each other, providing neuronal basis of the link between energy balance and reproduction. This review summarizes the advances made in our understanding of the physiological roles of the hypothalamic neuropeptides in energy balance and reproduction in teleosts, and discusses how they interact with GnRH, kisspeptin, and pituitary gonadotropins to control reproduction in teleosts.

Matched MeSH terms: Cholecystokinin
Effects of age on feeding response: Focus on the rostral C1 neuron and its glucoregulatory proteins

Ramlan H, Damanhuri HA

Exp Gerontol, 2020 01;129:110779.
PMID: 31705967 DOI: 10.1016/j.exger.2019.110779

BACKGROUND: Older people are likely to develop anorexia of aging. Rostral C1 (rC1) catecholaminergic neurons in rostral ventrolateral medulla (RVLM) are recently discovered its role in food intake control. It is well established that these neurons regulate cardiovascular function.
OBJECTIVE: This study aims to determine the effect of age on the function of rostral C1 (rC1) neurons in mediating feeding response.
METHOD: Male Sprague Dawley rats at 3-months (n = 22) and 24-months (n = 22) old were used and further divided into two subgroups; 1) treatment group with 2-deoxy-d-glucose (2DG) and 2) vehicle group. Feeding hormones such as cholecystokinin (CCK), ghrelin and leptin were analysed using enzyme-linked immunosorbent assay (ELISA). Rat brain was carefully dissected to obtain the brainstem RVLM region. Further analysis was carried out to determine the level of proteins and genes in RVLM that were associated with feeding pathway. Protein expression of tyrosine hydroxylase (TH), phosphorylated TH at Serine40 (pSer40TH), AMP-activated protein kinase (AMPK), phosphorylated AMPK (phospho AMPK) and neuropeptide Y Y5 receptor (NPY5R) were determined by western blot. Expression of TH, AMPK and NPY genes were determined by real-time PCR.
RESULTS: This study showed that blood glucose level was elevated in young and old rats following 2DG administration. Plasma CCK-8 concentration was higher in the aged rats at basal and increased with 2DG administration in young rats, but the leptin and ghrelin showed no changes. Old rats showed higher TH and lower AMPK mRNA levels. Glucoprivation decreased AMPK mRNA level in young rats and decreased TH mRNA in old rats. Aged rC1 neurons showed higher NPY5R protein level. Following glucoprivation, rC1 neurons produced distinct molecular changes across age in which, in young rats, AMPK phosphorylation level was increased and in old rats, TH phosphorylation level was increased.
CONCLUSION: These findings suggest that glucose-counterregulatory responses by rC1 neurons at least, contribute to the ability of young and old rats in coping glucoprivation. Age-induced molecular changes within rC1 neurons may attenuate the glucoprivic responses. This situation may explain the impairment of feeding response in the elderly.

Matched MeSH terms: Cholecystokinin/metabolism