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Fulltext Analysis of heavy metals in some commerc

Paudel, P. N., Pokhrel, B., Kafle, B. K, Gyawali, R.

International Food Research Journal, 2016;23(3):1005-1011.
MyJurnal

Since the most of the fish consumed in the Kathmandu Valley are brought from commercial farms
in the Terai region of Nepal and some from India, the quality characteristics of such fishes are
foremost importance. Therefore, this study was carried out to provide the information on heavy
metal concentrations in the muscles of nine commercial fish species available in the markets of
Kathmandu Valley and to make people aware of the possible health risk associated with their
consumption. The concentrations of Lead (Pb), Arsenic (As), Cadmium (Cd), Zinc (Zn), Manganese
(Mn) and Chromium (Cr) were determined in the muscles of Catla catla, Pampus species, Puntius
chola, Eutropiichthys vacha, Pampus chinensis, Clarias batrachus, Labeo bata, Labeo rohita and
Mystus tengara. The levels of heavy metals were measured by atomic absorption spectrophotometry
after digestion of the samples using the heating digester. There were significant variations among
heavy metal levels in the muscles of the nine fish species, and no fish types had the highest levels of
more than two metals. First, three maximum mean concentrations of potentially toxic elements were
found 16.75 µg/g in Puntius chola, 12.13 µg/g in Eutropiichthys vacha, 11.63 µg/g in Catla catla for
lead; 1.45 µg/g in Puntius chola, 1.35 µg/g in Pampus species and 1.15 µg/g in Mystus tengara for
cadmium; and 1.01 µg/g in Eutropiichthys vacha, 0.76 µg/g in Pampus species, 0.65 µg/g in Pampus
chinensis for arsenic. Similarly, first three maximum mean concentrations of essential elements
were found 9.88 µg/g in Puntius chola, 7.63 µg/g in Clarias batrachus, 5.75 µg/g in Catla catla
for manganese; 89.75 µg/g in Clarias batrachus, 68.37 µg/g in Catla catla, 65.38 µg/g in Puntius
chola for zinc; and 14.63 µg/g in Clarias batrachus, 13.13 µg/g in Pampus species, 10.50 µg/g in
Labeo rohita for chromium. The results showed that the heavy metals were found to be higher mean
concentrations in the sample of Puntius chola, then in Catla catla, Pampus species and Clarias
batrachus respectively; whereas they were found to be lower mean concentration in Eutropiichthys
vacha, Pampus chinensis, Labeo bata, Labeo rohita and Mystus tengara correspondingly. The
total mean concentration of manganese, lead and chromium in all fish samples was found to be
higher than the limits permitted by the Food and Agriculture Organization (FAO) of the United
Nations/World Health Organization (WHO) whereas the mean concentration of zinc and cadmium
was found lower than the permissible level of FAO/WHO, National Health and Medical Research
Council (NHMRC) and Malaysian Food and Regulations (MFR) guidelines. Similarly, the total
mean concentration of cadmium was also found to be lower than the permissible level of Centre
for Environment, Fisheries and Aquaculture Science (CEFAS), Boletin Oficial del Estado (BOE),
NHMRC, European Community Regulation (EU) and MRF in all fish samples. The total mean level
of lead was found lower than BOE guidelines. Likewise, the total mean level of chromium was
found slightly exceeded over limits suggested by the European Economic Community (EEC). This
study showed that all the fish samples examined were found to contain some heavy metals above the
FAO/WHO standard levels which may cause problems on the human health. At last, this research
work suggests that fish consumers should always bear in mind that standards cannot provide a
margin of safety when they are not enforced locall
Fulltext Emodin Derivatives as Multi-Target-Directed Ligands Inhibiting Monoamine Oxidase and Antagonizing Vasopressin V1A Receptors

Paudel P, Shrestha S, Park SE, Seong SH, Fauzi FM, Jung HA, et al.

ACS Omega, 2020 Oct 20;5(41):26720-26731.
PMID: 33110998 DOI: 10.1021/acsomega.0c03649

The brain neurotransmitter level is associated with the pathology of various neurodegenerative diseases, and age-dependent increase in the blood level of vasopressin, human brain monoamine oxidase (hMAO) level, oxidative stress, and imbalance in aminergic signaling are common disease-modifying factors leading to various neurodegenerative disorders. Based on the reports of emodin in hMAO inhibition and antagonist effect on the vasopressin V1A receptor, in this study we synthesized six emodin derivatives and evaluated their effects on MAO activity and G protein-coupled receptors. Among them, 4-hydroxyemodin and 5-hydroxyemodin were potent inhibitors of hMAO, and 2-hydroxyemodin and 5-hydroxyemodin were good V1AR antagonists. In silico molecular docking simulation revealed that the hydroxyl group at C2, C4, and C5 of the respective compounds interacted with prime residues, which corroborates the in vitro effect. Likewise, these three derivatives were predicted to have good drug-like properties. Overall, our study demonstrates that the hydroxyl derivatives of emodin are multi-target-directed ligands that may act as leads for the design and development of a therapy for central nervous system disorders.
Fulltext Establishing GPCR Targets of hMAO Active Anthraquinones from Cassia obtusifolia Linn Seeds Using In Silico and In Vitro Methods

Paudel P, Seong SH, Fauzi FM, Bender A, Jung HA, Choi JS

ACS Omega, 2020 Apr 07;5(13):7705-7715.
PMID: 32280914 DOI: 10.1021/acsomega.0c00684

The present study examines the effect of human monoamine oxidase active anthraquinones emodin, alaternin (=7-hydroxyemodin), aloe-emodin, and questin from Cassia obtusifolia Linn seeds in modulating human dopamine (hD1R, hD3R, and hD4R), serotonin (h5-HT1AR), and vasopressin (hV1AR) receptors that were predicted as prime targets from proteocheminformatics modeling via in vitro cell-based functional assays, and explores the possible mechanisms of action via in silico modeling. Emodin and alaternin showed a concentration-dependent agonist effect on hD3R with EC50 values of 21.85 ± 2.66 and 56.85 ± 4.59 μM, respectively. On hV1AR, emodin and alaternin showed an antagonist effect with IC50 values of 10.25 ± 1.97 and 11.51 ± 1.08 μM, respectively. Interestingly, questin and aloe-emodin did not have any observable effect on hV1AR. Only alaternin was effective in antagonizing h5-HT1AR (IC50: 84.23 ± 4.12 μM). In silico studies revealed that a hydroxyl group at C1, C3, and C8 and a methyl group at C6 of anthraquinone structure are essential for hD3R agonist and hV1AR antagonist effects, as well as for the H-bond interaction of 1-OH group with Ser192 at a proximity of 2.0 Å. Thus, based on in silico and in vitro results, hV1AR, hD3R, and h5-HT1AR appear to be prime targets of the tested anthraquinones.
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.
Fulltext Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M4 Receptor Antagonism by Tanshinone I

Prajapati R, Park SE, Seong SH, Paudel P, Fauzi FM, Jung HA, et al.

Biomolecules, 2021 Jul 08;11(7).
PMID: 34356625 DOI: 10.3390/biom11071001

Monoamine oxidases (MAOs) and muscarinic acetylcholine receptors (mAChRs) are considered important therapeutic targets for Parkinson's disease (PD). Lipophilic tanshinones are major phytoconstituents in the dried roots of Salvia miltiorrhiza that have demonstrated neuroprotective effects against dopaminergic neurotoxins and the inhibition of MAO-A. Since MAO-B inhibition is considered an effective therapeutic strategy for PD, we tested the inhibitory activities of three abundant tanshinone congeners against recombinant human MAO (hMAO) isoenzymes through in vitro experiments. In our study, tanshinone I (1) exhibited the highest potency against hMAO-A, followed by tanshinone IIA and cryptotanshinone, with an IC50 less than 10 µM. They also suppressed hMAO-B activity, with an IC50 below 25 µM. Although tanshinones are known to inhibit hMAO-A, their enzyme inhibition mechanism and binding sites have yet to be investigated. Enzyme kinetics and molecular docking studies have revealed the mode of inhibition and interactions of tanshinones during enzyme inhibition. Proteochemometric modeling predicted mAChRs as possible pharmacological targets of 1, and in vitro functional assays confirmed the selective M4 antagonist nature of 1 (56.1% ± 2.40% inhibition of control agonist response at 100 µM). These findings indicate that 1 is a potential therapeutic molecule for managing the motor dysfunction and depression associated with PD.
Luteolin, a Potent Human Monoamine Oxidase-A Inhibitor and Dopamine D4 and Vasopressin V1A Receptor Antagonist

Park SE, Paudel P, Wagle A, Seong SH, Kim HR, Fauzi FM, et al.

J Agric Food Chem, 2020 Sep 30;68(39):10719-10729.
PMID: 32869630 DOI: 10.1021/acs.jafc.0c04502

Luteolin, a flavonoid widely distributed in the plant kingdom, contains two benzene rings and hydroxyl groups, and this structural specificity contributes to its diverse biological activities. However, no previous studies have simultaneously investigated the therapeutic potency of luteolin isolated from a plant as an antipsychotic and antidepressant. Here, luteolin exhibited selective inhibition of hMAO-A (IC50 = 8.57 ± 0.47 μM) over hMAO-B (IC50 > 100 μM). In silico proteochemometric modeling predicted promising targets of luteolin, and verification via cell-based G protein-coupled receptor functional assays showed that luteolin is a selective antagonist of the vasopressin receptor V1AR (IC50 = 19.49 ± 6.32 μM) and the dopamine D4 receptor (IC50 = 39.59 ± 1.46 μM). Molecular docking showed the tight binding of luteolin with a low binding score and the high stability of the luteolin-receptor complex, corroborating its functional effect. Thus, hMAO-A, hD4R, and hV1AR are prime targets of luteolin and potential alternatives for the management of neurodegenerative diseases.