2,925 research outputs found

    Acute effects of exercise intensity on butyrylcholinesterase and ghrelin in young men: A randomized controlled study

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    Background/objectives: Butyrylcholinesterase (BChE), a liver-derived enzyme that hydrolyzes acylated ghrelin to des-acylated ghrelin, may trigger a potential mechanism responsible for the acute exercise-induced suppression of acylated ghrelin. However, studies examining the effects of an acute bout of high-intensity exercise on BChE and acylated ghrelin have yielded inconsistent findings. This study aimed to examine the acute effects of exercise intensity on BChE, acylated ghrelin and des-acylated ghrelin concentrations in humans. Methods: Fifteen young men (aged 22.7 ± 1.8 years, mean ± standard deviation) completed three, half-day laboratory-based trials (i.e., high-intensity exercise, low-intensity exercise and control), in a random order. In the exercise trials, the participants ran for 60 min (from 09:30 to 10:30) at a speed eliciting 70 % (high-intensity) or 40 % (low-intensity) of their maximum oxygen uptake and then rested for 90 min. In the control trial, participants sat on a chair for the entire trial (from 09:30 to 12:00). Venous blood samples were collected at 09:30, 10:00, 10:30, 11:00, 11:30 and 12:00. Results: The BChE concentration was not altered over time among the three trials. Total acylated and des-acylated ghrelin area under the curve during the first 60 min (i.e., from 0 min to 60 min) of the main trial were lower in the high-intensity exercise trial than in the control (acylated ghrelin, mean difference: 62.6 pg/mL, p < 0.001; des-acylated ghrelin, mean difference: 31.4 pg/mL, p = 0.035) and the low-intensity exercise trial (acylated ghrelin, mean difference: 87.7 pg/mL, p < 0.001; des-acylated ghrelin, mean difference: 43.0 pg/mL, p = 0.042). Conclusion: The findings suggest that BChE may not be involved in the modulation of ghrelin even though lowered acylated ghrelin concentration was observed after high-intensity exercise

    Artemisia absinthium L.: Chemical composition and biological activity : diploma thesis

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    Cilj ovog rada bio je izolirati i odrediti kemijski sastav eteri─Źnih ulja pelina (Artemisia absinthium L.) sakupljenih na razli─Źitim lokalitetima te u razli─Źitim sezonama, ispitati sposobnost inhibicije eteri─Źnih ulja na djelovanje enzima acetilkolinesteraze, butirilkolinesteraze i ╬▒-glukozidaze te istra┼żiti antioksidacijsku aktivnost. Predominantni spojevi eteri─Źnog ulja pelina iz Sinja su cis-sabinil-acetat i cis-epoksi-ocimen, eteri─Źnog ulja pelina iz Mostara su cis-epoksi-ocimen i cis-krizantemil-acetat, eteri─Źnog ulja pelina iz Zaboka su trans-tujon i cis- epoksi-ocimen te ulja pelina iz Obrovca je cis-epoksi-ocimen. Kod svih analiziranih uzoraka ulja ove biljke sabrane na razli─Źitim lokacijama i u razli─Źitim sezonama branja kao dominantne komponente ulja javljaju se oksidirani monoterpenski spojevi-monoterpenoidi. Eteri─Źna ulja biljke A. absinthium L. pokazuju umjerenu ili slabu sposobnost inhibicije enzima AChE i BChE, ne inhibiraju ili umjereno inhibiraju enzim ╬▒-glukozidazu, pokazuju slab redukcijski potencijal i ne pokazuju sposobnost hvatanja slobodnih DPPH radikala.The aim of this study was to isolate and determine the chemical composition of essential oils of wormwood (Artemisia absinthium L.) collected at different sites and in different seasons, to examine the ability to inhibit essential oils on the enzymes acetylcholinesterase, butyrylcholinesterase and ╬▒-glucosidase and to investigate antioxidant activity. The predominant compounds of wormwood essential oil from Sinj are cis-sabinyl-acetate and cis-epoxy-ocimen, wormwood essential oil from Mostar are cis-epoxy-ocimen and cis-chrysanthemum-acetate, wormwood essential oil from Zabok are trans-thujone and cis-epoxy-ocimen and oils wormwood from Obrovac is cis-epoxy-ocimen. In all analyzed oil samples of this plant collected at different locations and in different harvesting seasons, oxidized monoterpene compounds-monoterpenoids appear as the dominant oil components. The essential oils of A. absinthium L. show moderate or weak ability to inhibit the enzymes AChE and BChE, do not inhibit or moderately inhibit the enzyme ╬▒-glucosidase, show weak reduction potential and do not show the ability to capture free DPPH radicals

    Artemisia absinthium L.: Chemical composition and biological activity : diploma thesis

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    Cilj ovog rada bio je izolirati i odrediti kemijski sastav eteri─Źnih ulja pelina (Artemisia absinthium L.) sakupljenih na razli─Źitim lokalitetima te u razli─Źitim sezonama, ispitati sposobnost inhibicije eteri─Źnih ulja na djelovanje enzima acetilkolinesteraze, butirilkolinesteraze i ╬▒-glukozidaze te istra┼żiti antioksidacijsku aktivnost. Predominantni spojevi eteri─Źnog ulja pelina iz Sinja su cis-sabinil-acetat i cis-epoksi-ocimen, eteri─Źnog ulja pelina iz Mostara su cis-epoksi-ocimen i cis-krizantemil-acetat, eteri─Źnog ulja pelina iz Zaboka su trans-tujon i cis- epoksi-ocimen te ulja pelina iz Obrovca je cis-epoksi-ocimen. Kod svih analiziranih uzoraka ulja ove biljke sabrane na razli─Źitim lokacijama i u razli─Źitim sezonama branja kao dominantne komponente ulja javljaju se oksidirani monoterpenski spojevi-monoterpenoidi. Eteri─Źna ulja biljke A. absinthium L. pokazuju umjerenu ili slabu sposobnost inhibicije enzima AChE i BChE, ne inhibiraju ili umjereno inhibiraju enzim ╬▒-glukozidazu, pokazuju slab redukcijski potencijal i ne pokazuju sposobnost hvatanja slobodnih DPPH radikala.The aim of this study was to isolate and determine the chemical composition of essential oils of wormwood (Artemisia absinthium L.) collected at different sites and in different seasons, to examine the ability to inhibit essential oils on the enzymes acetylcholinesterase, butyrylcholinesterase and ╬▒-glucosidase and to investigate antioxidant activity. The predominant compounds of wormwood essential oil from Sinj are cis-sabinyl-acetate and cis-epoxy-ocimen, wormwood essential oil from Mostar are cis-epoxy-ocimen and cis-chrysanthemum-acetate, wormwood essential oil from Zabok are trans-thujone and cis-epoxy-ocimen and oils wormwood from Obrovac is cis-epoxy-ocimen. In all analyzed oil samples of this plant collected at different locations and in different harvesting seasons, oxidized monoterpene compounds-monoterpenoids appear as the dominant oil components. The essential oils of A. absinthium L. show moderate or weak ability to inhibit the enzymes AChE and BChE, do not inhibit or moderately inhibit the enzyme ╬▒-glucosidase, show weak reduction potential and do not show the ability to capture free DPPH radicals

    Alkyl chain replacement on position 1 of indazole dual inhibitors of butyrylcholinesterase and mitogen-activated kinase p38╬▒

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    Alzheimerjeva bolezen je kroni─Źna progresivna nevrodegenerativna bolezen, pri kateri so v ospredju znaki demence. Poleg kognitivnih motenj alzheimerjevo bolezen spremljajo tudi nevropsihiatri─Źni simptomi. Etiologija bolezni ┼íe ni popolnoma pojasnjena, venar pa med mo┼żne vzroke ┼ítejejo senilne lehe, nevrofibrilarne pentlje, moteno holinergi─Źno transmisijo, nevrovnetje in oksidativni stres. Trenutni terapevtski pristopi za zdravljenje alzheimerjeve bolezni vklju─Źujejo zaviralce acetilholinesteraz, zaviralce N-metil-D-aspartatnih receptorjev in protitelesa proti amiloidu beta. Registrirane u─Źinkovine se uporabljajo predvsem z namenom upo─Źasnitve upadanja kakovosti ┼żivljenja in ne vplivajo na proces bolezni, ob ─Źemer se pojavlja nuja po razvoju izbolj┼íanih u─Źinkovin za zdravljenje alzheimerjeve bolezni. Potencialno tar─Źo za zdravljenje bolezni predstavljata butirilholin esteraza, katere encimska aktivnost je pove─Źana v mo┼żganih bolnikov z alzheimerjevo boleznijo in z mitogenom aktivirana protein kinaza p38╬▒, ki prispeva k nevrovnetju in apoptozi nevronskih celic, mikroglije in astrocitov. Zato smo v magistrski nalogi sintetizirali ┼ítiri nove dvojne zaviralce butirilholin esteraze in z mitogenom aktivirane protein kinaze p38╬▒. Izhajali smo iz ┼że znane spojine ARRY-371797, znanega selektivnega zaviralca p38╬▒, ki zavira tudi butirilholin esterazo in vitro. Ohranili smo osrednji 5,6-disubstituiran indazolni skelet, pri ─Źemer je substituent na mestu 5 vedno predstavljala 2,4-difluorofenoksi skupina, za katero predvidevamo, da tvori pi-pi interakcije v acil-vezavnem ┼żepu BChE in ugodno zasede hidrofobno regijo I p38╬▒. Na mestu 6 smo ohranili N-(2-(dimetilamino)etil)amidni substituent, za katerega predvidevamo, da tvori mo─Źne kation-pi interakcije s Trp82 holin-vezavnega ┼żepa butirilholin esteraze, v aktivnem mestu p38╬▒ pa naj bi bil usmerjen proti topilu in tako ne bi motil vezave liganda v ATP-vezavno mesto. Z namenom, da bi dosegli mo─Źnej┼íe zaviralno delovanje na obe tar─Źi in prou─Źili vpliv razli─Źnih verig na aktivnost molekule, smo na mestu 1 indazolnega obro─Źa zamenjali izobutilno skupino z drugimi alkilnimi verigami. Z metodo po Ellmanu in ADP-Glo testom smo ovrednotili aktivnost sintetiziranih spojin 7A-E na oba encima in vitro in ugotovili, da spojina 7D z izopentilno alkilno verigo najmo─Źneje zavira encim butirilholin esterazo, najmo─Źnej┼íe zaviralno delovanje na z mitogenom aktivirano protein kinazo p38╬▒ pa smo dosegli s spojino 7E, pri kateri cikloheksen najverjetneje dodatno rigidizira strukturo spojine, da zasede najbolj┼ío lego v aktivnem mestu encima. Zaviralno delovanje spojine 7E (IC50 = 87,6 nM) je celo preseglo u─Źinkovitost ARRY-371797 na z mitogenom aktivirano protein kinazo p38╬▒. Dosegli smo selektivnost na butirilholin esterazo v primerjavi z acetilholinesterazo in u─Źinkovito zaviralno delovanje na z mitogenom aktivirano protein kinazo p38╬▒, kar predstavlja pomembno izhodi┼í─Źe za nadaljnji razvoj u─Źinkovin za zdravljenje AB.Alzheimer\u27s disease is a chronic progressive neurodegenerative disease in which the signs of dementia are prominent and, in addition to cognitive disorders, disease is also accompanied by neuropsychiatric symptoms. The etiology of the disease is not yet fully understood, but the possible causes and processes of Alzheimer\u27s disease are associated with senile plaques, neurofibrillary tangles, disturbed cholinergic transmission, neuroinflammation and oxidative stress. Current therapeutic approaches for the treatment of Alzheimer\u27s disease include acetylcholinesterase inhibitors, inhibitors of N-methyl-D-aspartate receptors and anti-amyloid-beta antibodies. Registered active substances are primarily used to slow down the decline in quality of life and do not affect the disease process. Because of that there is a need to find and synthesize improved active substances for the treatment of Alzheimer\u27s disease. Butyrylcholinesterase, whose enzyme activity is increased in the brains of patients with Alzheimer\u27s disease, and mitogen-activated protein kinase p38╬▒, which contribute to neuroinflammation and apoptosis of neurons, microglia and astrocytes, are potential targets for the treatment of the disease. Therefore, in our master\u27s thesis, we synthesized four new dual inhibitors of butyrylcholinesterase and mitogen-activated protein kinase p38╬▒. We started from the already known compound ARRY-371797, which has an inhibitory effect on both enzymes. We kept the central 5,6-disubstituted indazole skeleton, whereby the substituent in position 5 was always represented by a 2,4-difluorophenoxy group, which we predict forms pi-pi interactions in the acyl-binding pocket of butyrylcholinesterase and favorably occupies the hydrophobic region I of p38╬▒. The N-(2-(dimethylamino)ethyl)amide substituent was retained in position 6, which is predicted to form strong cation-pi interactions with Trp82 of the choline-binding pocket of butyrylcholinesterase, and in the active site of p38╬▒, it is expected to be directed towards the solvent and thus would not interfere with ligand binding to the ATP-binding site. In order to achieve a stronger inhibitory effect on both targets and to study the influence of different alkyl chains on the activity of the molecule, we replaced the isobutyl group at position 1 of the indazole ring with other alkyl chains. Using the Ellman method and the ADP-Glo test, we evaluated the synthesized compounds 7A-E and found that compound 7D with an isopentyl alkyl chain most strongly inhibits the BChE enzyme, and the strongest inhibitory effect on p38╬▒ MAPK was achieved with compound 7E, in which cyclohexene most likely additionally rigidifies the structure of the compound and occupies the best position in the active site of the enzyme. The inhibitory activity of compound 7E (IC50 = 87,6 nM) was even better that activity of ARRY-371797 on mitogen-activated protein kinase p38╬▒. We achieved selectivity for butyrylcholinesterase compared to acetylcholinesterase and effective inhibitory action on mitogen-activated protein kinase p38╬▒ which represents an important starting point for the further development of agents for the treatment of AD

    Artemisia absinthium L.: Chemical composition and biological activity : diploma thesis

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    Cilj ovog rada bio je izolirati i odrediti kemijski sastav eteri─Źnih ulja pelina (Artemisia absinthium L.) sakupljenih na razli─Źitim lokalitetima te u razli─Źitim sezonama, ispitati sposobnost inhibicije eteri─Źnih ulja na djelovanje enzima acetilkolinesteraze, butirilkolinesteraze i ╬▒-glukozidaze te istra┼żiti antioksidacijsku aktivnost. Predominantni spojevi eteri─Źnog ulja pelina iz Sinja su cis-sabinil-acetat i cis-epoksi-ocimen, eteri─Źnog ulja pelina iz Mostara su cis-epoksi-ocimen i cis-krizantemil-acetat, eteri─Źnog ulja pelina iz Zaboka su trans-tujon i cis- epoksi-ocimen te ulja pelina iz Obrovca je cis-epoksi-ocimen. Kod svih analiziranih uzoraka ulja ove biljke sabrane na razli─Źitim lokacijama i u razli─Źitim sezonama branja kao dominantne komponente ulja javljaju se oksidirani monoterpenski spojevi-monoterpenoidi. Eteri─Źna ulja biljke A. absinthium L. pokazuju umjerenu ili slabu sposobnost inhibicije enzima AChE i BChE, ne inhibiraju ili umjereno inhibiraju enzim ╬▒-glukozidazu, pokazuju slab redukcijski potencijal i ne pokazuju sposobnost hvatanja slobodnih DPPH radikala.The aim of this study was to isolate and determine the chemical composition of essential oils of wormwood (Artemisia absinthium L.) collected at different sites and in different seasons, to examine the ability to inhibit essential oils on the enzymes acetylcholinesterase, butyrylcholinesterase and ╬▒-glucosidase and to investigate antioxidant activity. The predominant compounds of wormwood essential oil from Sinj are cis-sabinyl-acetate and cis-epoxy-ocimen, wormwood essential oil from Mostar are cis-epoxy-ocimen and cis-chrysanthemum-acetate, wormwood essential oil from Zabok are trans-thujone and cis-epoxy-ocimen and oils wormwood from Obrovac is cis-epoxy-ocimen. In all analyzed oil samples of this plant collected at different locations and in different harvesting seasons, oxidized monoterpene compounds-monoterpenoids appear as the dominant oil components. The essential oils of A. absinthium L. show moderate or weak ability to inhibit the enzymes AChE and BChE, do not inhibit or moderately inhibit the enzyme ╬▒-glucosidase, show weak reduction potential and do not show the ability to capture free DPPH radicals

    Biochemical analysis of the reactivation of phosphylated butyrylcholinesterase in relation with the oxime structure

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    Sposobnost butirilkolinesteraze (BChE) da vezanjem organofosfornih (OP) spojeva sni┼żava njihovu koncentraciju u organizmu i time sprje─Źava inhibiciju acetilkolinesteraze (AChE) predstavlja novi temelj terapije kod otrovanja ovim spojevima. Budu─çi da za reaktivaciju BChE jo┼í uvijek nije prona─Ĺen u─Źinkovit oksim, cilj ovog istra┼żivanja bio je ispitati u─Źinkovitost i strukturne karakteristike dvaju razli─Źitih skupina oksima u reaktivaciji BChE fosfilirane razli─Źitim organofosfatima koriste─çi in silico i in vitro pristup. Od 123 spojeva 1-heksil-2- ((hidroksiimino)metil) piridinijev oksim pokazao se naju─Źinkovitijim reaktivatorom fosfilirane BChE, posebice u slu─Źaju inhibicije ciklosarinom. Molekulskim modeliranjem pokazano je njegovo povoljno pozicioniranje u blizini fosfoniliranog kataliti─Źkog serina uz stabilizaciju hidrofobnim interakcijama s Trp82 ┼íto omogu─çuje brzu nukleofilnu supstituciju fosfilne skupine s serina. Pseudokataliti─Źki par ovog oksima i BChE u ex vivo uvjetima razgradio je stostruki suvi┼íak ciklosarina uz povrat 70 % kataliti─Źke aktivnosti kolinesteraza unutar 2 minute. Zaklju─Źno, pentil/heksil-temeljeni monopiridinijevi oksimi pokazali su se kao perspektivni strukturni motiv za daljnji razvoj oksima i terapije u kojoj bi u─Źinkoviti reaktivatori s BChE omogu─çavali pseudokataliti─Źku degradaciju OP toksina u krvi.The ability of butyrylcholinesterase (BChE) to bind organophosphorus (OP) compounds lowering their concentration in the body and preventing the inhibition of acetylcholinesterase (AChE) represents a new basis for therapy in OP poisoning. Since no effective oxime has yet been found for the reactivation of BChE, the aim of this research was to examine efficiency and structural characteristics of two different oxime groups in the reactivation of BChE phosphorylated with different organophosphates using in silico and in vitro approaches. Out of 123 compounds, 1-hexyl-2-((hydroxyimino)methyl) pyridinium oxime proved to be the most effective reactivator of phosphorylated BChE, especially in the case of cyclosarin inhibition. Molecular modeling showed its favorable positioning near the phosphonylated catalytic serine stabilized by hydrophobic interactions with Trp82, which enables rapid nucleophilic substitution of the phosphyl group from serine. Pseudocatalytic pair of this oxime and BChE in ex vivo conditions degraded a hundredfold excess of cyclosarin with 70 % recovery of cholinesterase catalytic activity within 2 minutes. In conclusion, pentyl/hexyl-based monopyridinium oximes proved to be a promising structural motif for further development of oximes and therapy in which effective BChE reactivators would enable pseudocatalytic degradation of OP toxins in the blood

    Biochemical analysis of the reactivation of phosphylated butyrylcholinesterase in relation with the oxime structure

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    Sposobnost butirilkolinesteraze (BChE) da vezanjem organofosfornih (OP) spojeva sni┼żava njihovu koncentraciju u organizmu i time sprje─Źava inhibiciju acetilkolinesteraze (AChE) predstavlja novi temelj terapije kod otrovanja ovim spojevima. Budu─çi da za reaktivaciju BChE jo┼í uvijek nije prona─Ĺen u─Źinkovit oksim, cilj ovog istra┼żivanja bio je ispitati u─Źinkovitost i strukturne karakteristike dvaju razli─Źitih skupina oksima u reaktivaciji BChE fosfilirane razli─Źitim organofosfatima koriste─çi in silico i in vitro pristup. Od 123 spojeva 1-heksil-2- ((hidroksiimino)metil) piridinijev oksim pokazao se naju─Źinkovitijim reaktivatorom fosfilirane BChE, posebice u slu─Źaju inhibicije ciklosarinom. Molekulskim modeliranjem pokazano je njegovo povoljno pozicioniranje u blizini fosfoniliranog kataliti─Źkog serina uz stabilizaciju hidrofobnim interakcijama s Trp82 ┼íto omogu─çuje brzu nukleofilnu supstituciju fosfilne skupine s serina. Pseudokataliti─Źki par ovog oksima i BChE u ex vivo uvjetima razgradio je stostruki suvi┼íak ciklosarina uz povrat 70 % kataliti─Źke aktivnosti kolinesteraza unutar 2 minute. Zaklju─Źno, pentil/heksil-temeljeni monopiridinijevi oksimi pokazali su se kao perspektivni strukturni motiv za daljnji razvoj oksima i terapije u kojoj bi u─Źinkoviti reaktivatori s BChE omogu─çavali pseudokataliti─Źku degradaciju OP toksina u krvi.The ability of butyrylcholinesterase (BChE) to bind organophosphorus (OP) compounds lowering their concentration in the body and preventing the inhibition of acetylcholinesterase (AChE) represents a new basis for therapy in OP poisoning. Since no effective oxime has yet been found for the reactivation of BChE, the aim of this research was to examine efficiency and structural characteristics of two different oxime groups in the reactivation of BChE phosphorylated with different organophosphates using in silico and in vitro approaches. Out of 123 compounds, 1-hexyl-2-((hydroxyimino)methyl) pyridinium oxime proved to be the most effective reactivator of phosphorylated BChE, especially in the case of cyclosarin inhibition. Molecular modeling showed its favorable positioning near the phosphonylated catalytic serine stabilized by hydrophobic interactions with Trp82, which enables rapid nucleophilic substitution of the phosphyl group from serine. Pseudocatalytic pair of this oxime and BChE in ex vivo conditions degraded a hundredfold excess of cyclosarin with 70 % recovery of cholinesterase catalytic activity within 2 minutes. In conclusion, pentyl/hexyl-based monopyridinium oximes proved to be a promising structural motif for further development of oximes and therapy in which effective BChE reactivators would enable pseudocatalytic degradation of OP toxins in the blood

    Biochemical analysis of the reactivation of phosphylated butyrylcholinesterase in relation with the oxime structure

    No full text
    Sposobnost butirilkolinesteraze (BChE) da vezanjem organofosfornih (OP) spojeva sni┼żava njihovu koncentraciju u organizmu i time sprje─Źava inhibiciju acetilkolinesteraze (AChE) predstavlja novi temelj terapije kod otrovanja ovim spojevima. Budu─çi da za reaktivaciju BChE jo┼í uvijek nije prona─Ĺen u─Źinkovit oksim, cilj ovog istra┼żivanja bio je ispitati u─Źinkovitost i strukturne karakteristike dvaju razli─Źitih skupina oksima u reaktivaciji BChE fosfilirane razli─Źitim organofosfatima koriste─çi in silico i in vitro pristup. Od 123 spojeva 1-heksil-2- ((hidroksiimino)metil) piridinijev oksim pokazao se naju─Źinkovitijim reaktivatorom fosfilirane BChE, posebice u slu─Źaju inhibicije ciklosarinom. Molekulskim modeliranjem pokazano je njegovo povoljno pozicioniranje u blizini fosfoniliranog kataliti─Źkog serina uz stabilizaciju hidrofobnim interakcijama s Trp82 ┼íto omogu─çuje brzu nukleofilnu supstituciju fosfilne skupine s serina. Pseudokataliti─Źki par ovog oksima i BChE u ex vivo uvjetima razgradio je stostruki suvi┼íak ciklosarina uz povrat 70 % kataliti─Źke aktivnosti kolinesteraza unutar 2 minute. Zaklju─Źno, pentil/heksil-temeljeni monopiridinijevi oksimi pokazali su se kao perspektivni strukturni motiv za daljnji razvoj oksima i terapije u kojoj bi u─Źinkoviti reaktivatori s BChE omogu─çavali pseudokataliti─Źku degradaciju OP toksina u krvi.The ability of butyrylcholinesterase (BChE) to bind organophosphorus (OP) compounds lowering their concentration in the body and preventing the inhibition of acetylcholinesterase (AChE) represents a new basis for therapy in OP poisoning. Since no effective oxime has yet been found for the reactivation of BChE, the aim of this research was to examine efficiency and structural characteristics of two different oxime groups in the reactivation of BChE phosphorylated with different organophosphates using in silico and in vitro approaches. Out of 123 compounds, 1-hexyl-2-((hydroxyimino)methyl) pyridinium oxime proved to be the most effective reactivator of phosphorylated BChE, especially in the case of cyclosarin inhibition. Molecular modeling showed its favorable positioning near the phosphonylated catalytic serine stabilized by hydrophobic interactions with Trp82, which enables rapid nucleophilic substitution of the phosphyl group from serine. Pseudocatalytic pair of this oxime and BChE in ex vivo conditions degraded a hundredfold excess of cyclosarin with 70 % recovery of cholinesterase catalytic activity within 2 minutes. In conclusion, pentyl/hexyl-based monopyridinium oximes proved to be a promising structural motif for further development of oximes and therapy in which effective BChE reactivators would enable pseudocatalytic degradation of OP toxins in the blood

    Antioxidant and anticholinesterase properties of Echinometra mathaei and Ophiocoma erinaceus venoms from the Persian Gulf

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    Introduction: The Persian Gulf is home to a diverse range of marine life, including various species of fish, crustaceans, mollusks, and echinoderms. This study investigates the potential therapeutic properties of venoms from echinoderms in the Persian Gulf, specifically their ability to inhibit cholinesterases (Acetylcholinesterase and butyrylcholinesterase) and act as antioxidants.Methods: Four venoms from two echinoderm species, including the spine, gonad, and coelomic fluids of sea urchins, as well as brittle star venoms, were analyzed using various methods, including LD50 determination, protein analysis, antioxidant assays, GC-MS for secondary metabolite identification, and molecular docking simulations.Results and discussion: The studyÔÇÖs results revealed the LD50 of the samples as follows: 2.231 ┬▒ 0.09, 1.03 ┬▒ 0.05, 1.12 ┬▒ 0.13, and 6.04 ┬▒ 0.13┬ámg/mL, respectively. Additionally, the protein levels were 44.037 ┬▒ 0.002, 74.223 ┬▒ 0.025, 469.97 ┬▒ 0.02, and 104.407 ┬▒ 0.025┬á╬╝g/mL, respectively. SDS-PAGE and total protein studies indicated that at least part of the venom was proteinaceous. Furthermore, the study found that the brittle star samples exhibited significantly higher antioxidant activity compared to other samples, including the standard ascorbic acid, at all tested concentrations. GC-MS analysis identified 12, 23, 21, and 25 compounds in the samples, respectively. These compounds had distinct chemical and bioactive structures, including alkaloids, terpenes, and steroids.Conclusion: These venoms displayed strong cholinesterase inhibitory and antioxidant activities, likely attributed to their protein content and the presence of alkaloids, terpenes, and steroids. Notably, the alkaloid compound C7 was identified as a promising candidate for further research in AlzheimerÔÇÖs disease therapy. In conclusion, echinoderms in the Persian Gulf may hold significant potential for discovering novel therapeutic agents

    Dementia with Lewy Bodies: Genomics, Transcriptomics, and Its Future with Data Science

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    Dementia with Lewy bodies (DLB) is a significant public health issue. It is the second most common neurodegenerative dementia and presents with severe neuropsychiatric symptoms. Genomic and transcriptomic analyses have provided some insight into disease pathology. Variants within SNCA, GBA, APOE, SNCB, and MAPT have been shown to be associated with DLB in repeated genomic studies. Transcriptomic analysis, conducted predominantly on candidate genes, has identified signatures of synuclein aggregation, protein degradation, amyloid deposition, neuroinflammation, mitochondrial dysfunction, and the upregulation of heat-shock proteins in DLB. Yet, the understanding of DLB molecular pathology is incomplete. This precipitates the current clinical position whereby there are no available disease-modifying treatments or blood-based diagnostic biomarkers. Data science methods have the potential to improve disease understanding, optimising therapeutic intervention and drug development, to reduce disease burden. Genomic prediction will facilitate the early identification of cases and the timely application of future disease-modifying treatments. Transcript-level analyses across the entire transcriptome and machine learning analysis of multi-omic data will uncover novel signatures that may provide clues to DLB pathology and improve drug development. This review will discuss the current genomic and transcriptomic understanding of DLB, highlight gaps in the literature, and describe data science methods that may advance the field
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