Currently, most of the drugs used in clinical applications show their pharmacological influences by inhibiting or activating enzymes. Therefore, enzyme inhibitors have an essential place in the drug ...design for many diseases.
The current study aimed to contribute to this growing drug design field (i.e., medicine discovery and development) by analyzing enzyme-drug interactions.
For this reason, Paraoxonase-I (PON1) enzyme was purified from fresh human serum by using rapid chromatographic techniques. Additionally, the inhibition effects of some antineoplastic agents were researched on the PON1.
The enzyme was obtained with a specific activity of 2603.57 EU/mg protein. IC50 values for pemetrexed disodium, irinotecan hydrochloride, dacarbazine, and azacitidine were determined to be 9.63μM, 30.13μM, 53.31μM, and 21.00mM, respectively. These agents found to strongly inhibit PON1, with Ki constants ranging from 8.29±1.47μM to 23.34±2.71mM. Dacarbazine and azacitidine showed non-competitive inhibition, while other drugs showed competitive inhibition. Furthermore, molecular docking was performed using maestro for these agents. Among these, irinotecan hydrochloride and pemetrexed disodium possess the binding energy of -5.46 and -8.43 kcal/mol, respectively.
The interaction studies indicated that these agents with the PON1 possess binding affinity.
Pd(II) complexes (
Pd1
,
Pd2
, and
Pd3
) were synthesized for the first time using asymmetric isatin bisthiocarbohydrazone ligands and PdCl
2
(PPh
3
)
2
. All complexes were characterized by a range ...of spectroscopic and analytical techniques. The molecular structures of
Pd1
and
Pd3
have been determined by single-crystal X-ray diffraction analysis. The complexes are diamagnetic and exhibit square planar geometry. The asymmetric isatin bisthiocarbohydrazone ligands coordinate to Pd(II) ion in a tridentate manner, through the phenolic oxygen, imine nitrogen and thiol sulfur, forming five- and six-membered chelate rings within their structures. The fourth coordination site in these complexes is occupied by PPh
3
(triphenylphosphine). The free ligands and their Pd(II) complexes were evaluated for their carbonic anhydrase I, II (hCAs) and acetylcholinesterase (AChE) inhibitor activities. They showed a highly potent inhibition effect on AChE and hCAs.
K
i
values are in the range of 9 ± 0.6 – 30 ± 5.4 nM for AChE, 7 ± 0.5 – 16 ± 2.2 nM for hCA I and 3 ± 0.3–24 ± 1.9 nM for hCA II isoenzyme. The results clearly demonstrated that the ligands and their Pd(II) complexes effectively inhibited the used enzymes.
Graphical abstract
Serum paraoxonase (PON1) is a key enzyme related to high‐density lipoprotein (HDL)‐cholesterol particle. It can prevent the oxidation of low‐density lipoprotein (LDL) and HDL. The present article ...focuses on the in vitro inhibition role of some antiepileptic drugs (AEDs) such as valproic acid, gabapentin, primidone, phenytoin, and levetiracetam on human paraoxonase (hPON1). Therefore, PON1 was purified from human serum with a specific activity of 3976.36 EU/mg and 13.96% yield by using simple chromatographic methods. The AEDs were tested at various concentrations, which showed reduced in vitro hPON1 activity. IC50 values for gabapentin, valproic acid, primidone, phenytoin, and levetiracetam were found to be 0.35, 0.67, 0.87, 6.3, and 53.3 mM, respectively. Ki constants were 0.261 ± 0.027, 0.338 ± 0.313, 0.410 ± 0.184, 10.3 ± 0.001, and 43.01 ± 0.003 mM, respectively. Gabapentin exhibited effective inhibitory activity as compared with the other drugs. The inhibition mechanisms of all compounds were noncompetitive.
News-commenting in social media is a platform that offers an opportunity for online deliberation through argumentative discussion. Yet aggressive exchanges between commenters with clashing ideologies ...have become a prominent feature of online news-commenting. One example of the aggressive exchanges is the use of direct personal attacks among news-commenters, namely abusive ad hominem. In this paper, I aim to reveal the patterns of responses given to abusive ad hominem attacks by studying the comments to news items in Facebook. The reason is to shed light on how the discussion evolves after the ad hominem attack. The patterns that this paper illustrates are a summary of studying the responses to 20 ad hominem attacks that figure in the comments to news items topicalizing various social problems in Turkey. The examples were drawn from those that topicalise ‘violence against women in Turkey’. Three patterns were identified: (1) abusive ad hominem as a response to an abusive ad hominem attack; (2) refusing to carry on the discussion; and (3) critically evaluating the abusive ad hominem attack. These patterns show that the pragma-dialectical definition of the ad hominem fallacy proves to be functional in understanding its role in blocking the way to the resolution.
Sosyal medyada haber yorumlama, kişilerin tartışarak çeşitli konuları çevrimiçi müzakere etmelerine olanak tanıyan bir platformdur. Ancak kullanıcılar arasındaki agresif iletişim, bu platformun önemli bir özelliği haline gelmiştir. Bu agresif iletişim örneklerinden biri yorumcuların karşıtlarına adam karalama safsatası yoluyla saldırmalarıdır. Bu çalışmada, Facebook haber yorumları incelenerek, adam karalama safsatasına verilen yanıtlarının argümantatif modellemesini yapmak amaçlanmaktadır. Bu sayede, bu tip saldırılardan sonra tartışmanın nasıl ilerleyebileceğine ışık tutulacaktır. Çalışmada 20 adet yanıt incelenmiştir. Bu yanıtlar, Türkiye’deki çeşitli sosyal problemleri konu eden haberlere yapılan yorumlardaki adam karalama safsatalarına verilen yanıtlardandır. Örnek vaka olarak, Türkiye’de ‘kadına yönelik şiddet’ haberlerine yapılan yorumlar kullanılmıştır. Analizler sonunda üç adet model ortaya çıkmıştır: (1) adam karalamaya yönelik saldırıya yine adam karalama safsatasıyla yanıt vermek; (2) tartışmaya devam etmeyeceğini belirtmek; ve (3) adam karalama safsatasını eleştirmek. Bu modeller, edimsel-eytişimsel yaklaşımın önerdiği adam karalama safsatası tanımının, bu saldırıların görüş ayrılığının ortadan kaldırılmasının önünde nasıl bir engel oluşturduğunu anlamak açısından işlevsel bir tanım olduğunu göstermektedir.
Countries are often reluctant to publicly recognize and express regret for past wrongdoings despite urgent pressures or calls to do so, and in the past decades there have been numerous examples of ...states that have issued statements that evade an admission of wrongdoing or apology. Evading an apology requires politicians in authority to make argumentative maneuvers to steer the discourse to their own advantage. But what do such maneuvers look like? This paper sets out to address this question by drawing on a Turkish example and by analyzing President Erdoğan’s message of condolences addressed to the Armenian community in 2014, when he was the Prime Minister of Turkey. We utilized the pragma-dialectical notion of ‘strategic maneuvering’ in uncovering how he exploited the topical potential, addressed the audience expectations, and chose from available presentational means to defend the standpoint that ‘Turkey should not be blamed for the events of 1915’. Our analysis suggests that even when political authorities evade an apology, they may still try to observe dialectically reasonable and rhetorically effective argumentation. The message we analyzed shows how this can be done by pairing evasive language about past atrocities with expressions of empathy with the victims and by highlighting the importance of dialogue, mutual tolerance, and compromise in establishing a common future.
In this work, nine new bromophenol derivatives were designed and synthesized. The alkylation reactions of (2-bromo-4,5-dimethoxyphenyl)methanol (7) with substituted benzenes 8–12 produced new diaryl ...methanes 13–17. Targeted bromophenol derivatives 18–21 were synthesized via the O-Me demethylation of diaryl methanes with BBr3. Moreover, the synthesized bromophenol compounds were tested with some metabolic enzymes such as acetylcholinesterase (AChE), carbonic anhydrase I (CA I), and II (CA II) isoenzymes. The novel synthesized bromophenol compounds showed Ki values that ranged from 2.53 ± 0.25 to 25.67 ± 4.58 nM against hCA I, from 1.63 ± 0.11 to 15.05 ± 1.07 nM against hCA II, and from 6.54 ± 1.03 to 24.86 ± 5.30 nM against AChE. The studied compounds in this work exhibited effective hCA isoenzyme and AChE enzyme inhibition effects. The results show that they can be used for the treatment of glaucoma, epilepsy, Parkinson’s as well as Alzheimer’s disease (AD) after some imperative pharmacological studies that would reveal their drug potential.
Paraoxonase‐1 (PON1) has essential roles such as protecting low‐density lipoprotein against detoxification and oxidation of highly toxic compounds. Quinones are a class of compounds and a type of ...plant‐derived secondary metabolites. Here, PON1 was purified using very simple methods and evaluation of the interactions between the enzyme and some quinones. It was found that these quinones displayed effective inhibitor properties for PON1 with the IC50 values in the range of 3.27–82.90 μM and the K
i values in the range of 2.50 ± 0.65 to 30.90 ± 7.20 μM. These quinones displayed distinct inhibition mechanisms. It was determined that except for 5‐hydroxy‐2‐methyl‐1,4‐naphthoquinone and 2‐methyl‐1,4‐naphthoquinone all quinones exhibit competitive inhibition effects. Also, molecular docking and in silico ADME studies were performed. Usage of drugs including quinone derivatives in structure with biological activity would be hazardous in some cases.
Objectives
Paraoxonase‐1 (PON1) enzyme is related to high‐density lipoprotein (HDL), which is calcium dependent. It has essential roles such as protecting LDL against oxidation and detoxification of ...highly toxic substances. It is a significant risk to reduce the levels of this enzyme in patients with diabetes mellitus, cardiovascular diseases, hyperthyroidism and chronic renal failure.
Methods
Here, it was reported that the purification of human serum PON1 using straightforward methods and determination of the interactions between some antihypertension drugs and the enzyme.
Key finding
It was found that these drugs exhibit potential inhibitor properties for human serum PON1 with IC50 values in the range of 131.40–369.40 μm and Ki values in the range of 56.24 ± 6.75–286.74 ± 28.28 μm. These drugs showed different inhibition mechanisms. It was determined that midodrine and nadolol were exhibited competitive inhibition, but atenolol and pindolol were exhibited non‐competitive inhibition.
Conclusion
Usage of these drugs would be hazardous in some cases.
Pain, as a sensible alarm signal of living organisms to avoid tissue damage, is a common and debilitating consequence of a lot of disorders and diseases. The management of chronic pain is ...particularly challenging. For pain treatment, many analgesic drugs are used for their therapeutic effects. In this study, some nonsteroidal anti-inflammatory drugs including etofenamate, meloxicam, diclofenac, and tenoxicam were tested against α-glycosidase from
Saccharomyces cerevisiae,
sorbitol dehydrogenase (SDH), and aldose reductase (AR) enzymes from sheep liver
.
Nonsteroidal anti-inflammatory drugs demonstrated useful inhibition properties against α-glycosidase, AR, and SDH enzymes.
K
i
values were found in the range of 11.93 ± 3.77–364.88 ± 40.01 μM for α-glycosidase, 3.36 ± 1.08μM–17.68 ± 3.39 mM for AR, and 1.68 ± 0.02 μM–30.98 ± 14.31 mM for SDH. They can be selective drugs as antidiabetic agents, because of their inhibitory properties against SDH, α-glycosidase, and AR enzymes.
The gill tissue is the main site of metabolic enzymes or compensation, with the kidney tissue playing a supporting role. At the gill tissue, carbonic anhydrase enzymes (CAs) catalyze the hydration of ...CO
2
to HCO
3
−
and H
+
for production to the H
2
O. In this work, the CA enzyme was purified from horse mackerel (
Trachurus trachurus
) gill with a specific activity of 21,381.42 EU/mg, purification fold of 150.61, total activity of 2347.68 EU/mL, and a yield of 16.13% using sepharose 4B-L-tyrosine-sulfanilamide affinity gel chromatography. For recording the enzyme purity, gel electrophoresis was performed, and single band was seen. The molecular weight of this enzyme was found approximately 35 kDa. Also, the inhibitory effects of different pesticides such as thiram, clofentezine, propineb, deltamethrin, azoxystrobin, and thiophanate and heavy metal ions such as Fe
2+
, Cu
2+
, Co
2+
, Pb
2+
Hg
2+
, and As
3+
on horse mackerel gill tissue CA enzyme activities were investigated. Our results indicated that these pesticides and metal ions showed inhibitory effects at low nanomolar and millimolar concentrations for fish gill CA enzymes, respectively.
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