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We synthesised eight derivatives of 4-aminoquinolines differing in the substituents attached to the C(4)-amino group and C(7) carbon of 4-aminoquinoline, and tested their potency to inhibit human AChE and BChE. All of the compounds reversibly inhibited both enzymes with dissociation inhibition (K_i) constants from 0.50 to 50 µM exhibiting selectivity. In other words, for all compounds, AChE exhibited higher affinity than BChE. The most potent inhibitors of AChE were compounds with an octyl chain or adamantane, regardless of the group in position C(7). The shortening of the chain length caused the AChE inhibition decrease by 5-20 times. Docking studies made it clear that the high AChE affinity resulted from simultaneous interactions of the quinoline group with aromatic residues of both the catalytic active site and the peripheral site. In conclusion, the inhibition potency and selectivity classify several novel compounds as leads for further modification and optimization towards the development of new inhibitors of AChE and potential drugs for treatment of neurodegenerative diseases.

Signal transducer and activator of transcription-3 (STAT3) is the most studied member from seven latent cytoplasmatic transcription factors (STATs 1-4, 5a, 5b and 6) that are closely associated with the occurrence of many types of cancer (breast, leukemia, lung, lymphoma, ovarian and prostate). STAT3 contains four functional domains, from which the Src homology 2 domain (SH2 domain) is the major target for inhibition of these proteins. Inhibition results in STAT3 tyrosine 705 (Y705) phosphorylation, dimerization, nuclear transport, DNA binding and transcription induction. The benzo[b]thiophene 1,1-dioxide (BTP) as a pharmacophore is part of many STAT3 inhibitors, such as Stattic, HJC0123, HJC0149 and HJC0416 (1,2,3). Stattic (6-nitro derivate of BTP) is a small molecule which selectively inhibited STAT3 SH2 domain function in vitro (3). HJC0123, HJC0149 and HJC0416 are carboxamides made from 6-amino derivate of BTP and substituted aromatic carboxylic acids (1,2). In this study we have in silico designed, synthesized and purificated 8 new Stattic-carboxamides. Their physical chemical properties were predicted in silico and then experimentally evaluated. Their biological activity was tested on murine and human cancer cell lines. Results were evaluated and compared to Stattic as a reference compound.

Monoterpenes, volatile molecules widely distributed in plants, are used in folk medicines, pharmaceutical and food industries, and cosmetics. Most terpenoids easily enter the human body by oral absorption, skin penetration, or inhalation leading to measurable blood concentrations. Numerous biological activities, including antitumor activity, of monoterpenes have been reported. On the other hand, some monoterpenes were reported to exhibit toxic effects in various organs of human organism, mostly in liver (1). The monoterpenes are also able to modulate the activity and/or expression of some drug-metabolizing enzymes. Present research was carried out to evaluate the effect of α-thujone (THU) or piperitone (PIP) on the activity and mRNA expression of the main detoxification enzymes in human liver. For this purpose, precision-cut liver slices (PCLS) were prepared from human liver samples (n=8) and incubated with THU or PIP (10 and 50 µM) for 24 h. These concentrations were non-toxic in primary rat hepatocytes. In human PCLS, THU and PIP in both concentrations caused significant increase in the specific activity of glutathione S-transferase (GST), however, the extent was dependent on basal GST activity. Regarding mRNA expression, induction of NAD(P)H:quinone oxidoreductase, cytochrome P450 2B6, glutathione peroxidase 3, and superoxide dismutase 1 was observed in samples treated with PIP 50 µM. The mRNA expression of GSTA and GSTP was induced by both compounds in several PCLS.

Tacrine was the first drug to be approved for Alzheimer´s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. Squaramides (SQ) are derivatives of squaric acid that are widely used in a variety fields of experties. Examples of small molecules with incorporated squaramide scaffold are Perzinfotel or Navarixin. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various acetylcholinesterase inhibitors (AChEIs). All new derivatives were evaluated for their anti-cholinesterase activities, hepatotoxicity and screened to predict their ability to cross the blood-brain barrier. In ongoing study, we also demonstrate that a common butyrylcholinesterase variant confers resistance to tacrine, which can be overcome by using derivatives from tacrine-squaramaide family. These findings underscore the importance of genetic drug target variability for personalized medicine.

The toxicity of organophosphorus compounds (OPs) cannot be explained only by action on acetylcholinesterase or neuropathy target esterase (NTE). A fraction of the membrane bound phenylvalerate esterase activity (PVase) is associated to NTE, the key initiating molecular event in the OP-induced delayed neuropathy (OPIDN). An enzymatic fraction in chicken brain soluble PVase has been reported to be due to a butyrylcholinesterase protein, and we suggested that this enzymatic fraction could be related to the mode of action of the potentiation/promotion phenomenon of the OPIDN. We showed that human butyrylcholinesterase (hBuChE) shows PVase activity. Mipafox, iso-OMPA or PMSF inhibited both activities with similar kinetic constants for both activities. Moreover, the substrates acethylthiocholine and phenyl valerate showed competition in their activities. The results suggest that both activities are related to the same active center. This work studies in depth the kinetic interactions between phenyl valerate and acetylthiocholine in human butyrylcholinesterase, showing that the interactions are different to the competitive model of substrates according to the Michaelis-Menten reaction. The approach introduced in this work suggests that other site could be involved in the interaction with phenyl valerate. In addition, we have observed that human acetylcholinesterase has also phenyl valerate esterase activity, but with lower activity than human butyrylcholinesterase. The level of phenylvalerate esterase activity in cholinesterases depends on the species and the type of cholinesterase. Further evaluation of the molecular interactions is under study.

Alzheimerʼs disease (AD) is a devastating neurodegenerative disorder characterized by a severe, progressive loss of memory. Currently, AD therapy is limited on the administration of cholinesterase inhibitors (ChEIs) and the N-methyl-D-aspartate (NMDA) antagonist, memantine. Tacrine as the first registered acetylcholinesterase (AChE, E.C. 3.1.1.7) inhibitor was withdraw due to its adverse effects. 7-Methoxytacrine (7-MEOTA) was prepared as a pharmacologically equal active compound with lower toxicity compared to THA. Donepezil as a highly selective inhibitor for AChE was connected with 7-MEOTA scaffold due to the ability to interact within calatytic anionic site (CAS) as well as peripheral anionic site (PAS) regions of AChE [1]. Recent research has been focused on studying the association between the intracellular amyloid beta (Aβ) cascade and the dysfunction of subcellular organelles, especially mitochondria. Mitochondrial enzyme amyloid beta binding alcohol dehydrogenase (ABAD) might contribute to the neuronal dysfunction associated with AD by interacting with intracellular Aβ [2]. These derivatives embodying 7-MEOTA and donepezil moieties [3] could be effective in the treatment of AD with the respect of their ability to interact with the multiple targets. Within our contribution, synthesis, in vitro biological evaluation including cholinesterase inhibitory activity and effects on mitochondrial function of 7-MEOTA-donepezil series will be reported.

Ten phenyltetrahydroisoquinoline-based compounds synthesized using alkyne+azide [3+2] building block cycloaddition were tested as potential reactivators of human acetylcholinesterase (hAChE) inhibited by different organophosphates. Computational docking indicated molecule phenyltetrahydroisoquinoline moiety association with the hAChE peripheral anionic binding site (Trp286, Tyr337 and Tyr341). Therefore, stabilization near the gorge opening seemed to control the general orientation of the pyridinium ring with its attached aldoxime group inserted into the internal gorge of the hAChE active center. All of the oximes were tested in vitro as potential reactivators of sarin-, cyclosarin-, tabun- and VX-conjugated hAChE and potent reactivators were identified, especially with the cyclosarin-hAChE conjugate. Nevertheless, in order to acquire results applicable to reactivation in vivo, compounds should be tested at concentrations higher than 10µM, which proved limiting due to the concomitant reversible inhibition of unconjugated hAChE. High oxime affinity was observed for hAChE, but not for human butyrylcholinesterase, where an aromatic peripheral site is absent. Therefore, we tested the oximes as reversible inhibitors of hAChE. All of the compounds potently inhibited hAChE with dissociation inhibition constants in nM range. To further explore potential for safe antidotal activity, we tested oxime cytotoxicity on the human neuroblastoma SH-SY5Y cell line. No cytotoxicity was observed at studied concentrations. In conclusion our study has shown that likely binding poses of an oxime in the hAChE active center do not always ensure enhanced enzyme activity for in vivo reactivation. Very high affinity of a candidate oxime for unconjugated hAChE may prove counterproductive for reactivation in tissue.

Background and Purpose: Different oak species (Quercus spp.) are widely distributed in Asia, Africa, Europe, and North America. The oak plant and its fruit hull have considerable antiinflammatory, antimicrobial, and antioxidant effects with important potential to be applied in wound healing products.Methods: The systematic review of documents and manuscripts from clinical trials, and scientific societies has been carried out. The surveys of interest were indexed in “PubMed”, “Web of Science”, “SciFinder”, and “Elsevier”. As a research strategy to carry out this review, two reviewers were responsible for searching the publications. Relevant literature has been obtained using the keywords “antimicrobial activity”, “antioxidant activity”, “flavonoids”, “oak”, “oak fruit”, “phytochemicals”, “tannins”, and “natural components”. The selection criterion was to include research papers on the most important topics, using in vitro or in vivo studies.Results: The most important Quercus species are Quercus infectoria, Quercus ilex, Quercus cerris, Quercus brantii, Quercus virgiliana, Quercus suber, Quercus rotundifolia, and Quercus robur. Important chemical com-ponents in lipophilic compounds are aliphatic alcohols such as octacosanol, hexacosanol, tetracosanol, and docosanol; fatty acids such as oleic acid and α linolenic acid; tannins such as castalagin, pedunculagin, and diagalloyl hexose; terpenoids such as cornin, agnuside, lamioside, and gibberellin A4 glucosylester; tocopherols such as α-tocopherol, β-tocopherol, and γ-tocopherol. The most important chemical constituents in its hydrophilic compounds are flavonoids, phenolic acids, tannin, amino acids, peptides, and analogues, carbohydrates and carbohydrate conjugates, and other phenolic compounds. Acorns are affordable and easily accessible raw material known in different cultures and regions which can be used in medicine, pharmacology, and food industry. Acorns are rich in many bioactive components with importance in food products with high health-promoting activities. Different parts of oak, especially its bark can be used as an antiseptic and hemostatic, which makes it appropriate to cure gastropathies, and toothache with beneficial activities as healing agents in burn.Conclusions: The general conclusion is that different parts of oak can be used more widely as an important ingredient in drugs, supplements, and functional foods.

Alzheimer’s disease (AD) is a broadly spread neurodegenerative disorder of ageing population manifesting itself in progressing loss of cognitive functions down to total demolition of intellect and disability. Profound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer’s disease. Here we show the protective effects against amyloid-induced synaptic toxicity of C-35, a potent reversible inhibitor of acetylcholinesterase (AChE). Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge. Molecular dynamics simulations indicated that the external flexible part of the ligand establishes multiple transient interactions with the enzyme peripheral anionic site. Thus, C-35 is a dual binding site inhibitor of AChE. In amyloid-transgenic mice, C-35, when administered after disease onset, reversed synapse loss, decreased the number of amyloid plaques and restored learning and memory. When administration of C-35 and the clinically relevant AChE dual inhibitor donepezil was terminated three weeks after the trial started, animals, that were receiving C-35 showed a much better ability to learn than those who received physiological saline or donepezil. Our results provide evidence that C-35 has a more pronounced Alzheimer’s disease-modifying action than donepezil.

Alzheimer disease comorbidities, such as hypertension, obesity, metabolic syndrome, diabetes mellitus and inflammation are all associated with impaired sympathetic/parasympathetic response. Inherited and/or acquired sympathetic prone state, expressed by elevated serum Acetylcholinesterase (AChE) can lead to excessive inflammatory load and cognitive decline. To evaluate the sympathetic/parasympathetic balance we measured serum cholinesterase activities in stroke, myocardial infarction, diabetes mellitus, morbid obese patients and apparently healthy control. Our findings identify the potential value cholinesterases as possible biomarkers in diseases associated with cerebro-cardiovascular outcome. Recently we found that serum AChE activity increased with BMI in a dose-dependent manner until it reached a peak level at BMI of 30-35 kg/m², followed by a plateau (p<0.001, n=1,450). Similarly, AChE activity increased with waist circumference categories (p < 0.001 for men and P = 0.013 for women). The Obesity-related AChE resistance phenotype may be reversed following laparoscopic sleeve gastrectomy (LSG) surgery and correlates with metabolic outcomes (% excess weight loss, %fat, and delta Homeostasis Model Assessment (HOMA)). Further long-term studies will be needed to validate and evaluate the beneficial effect of AChE reduction post bariatric surgery and its possible relation to cognitive decline.

New screening methodologies capable of identifying new enzyme inhibitors in a faster, more reproducible and automated way may help early drug discovery. Indeed high throughput screening methodologies for the identification of new cholinesterase inhibitors can reduce screening time and screening costs. In this frame, “immobilized enzymes” [1] can serve as handy and efficient alternatives to conventional in-solution methods. On the other hand, other than massive screening, highly informative approaches may provide decisive information in the selection of best-in-class compounds. Hence, combination of several parameters spanning from inhibition, binding mechanisms and kinetic parameters is important to be considered. In particular, estimation of residence time has recently emerged as critical feature [2]. Therefore, accessing kinetic information on drug binding events at initial stages of the drug discovery process is gaining increasing interest among medicinal chemists. In the light of these considerations, the talk will present different approaches involving immobilized human cholinesterases (ChEs). Micro-immobilized enzyme reactors (IMERs) can be used in combination with HPLC systems while SPR biosensing technology can be exploited for binding and kinetic investigation. ChE-based IMERs and single or multiple sensing surface(s) can be used in combination as valuable screening tools, which allow to quickly retrieve a set of highly useful information which can assist scientists in the selection of new chemical entities to be further developed.

Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. First, a hierarchical virtual screening was performed followed by biochemical evaluation of highest scoring hit compounds. Three compounds showed significant inhibitory activities against BChE and the best inhibitor was selected for further SAR studies. More than 100 different analogues were synthesized and among them, two compounds were found to be promising lead compounds as they were not cytotoxic, they crossed the blood-brain barrier and improved memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. The solved crystal structures of human BChE in complex with the most potent inhibitors revealed their binding modes and provided the structural basis for their further development into multi-target-directed ligands, which in addition to good inhibition of BChE possess good antioxidant, metal chelating, neuroprotective and other properties beneficial for AD.

C. elegans is a free-living worm widely used as model to study neurotoxicology. Despite its simplicity, C. elegans has a high level of genetic and molecular conservation with vertebrates. Similar to mammals, intoxication with anti-cholinestereses triggers the accumulation of synaptic acetylcholine causing continuous stimulation of both nicotinic and muscarinic receptors, hypercontracting the muscles of the worm¹. The pharynx, the nematode feeding organ, depends on cholinergic function. Pharyngeal movements, readily observed in whole organism, are disrupted by impairments in cholinergic transmission. Therefore, quantitative analysis of pharyngeal structure and function has excellent potential to probe anti-cholinesterase mode of action that may translate to human toxicology. We establish the IC₅₀ values for the carbamate aldicarb and the organophosphates paraoxon-ethyl, paraoxon-methyl and DFP, highlighting a distinct dose-time dependence inhibition of pharyngeal activity. In recovery experiments, aldicarb and paraoxon-ethyl but not paraoxon-methyl or DFP intoxicated worms recover the pharyngeal function onto empty and oxime plates. A cycle of aldicarb intoxication-recovery-intoxication revealed aldicarb-induced plasticity as a reduced sensitivity of pre-conditioned worms to a subsequent drug exposure. We investigated molecular determinants of this plasticity by using uncoordinated locomotion and reduced pharyngeal movement mutant worms due to impairments in cholinergic transmission. Interestingly, preconditioned mutant worms exhibits a switch in the aldicarb-induced plasticity observed in wild type, becoming more sensitive to post-exposure of aldicarb. Defining the molecular identity of this mutant will reveal pathways that mediate cholinesterase induced structural reorganization at the pharyngeal NMJ. Thus, the drug and genetic tractability of C. elegans offers a new route to anti-cholinesterase poisoning antidotes.

This study focused on the evaluation of the use of quinuclidinium oximes as potential antidotes in organophosphorus compound (OPs) poisoning. We determined the reversible inhibition of human red blood cell acetylcholinesterase (AChE) and human plasma butyrylcholinesterase (BChE) by 14 quinuclidinium oximes as well as the reactivation of tabun-, VX-, paraoxon-, sarin- and cyclosarin-inhibited enzymes. Reversible inhibition constants were within 3 μM to 4 mM, depending on the oxime structure. The highest inhibition was observed for Q5, which has a long aliphatic chain on the quinuclidinium ring quaternary nitrogen. It seems that AChE is selective toward oximes that have groups in meta position on the benzene ring and BChE to those with a group in para position. Quinuclidinium potency to reactivate organophosphorus-inhibited cholinesterases in vitro proved promising in restoring cholinesterase activity. VX- and paraoxon-inhibited AChE was reactivated by several candidates at up to 90 - 100 % within 1-4 hours. Oximes with a group in para position showed reactivation potency for cyclosarin-inhibited BChE with reactivation up to 90-100 %. Furthermore, at the very beginning of antidote development, we investigated if quinuclidinium oximes are cytotoxic to selected cell lines. As results indicate, quinuclidinium oximes did not show cytotoxic profiles up to 800 μM. An exception was observed only for Q5, an oxime with a long aliphatic chain in the structure, influencing cell vitality at concentrations significant for reactivation of cholinesterases.

Drug-mediated induction of the intestinal ABCB1 and CYP3A4 is a clinically relevant phenomenon associated with reduced drug bioavailability. Well-established human models to assess the induction are currently missing, so drug regulatory authorities provide no recommendations to test in vitro/ex vivo drugs' induction activity. Human precision-cut intestinal slices (hPCIS) contain cells in their natural environment and express physiological levels of nuclear factors required for induction. We recently found that hPCIS incubated for 48 h retained intact morphology, ATP content, and ABCB1 activity. We also confirmed that rifampicin (30 µM) induces gene expression and protein level of the ABCB1 over the 48-h incubation. Here, we aim to evaluate whether model ligands for glucocorticoid receptor (dexamethasone) and vitamin D receptor (vitamin D₃) induce ABCB1 and CYP3A4 expression in hPCIS over the 48-h incubation. Moreover, darunavir, a clinically used anti-HIV drug, was evaluated using this model. Dexamethasone (100 µM) increased the CYP3A4 and ABCB1 gene expression significantly after 48-h, 19.68- and 3.00-fold, respectively. Darunavir (50 µM) after 24-h significantly increased CYP3A4 and ABCB1 gene expression 7.42- and 2.07-fold, respectively. Vitamin D₃ (100 nM) increased CYP3A4 expression 2.29-fold after 48-h incubation; however, confirmation of inducibility requires multiple repeats. On ABCB1 expression, vitamin D₃ had no effect. To conclude, hPCIS is a promising model for investigating drug induction potential. The study was supported by the GAUK 364521 and SVV 260 549.

Background and Purpose: The application of medicinal plants and herbs to cure diverse animal and human ailments predates recorded history. Gastrointestinal disorders have a high prevalence in human societies.Methods: This research examined the scientific literature from 1990 to June 2025 by conducting a bibliometric analysis of the literature published on the Web of Science database, including more than one thousand articles. The information provided was obtained from randomized control experiments, analytical observations, review articles, and studies which were gathered from different literature sources such as Google Scholar, Scopus, Science Direct, and PubMed.Results: The gastrointestinal tract is one of the most important organs in the human body, and it is vulnerable to great diversity of diseases such as infectious and parasitic disorders, constipation, gastroenteritis, reflux, diarrhea, and bloating. Some of the most important medicinal plants which have been used in different traditional medicinal sciences for the treatment of dyspepsia symptoms are chamomile (Matricaria recutita), cinnamon (Cinnamomum verum), ginger (Zingiber officinalis), licorice (Glycyrrhiza glabra), peppermint (Mentha piperita), and guava (Psidium guajaba). The most notable herbs used to treat bloating are aniseed (Pimpinella anisum), cassia (Cinnamomum aromaticum), celery (Apium graveolens), cinnamon (Cinnamomum verum), dill (Anethum graveolens), fennel (Foeniculum vulgare), ginger (Zingiber officinalis), parsley (Petrosilenum crispus), pennyroyal (Mentha pulegium), peppermint (Mentha spicata), star anise (Illicium verum), and thyme (Thymus vulgaris). Phytochemicals such as seaweed-derived polysaccharide, phytohemagglutinin, and allicin have been reported as important components to induce precocious gut maturation. Phytochemicals can also change the composition of gut microbiota, digest normally indigestible molecules into bioavailable molecules, and enhance nutrient availability. Ganoderma lucidum, Gegen Qinlian decoction, Huang-qin decoction, and Glycyrrhiza uralensis Fisch. are important traditional Chinese medicine with significant effects on intestinal flora and different microbial communities.Conclusions: The review article aims to study and survey the importance of medicinal plants and herbs while considering their mechanisms of action for treatment of gastrointestinal disorders.

Human activity has had severe effects on the changes in climate over the last decades affecting, as a consequence, human security overall. The importance of changes in climate and their consequent effects have been long overlooked to the point that nowadays human health is being threatened by sea rise, extreme weather events, lack of adequate basic resources, and the spread of numerous diseases, to name some. This article aims to demonstrate how these variations have promoted the spread of vector-borne diseases (VBD). More specifically, it follows the developments of Dengue fever (DENV) as a result of higher temperatures and abundant precipitations, with a particular focus on the effects of humidity and a warm environment on the proliferation of VBD. To provide evidence of these climate consequences, two empirical cases are analysed and explained, one in Bangladesh and another in Ecuador. Overall, the analysis shows a positive correlation between the increase in temperatures and the changes in the weather and the proliferation of DENV in the above-mentioned territories. This article concludes that the increased temperatures, together with the evolution of extreme weather events have facilitated the reproduction of mosquitoes carrying DENV, and have enlarged the geographic and temporal distribution in which they inhabit. On this basis, the importance of climate change and its effects on human health should be tagged as a primary concern when facing challenges over human security.

Acetylcholinesterase (AChE) is the target of pesticides like organophosphates (OP). OP exert their toxic effect by irreversible phosphorylation of the AChE leading to cholinergic crisis and neurotoxicity. Erythrocyte AChE is the surrogate biomarker for the detection of inhibition by OP. There are numerous methods for the detection of AChE activity.¹ Unfortunately, the method popularly used for AChE detection has inherent limitations.¹ To overcome such a problem, we have explored 1-Naphthyl acetate (1-NA) as an alternative substrate for the assessment of AChE activity using in silico tools and in vitro experiments. The in silico results have shown that 1-NA is a better substrate for AChE. The fluorescence and chromogenic properties of 1-naphthol were studied. The results proved that 1-NA has specificity for AChE similar to Acetylthiocholine. Moreover, it was observed that in terms of Michaelis constant (Km) 1-NA is a better substrate than Acetylthiocholine. We believe that 1-NA is a candidate substrate for development of a method for screening of OP poisoning.

The annual or ephemeral plant Parthenium hysterophorus L. is an upright and heavily branched member of the Asteraceae family. The herb is used to treat heart issues, fever, anemia, wounds, and ulcerated sores. It is applied topically to treat skin issues, while the plant’s decoction is frequently taken orally to address a wide range of ailments. Psoriasis, rheumatoid arthritis, diarrhea, urinary tract infections, dysentery, malaria, psoriasis, allergies, asthma, tinnitus, nausea, vomiting, and neuralgia are just a few of the health benefits that P. hysterophorus L. can provide. Asthma, bronchitis, dermatitis, and hay fever are some of the major problems caused by this weed, which is harmful to all living things because it also depletes nutrient levels and competes with the cultivation of major crops and vegetation. This review discusses the potential health benefits as well as the origin, distribution, morphology, and harmful effects of the plant on human health.

The increasing antibiotic resistance of microbial pathogens isolated from farm animals tissues and the environment has been the one of the most important challenges associated with the use of antibiotics. In order to achieve better production on a farm, animal feed is enriched with antibiotics often originally intended for therapeutic purposes, which may lead to notable increases in microbial resistance. One possible approach to decreasing the excessive use of antibiotics in livestock as well as antimicrobial resistance is utilizing the antimicrobial properties of natural substances.The aim of this study was to evaluate the antimicrobial activity of natural substances including carvacrol, thymol, eugenol, gallic acid, octyl gallate, cnicin and usnic acid against a wide spectrum of microorganisms. Cnicin was the only compound which was isolated from the plant with use of column chromatography. The antimicrobial activities of these natural substances were determined on the basis of their minimum inhibitory, minimum bactericidal and minimum fungicidal concentrations using the microdilution method.This determination of antimicrobial activity revealed thymol and cnicin to be effective natural substances against all tested microorganisms. Octyl gallate had a strong inhibitory and bactericidal effect against gram-positive bacteria and was the most effective against Candida strains. Usnic acid was shown to have the lowest minimum inhibitory concentrations for gram-positive bacteria. These results suggest the possible incorporation of natural substances in animal rearing in order to reduce the high amount of antibiotics which are not used directly to treat animal diseases.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and function thereby as regulators of cholinergic neurotransmission. Recently, interest has greatly increased in BChE. Firstly, BChE is a good broad spectrum bioscavenger of nerve agent and its efficiency could be significantly increased by the mean of specific reactivators. Secondly, BChE activity in the brain increases with the progression of Alzheimer’s disease, thus classifying BChE as a promising drug target in the advanced phase of the disease. AChE and BChE display specificities for substrates and ligands that only partially overlap. This disparity is largely due to differences in the number of aromatic residues lining the active site gorge, which leads to large differences in the shape of the gorge and potentially to distinct interactions with an individual ligand. Considerable structural information is available for the binding of a wide diversity of ligands to AChE. In contrast, structural data on the binding of reversible ligands to BChE was lacking. In the recent years, we solved the X-ray structures of multiple BChE-ligand complexes. Here we will present BChE structures with various ligands, some recently synthesized, to highlight the structural elements leading to their BChE affinity and specificity. These structural data will help to design specific reversible ligands that behave as inhibitors or reactivators.

The combination of cholinesterase inhibitors with GPCR ligands in hybrid molecules seems highly promising for Alzheimer’s disease (AD) therapy, since two very different molecular targets can be addressed at the same time. Nevertheless, significant challenges come with this rationale: a) hybrids might possess too high molecular weights to be orally bioavailable and/or pass the blood-brain-barrier, b) the compounds might act in different concentration ranges, c) and selectivity and affinity has to be optimized for several very distinct targets. We have designed – applying computational methods - and synthesized dual-acting ChE-inhibitors that act with high potency and selectivity also at the histamine 3 receptor (hH₃R) [1], and the same could be achieved for cannabinoid 2 receptors (hCB₂R) [2, 3], both GPCRs represent important AD targets. Regarding dual-acting ChE inhibitors and hCB₂R agonists both covalently connected hybrids using the unselective ChE inhibitor tacrine as well as merged small molecules with high butyrylcholinesterase (BChE) selectivity have been obtained and pharmacologically characterized in vitro. Representative examples from all sets of compounds have been investigated in vivo in different AD mice models [3]. The case studies demonstrate that it is possible to obtain dual-acting compounds that a) act highly selectively and with high affinity at the respective targets, b) work in the same concentration range (“balanced affinity”), c) exhibit pronounced in vivo activity.

Natural cholinesterase inhibitors were found in many biological sources: bacteria, blue-greens, plants, marine sponges, microscopic fungus, and in a smaller scale also in mushrooms, fruiting body of macroscopis fungus. Only cholinesterase inhibitors isolated from mushrooms are subjects of this minireview. These natural compounds with anticholinergic activity may be considered as prospective drugs against Alzheimer's disease.

The number of successful drug development projects has been stagnant for decades despite major breakthroughs in chemistry, molecular biology and genomics. Unreliable translatability of preclinical in vitro and in vivo models has been identified as the cause of most failure. Organotypic and microphysiological culture of primary human cells has emerged as a set of promising tools for preclinical drug development to narrow this translation gap. In this talk I will provide an overview of our recent efforts in developing 3D human tissue cultures and microfluidic models for both efficacy and safety assessments. In addition, the talk will present recent use cases where the use of such organotypic cultures has had direct impacts on market authorizations.

The primary toxicological mechanism of organophosphorus compounds (OPCs) is the irreversible inhibition of acetylcholinesterase (AChE), leading to the accumulation of acetylcholine and subsequent cholinergic crisis, which can result in fatal respiratory failure. Conventional oxime reactivators, such as pralidoxime and obidoxime, are limited by their inability to permeate the blood-brain barrier (BBB) and inconsistent efficacy across different OPC types. To address these limitations, we designed a novel non-quaternary oxime reactivator codenamed K1396, with enhanced lipophilicity for improved BBB penetration and dual-binding capability at both the peripheral anionic site (PAS) and the catalytic active site (CAS) of AChE. This study compares the in vitro reactivation potency, cytotoxicity, and BBB penetration potential of K1396 with standard oximes. K1396 demonstrated comparable or superior reactivation potency, particularly against VX-inhibited AChE, and showed lower cytotoxicity in specific cell lines. Furthermore, K1396 exhibited favorable permeability across the lipid layer, suggesting potential CNS availability. The findings support the therapeutic potential of K1396 as an effective and broad-spectrum reactivator for OPC poisoning.

Human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) are related enzymes. hAChE plays a key role in neurotransmission and is the target of organophosphorus nerve agents. hBChE is good a natural stoichiometric scavenger of nerve agents, preventing their diffusion to the central and peripheral nervous system where they inhibit hAChE. hAChE and hBChE display different specificities for substrates and ligands due to differences in the number of aromatic residues lining the active site gorge. These aromatic residues are essential for the binding of quaternary and aromatic ligands. Some molecules containing quaternary and/or aromatic moieties form supramolecular structures by chelating Zinc. The nature of these molecules suggested that they could have affinity for the aromatic residues in the active site gorge of human cholinesterases. It was confirmed by determining their inhibition properties. A key question was whether these supramolecular ligands bind to human cholinesterases as their Zn-complex or monomeric form? The X-ray structures of two supramolecular complexes binding to the gorge of the hAChE and the hBChE reported herein showed that either cases are possible. These structural data on two new types of ligand can be used to design original cholinesterases inhibitors or reactivators.

Current pharmacotherapy for Alzheimer's disease (AD) involves compounds aimed at increasing the levels of acetylcholine in the brain through inhibition of AChE. These drugs, known as acetylcholinesterase inhibitors, have been shown to improve cognition and global functions but have little impact on improving the eventual progression of the disease. However, there are evidences that other cholinesterases such as butyrylcholinesterase (BuChE) can play an important role in cholinergic function in the brain, and the long-suspected non-cholinergic actions of acetylcholinesterase, mainly the interference with the beta-amyloid protein cascade, have recently driven a profound revolution in cholinesterase drug research [1-2]. We will present our journey from dual binding site AChE inhibitors as potent beta-amyloid modulators to the more recent serie of indolylpiperidines hybrids with an unexpected and very potent hBuChE inhibition. Experimental and computational studies have revealed the chameleon behavior of these molecules able to change their bioactive conformation depending on the cholinesterase binding site. Based on the potent activity of these compounds targeting BuChE, the low cellular toxicity and the in vivo target engagement, we can propose these indolylpiperidine derivatives as valuable tools for the study of the role of BuChE in AD and probably as potential drugs candidates for its future pharmacotherapy.

BACKGROUND: Managing burden of Coronary Artery Disease (CAD) is a battle for researchers over the globe as disease seems to be multifactorial. Duet concert of genetics and environmental factors over oxidative stress and inflammation accounts for disease progression. Human Paraoxonase 3 an HDL associated endogenous antioxidant enzyme, has been identified as antiatherogenic entity. Modifiable risk factors like diet and lifestyle play a supreme role in regulating paraoxonase activity. RATIONALE: To understand how the activity of Paraoxonase 3 can be modulated by using various pharmacological agents to derive the therapeutic benefit in CAD patients. METHODOLOGY: After approval of Institutional review board (No.55/IAEC/293), Hepatoma derived cell line (HepG2) was exposed to resveratrol, tempol, quercetin, simvastatin and nicotine in varying doses. MTT based optimum dose was selected and measured the PON3 enzymatic activity (Spectrophotometry/ HPLC), concentration (ELISA), cellular ROS (using H₂DCFH-DA), NOS (Griess assay) and protein expression (western blot) in cell lysates and supernatants. RESULTS: Resveratrol treatment led to significant increase in PON3 activity (p≤0.001) in HepG2 cells whereas other pharmacological agents had no major significant effect on PON3 activity, expression and concentration. CONCLUSION: PON3 induction by resveratrol translates new avenues in cardio-therapeutics.

Bioscavengers are considered to be a promising approach in the prophylaxis or treatment of poisoning by organophosphorus inhibitors (OPI; nerve agents and organophosphate pesticides). They can efficiently neutralize diverse OPIs in the bloodstream before they reach their natural targets - cholinesterases. Antidotal efficacy of administered butyrylcholinesterase (BChE; EC 3.1.1.8), one of the possible bioscavengers, could be further increased when it is co-administered with an oxime reactivator of a sufficient reactivation potency. Therefore, the activity of BChE, inhibited by OPI, could be continuously renewed (pseudo-catalytic bioscavenger). In this study, we evaluated the ability of standard reactivators (pralidoxime, obidoxime, HI-6, methoxime and  trimedoxime) and newly developed ones (K027, K048 and K203) to reactivate human plasma BChE inhibited by nerve agents (sarin, cyclosarin, VX and tabun) and dimethoxy and diethoxy pesticide (dichlorvos and paraoxon). Overall reactivation potency was decreased as follows: cyclosarin > sarin > VX > paraoxon > dichlorvos > tabun. HI-6 was the most efficient reactivator of cyclosarin- and sarin-inhibited BChE, whereas pralidoxime achieved highest potency for VX. Obidoxime was the most active in the case of pesticide inhibited enzyme. Reactivation of tabun-inhibited BChE was negligible for all tested compounds. Generally, reactivation ability of examined standard reactivators was deficient and uneven as they were designed for the reactivation of acetylcholinesterase. Therefore, there is a need for development of both more balanced and potent reactivators, suitable for pseudo-catalytic bioscavengers. Assayed oximes will serve for further standardization of our in vitro testing method and subsequent evaluation of newly synthesized BChE reactivators.

This paper’s aim is to provide clear basic explanation of the relationship between human health and climate change. It focuses on global warming, connecting it with the greenhouse effect and describing various effects the global warming has already had on human health. After the disclosure of other threats connected to climate change, the paper studies the history of it according to the Anthropocene concept theory. It also uses the perspective of weather extremes to explain climate change in the past and its connection to human health. Furthermore, this article focuses on the air pollution and its impact on the health of human population. Lastly, it touches on the topic of health inequalities and provides collected data and numbers for the future of climate change and human health.