Enzyme Inhibitors Research Articles

Angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis: Should we consider further implications?

This editorial contains comments on the article by Zhao et al in print in the World Journal of Gastroenterology . The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis. Here, we recapitulated the complexity of the renin-angiotensin system, discussed the role of hepatic stellate cell (HSC) autophagy in liver fibrogenesis, and analyzed the possible implications in the development of hepatocarcinoma (HCC). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers definitively contribute to reducing hepatic fibrogenesis, whereas their involvement in HCC is more evident in experimental conditions than in human studies. Angiotensin-converting enzyme 2 (ACE2), and its product Angiotensin (Ang) 1-7, not only regulate HSC autophagy and liver fibrosis, but they also represent potential targets for unexplored applications in the field of HCC. Finally, ACE2 overexpression inhibits HSC autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. In this case, Ang 1-7 acts binding to the MasR, and its agonists could modulate this pathway. However, since AMPK utilizes different targets to suppress the mTOR downstream complex mTOR complex 1 effectively, we still need to unravel the entire pathway to identify other potential targets for the therapy of fibrosis and liver cancer.

Exploring antioxidant and α-glucosidase inhibition in Eugenia L. extracts: a comprehensive phytochemicalstudy.

This study analysed extracts obtained from the leaves of Eugenia uniflora, E. involucrata, and E. myrcianthes to determine their chemical composition, antioxidative properties, and α-glucosidase inhibitory capacity. By using liquid chromatography with a diode array detector, we identified chlorogenic acids, flavonoids, tannins, proanthocyanidins, saponins, and triterpenes in the extracts. The antioxidant activities of the extracts were found to be directly related to their total phenolic, flavonoid content and enzyme inhibition. The E. uniflora aqueous extract showed significant inhibition of α-glucosidase (IC50 0.98 µg mL-1), indicating its potential as a non-competitive inhibitor for managing Diabetes Mellitus. This study contributes to the existing knowledge on the chemical and biological aspects of Eugenia genus.

Alternative weighting schemes for fine‐tuned extended similarity indices

AbstractExtended similarity indices (i.e., generalization of pairwise similarity) have recently gained importance because of their simplicity, fast computation, and superiority in tasks like diversity picking. However, they operate with several meta parameters that should be optimized. Earlier, we extended the binary similarity indices to “discrete non‐binary” and “continuous” data; now we continue with introducing and comparing multiple weighting functions. As a case study, the similarity of CYP enzyme inhibitors (4016 molecules after curation) was characterized by their extended similarities, based on 2D descriptors, MACCS and Morgan fingerprints. A statistical workflow based on sum of ranking differences (SRD) and analysis of variance (ANOVA) was used for finding the optimal weight function(s). Overall, the best weighting function is the fraction (“frac”), which corresponds to the principle of parsimony. Optimal extended similarity indices were also found, and their differences are revealed across different data sets. We intend this work to be a guideline for users of extended similarity indices regarding the various weighting options available. Source code for the calculations is available at https://github.com/mqcomplab/MultipleComparisons.

Multifaceted Activity of Fabimycin: Insights from Molecular Dynamics Studies on Bacterial Membrane Models.

Membranes─cells' essential scaffolds─are valid molecular targets for substances with an antimicrobial effect. While certain substances, such as octenidine, have been developed to target membranes for antimicrobial purposes, the recently reported molecule, fabimycin (F2B)─a novel agent targeting drug-resistant Gram-negative bacteria─has not received adequate attention regarding its activity on membranes in the literature. The following study aims to investigate the effects of F2B on different bacterial membrane models, including simple planar bilayers and more complex bilayer systems that mimic the Escherichia coli shell equipped with double inner and outer bilayers. Our results show that F2B exhibited more pronounced interactions with bacterial membrane systems compared to the control PC system. Furthermore, we observed significant changes in local membrane property homeostasis in both the inner and outer membrane models, specifically in the case of lateral diffusion, membrane thickness, and membrane resilience (compressibility, tilt). Finally, our results showed that the effect of F2B differed in a complex system and a single membrane system. Our study provides new insights into the multifaceted activity of F2B, demonstrating its potential to disrupt bacterial membrane homeostasis, indicating that its activity extends the currently known mechanism of FabI enzyme inhibition. This disruption, coupled with the ability of F2B to penetrate the outer membrane layers, sheds new light on the behavior of this antimicrobial molecule. This highlights the importance of the interaction with the membrane, crucial in combating bacterial infections, particularly those caused by drug-resistant strains.

Itaconic acid inhibits nontuberculous mycobacterial growth in pH dependent manner while 4-octyl-itaconic acid enhances THP-1 clearance of nontuberculous mycobacteria in vitro.

Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum identified lower levels of the host metabolite itaconate in those infected with NTM. Itaconate can inhibit the growth of M. tuberculosis (MTB) in vitro via the inhibition of the glyoxylate cycle enzyme (ICL), but its impact on NTM is unclear. To test itaconic acid's (IA) effect on NTM growth, laboratory and CF clinical strains of Mycobacterium abscessus and Mycobacterium avium were cultured in 7H9 minimal media supplemented with 1-10 mM of IA and short-chain fatty acids (SCFA). M. avium and M. abscessus grew when supplemented with SCFAs, whereas the addition of IA (≥ 10 mM) completely inhibited NTM growth. NTM supplemented with acetate or propionate and 5 mM IA displayed slower growth than NTM cultured with SCFA and ≤ 1 mM of IA. However, IA's inhibition of NTM was pH dependent; as similar and higher quantities (100 mM) of pH adjusted IA (pH 7) did not inhibit growth in vitro, while in an acidic minimal media (pH 6.1), 1 to 5 mM of non-pH adjusted IA inhibited growth. None of the examined isolates displayed the ability to utilize IA as a carbon source, and IA added to M. abscessus isocitrate lyase (ICL) decreased enzymatic activity. Lastly, the addition of cell-permeable 4-octyl itaconate (4-OI) to THP-1 cells enhanced NTM clearance, demonstrating a potential role for IA/itaconate in host defense against NTM infections.

Methane Production Reduced by Lignin Derivatives in Pulping Wastewater: Inhibition of Free Hydrolase

The lignin derivatives generated during pulping might be responsible for the suboptimal performance of anaerobic reactors during the treatment of pulping wastewater. However, the exact mechanisms by which these derivatives exert influence remain unclear. This study investigated the influence of lignin derivatives, simulated using humic acids (HAs), in anaerobic granular sludge (AnGS). Compared to the enzymes present during floc-bonding and granule-bonding, the HAs impeded the conversion of unhydrolyzed substrates into methane and caused considerable inactivation of free enzymes. Simultaneously, the HAs suppressed agglomeration and weakened the strength of the AnGS. Furthermore, calcium ions helped maintain the integrity of the sludge structure. Therefore, the inhibition of extracellular enzymes using lignin derivatives delays the methanation of unhydrolyzed substrates, resulting in a reduced biomass within AnGS reactors owing to sludge disintegration and biomass loss. This study serves as a reference for investigating the persistent risks originating from lignin derivatives associated with using anaerobic granular-sludge bed reactors to treat pulping wastewater.

Direct a-Hydroxy Acid Loading onto a Bacterial Thiotemplate Assembly Line via a Multienzyme Gateway.

Various nonribosomal peptide synthetases (NRPS) create structural and functional diversity by incorporating a-hydroxy acids into peptide backbones. Trigonic acid, an unusual cyclopropanol-substituted hydroxy acid, is the source of the molecular warhead of malleicyprol, a critical virulence factor of human and animal pathogens of the Burkholderia pseudomallei (BP) group. The process of selecting and loading this building block remained enigmatic as the NRPS module designated for this task is noncanonical. Using a combination of bioinformatics, mutational analyses, targeted metabolomics, and in vitro biochemical assays, we show that two trans-acting enzymes are required to load this central building block onto the modular assembly line. An adenylation-thiolation didomain enzyme (BurJ) activates trigonic acid, followed by the translocation of the enzyme-bound α-hydroxy acid thioester by an FkbH-like protein with a mutated phosphatase domain (BurH). This specialized gateway is the first reported direct loading of a hydroxy acid onto a bona fide NRPS module in bacteria and expands the synthetic biology toolbox for the site-specific incorporation of non-canonical building blocks. Moreover, insight into the biochemical basis of virulence factor biosynthesis can provide a foundation for developing enzyme inhibitors as anti-virulence therapeutics against BP pathogen infections.

Direct a‐Hydroxy Acid Loading onto a Bacterial Thiotemplate Assembly Line via a Multienzyme Gateway

Various nonribosomal peptide synthetases (NRPS) create structural and functional diversity by incorporating a‐hydroxy acids into peptide backbones. Trigonic acid, an unusual cyclopropanol‐substituted hydroxy acid, is the source of the molecular warhead of malleicyprol, a critical virulence factor of human and animal pathogens of the Burkholderia pseudomallei (BP) group. The process of selecting and loading this building block remained enigmatic as the NRPS module designated for this task is noncanonical. Using a combination of bioinformatics, mutational analyses, targeted metabolomics, and in vitro biochemical assays, we show that two trans‐acting enzymes are required to load this central building block onto the modular assembly line. An adenylation‐thiolation didomain enzyme (BurJ) activates trigonic acid, followed by the translocation of the enzyme‐bound α‐hydroxy acid thioester by an FkbH‐like protein with a mutated phosphatase domain (BurH). This specialized gateway is the first reported direct loading of a hydroxy acid onto a bona fide NRPS module in bacteria and expands the synthetic biology toolbox for the site‐specific incorporation of non‐canonical building blocks. Moreover, insight into the biochemical basis of virulence factor biosynthesis can provide a foundation for developing enzyme inhibitors as anti‐virulence therapeutics against BP pathogen infections.

Valorization of Wine Lees: Assessment of Antioxidant, Antimicrobial and Enzyme Inhibitory Activity of Wine Lees Extract and Incorporation in Chitosan Films

AbstractWine lees, as one of the main by-products of winery wastes, is considered a rich source of bioactive compounds such as polyphenols. Recovery of such bioactive compounds would amplify the valorization of winery by-products, as well as promote their use in cosmetics and health applications. Towards this aim, the objective of this work is the recovery of phenolic compounds from wine lees by ultrasound-assisted extraction. The effect of extraction time, and ethanol content on the extraction yield of total phenolics was investigated, while the phenolic profile of the extract was monitored by GC-MS. Under the optimized conditions, the total phenolic content was calculated at 302.6 mg gallic acid equivalents g− 1 dry extract; the dry extract was investigated for its biological activities, exhibiting excellent antioxidant and antimicrobial activity. Moreover, the extract was found to be a potent inhibitor of tyrosinase, elastase, collagenase, α-glucosidase, and α-amylase with IC50 values of 53.3, 83.5, 82.7, 19.0, and 31.3 µg mL− 1, respectively. Finally, the wine lees dry extract was incorporated into chitosan films, reinforcing the properties of the films, and providing them with excellent antioxidant activity. The results support that wine lees extract exhibits high antioxidant activity and can be used as a highly efficient inhibitor of enzymes with pharmaceutical and health interest. Moreover, the chitosan film enriched with wine lees extract is a promising material with high antioxidant potential and can lead to the development of novel food packaging films in the food industry. Graphical Abstract

Attention to STEMI patients in our region: what is the adherence to the quality indicators from a population perspective?

Abstract Funding Acknowledgements None. Introduction The use of quality indicators (QI) proposed by the Association for Acute Cardiovascular Care (ACVC) for processes carried out in cardiology services represents an excellent internal quality control of their operation. Purpose The aim is to assess adherence to the main QI in the care of acute ST-elevation myocardial infarction (STEMI) in our region, according to data from the population-based registry of myocardial infarction in that area. Methods Evaluation of adherence to the main QI proposed by the ESC Association for ACVC, by retrospective analysis (data from in-hospital and out-of-hospital care) of patients with STEMI from our regional Infarction Registry attended between 2017 and 2020, in both tertiary and secondary hospitals of the public and private care network, providing data with a population-based character. Results QI were analysed in 1355 patients categorised as STEMI in our regional Infarction Registry between 2017 and 2020. 71% of patients were male. The number of STEMI per year ranged from 358 in 2019 to 316 in 2020. Primary percutaneous coronary intervention (PCI) was performed in 87% of patients. In 53% the first medical contact occurs in out-of-hospital care, while 25% occur in emergency departments (ED) of PCI capable hospitals and 12% in emergency departments of non-PCI hospitals. Forty-two percent of patients firstly attended out-of-hospital or in non-PCI centres achieve revascularisation in less than 90 minutes, but less than 30% of patients seen in PCI centres achieve revascularisation in less than 60 minutes. Radial access was used in 92% of cases. LVEF was assessed during admission in 98% and LDL-cholesterol was determined in 87%. Ninety-one per cent of patients were discharged on dual antiplatelet therapy, 96% on statins and a large proportion of patients with left ventricular dysfunction received angiotensin-converting enzyme inhibitors (78%) and beta-blockers (88%). Conclusion There is good overall adherence to major QI related to care of patients with STEMI in our region. However, there are indicators that could be optimised, particularly those related to timely primary reperfusion. Networked care thanks to the local Infarction Code means a significant reduction in reperfusion times, avoiding unnecessary referrals to Emergency Departments.

Association between types of antihypertensive medication and the risk of atrial fibrillation: a nationwide population study

BackgroundPatients with hypertension are at a high risk of atrial fibrillation (AF). Recent research has indicated the varying effects of antihypertensive medications on developing AF.ObjectivesWe investigated the relationship between different types of antihypertensive medications and the risk of AF occurrence.MethodsWe analyzed data from 113,582 subjects with national health screening examinations between 2009 and 2014. The study population was categorized according to antihypertensive medication type. The primary outcome was the incidence of AF.ResultsAmong 113,582 subjects (mean age 59.4 ± 12.0 years, 46.7% men), 93,557 received monotherapy [angiotensin receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACEi), beta-blockers, calcium channel blockers (CCB), or diuretics], while 34,590 received combination therapy (ARB/beta-blockers, ARB/CCB, ARB/diuretics, or ARB/CCB/diuretics). During a mean follow-up duration of 7.6 ± 2.1 years, 3.9% of patients were newly diagnosed with AF. In monotherapy, ACEi and CCB had similar AF risks as ARB, while beta-blockers and diuretics showed higher AF risks than ARB. In combination therapy, ARBs/CCBs and ARBs/diuretics had the lowest AF risk, whereas ARBs/beta-blockers had the highest compared to ARB/CCB. Among the specific ARBs, the AF risk varied insignificantly, except for telmisartan and candesartan.ConclusionsIn hypertensive patients receiving monotherapy, ACEi and CCB showed a similar AF risk as ARBs, while beta-blockers and diuretics were associated with a higher risk. Among those receiving combination therapy, ARBs/CCBs and ARBs/diuretics had the lowest AF risk, whereas ARBs/beta-blockers showed the highest risk. Various types of ARBs have different associations with AF risk.

Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease

The long interspersed nuclear element-1 (LINE-1 or L1) retrotransposon is the only active autonomously replicating retrotransposon in the human genome. L1 harms the cell by inserting new copies, generating DNA damage, and triggering inflammation. Therefore, L1 inhibition could be used to treat many diseases associated with these processes. Previous research has focused on inhibition of the L1 reverse transcriptase due to the prevalence of well-characterized inhibitors of related viral enzymes. Here we present the L1 endonuclease as another target for reducing L1 activity. We characterize structurally diverse small molecule endonuclease inhibitors using computational, biochemical, and biophysical methods. We also show that these inhibitors reduce L1 retrotransposition, L1-induced DNA damage, and inflammation reinforced by L1 in senescent cells. These inhibitors could be used for further pharmacological development and as tools to better understand the life cycle of this element and its impact on disease processes.

Bioactivity Profiling of Daedaleopsis confragosa (Bolton) J. Schröt. 1888: Implications for Its Possible Application in Enhancing Women’s Reproductive Health

This study investigates the bioactivity profile of wood-rotting fungal species Daedaleopsis confragosa (Bolton) J. Schröt. 1888, focusing on its antioxidant, cytotoxic, and genotoxic activities and enzyme modulation properties with respect to its possible application in terms of enhancing women’s reproductive health. Two types of extracts, including those based on EtOH extraction (DC) and hydrodistillation (DCHD), were investigated. The results indicate that the radical scavenging capacity against the DPPH radical and reduction potential were stronger in the DC extracts owing to the higher total phenolic content (TPC) and total flavonoid content (TFC) (25.30 ± 1.05 mg GAE/g d.w. and 2.84 ± 0.85 mg QE/g d.w., respectively). The same trend was observed in the protein phosphatase-1 (PP1) activity and in the genotoxic activity against the δ virus since only the DC extract exhibited DNA disintegration regarding a dilution of 1:100. Conversely, the DCHD extract exhibited increased hemolytic and cytotoxic effects (339.39% and IC50 = 27.76 ± 0.89 μg/mL—72 h incubation, respectively), along with greater inhibition of the AChE enzyme (IC50 = 3.11 ± 0.45 mg/mL) and hemolytic activity. These results suggest that terpenoids and steroids may be responsible for the observed activity in DCHD as these compounds could potentially be extracted following the HD procedure. This comprehensive bioactivity profiling offers valuable insights into the potential therapeutic applications of D. confragosa from Serbia and underscores the importance of further investigations for harnessing its pharmacological potential.

Box–Behnken Design-Based Optimization of Phytochemical Extraction from Diplazium esculentum (Retz.) Sw. Associated with Its Antioxidant and Anti-Alzheimer’s Properties

A previous study reported that the ethanolic extract of the edible fern, Diplazium esculentum (Retz.) Sw. (DE), obtained from a non-optimized extraction condition exhibited anti-Alzheimer’s disease (AD) properties through the inhibition of a rate-limiting enzyme in amyloid peptide formation, β-secretase-1 (BACE-1). Nevertheless, a non-optimized or suboptimal extraction may lead to several issues, such as a reduction in extraction efficiency and increased time and plant materials. In this study, extraction of the DE was optimized to obtain appropriate BACE-1 inhibition using a Box–Behnken design (BBD) and response surface methodology (RSM). Data revealed that the optimal extraction condition was 70% (v/v) aqueous ethanol, 50 min extraction time, 30 °C extraction temperature, and 1:30 g/mL solid/liquid ratio, giving BACE-1 inhibition at 56.33%. In addition, the extract also exhibited significant antioxidant activities compared to the non-optimized extraction. Metabolomic phytochemical profiles and targeted phytochemical analyses showed that kaempferol, quercetin, and their derivatives as well as rosmarinic acid were abundant in the extract. The optimized DE extract also acted synergistically with donepezil, an AD drug suppressing BACE-1 activities. Data received from Drosophila-expressing human amyloid precursor proteins (APPs) and BACE-1, representing the amyloid hypothesis, showed that the optimized DE extract penetrated the fly brains, suppressed BACE-1 activities, and improved locomotor functions. The extract quenched the expression of glutathione S transferase D1 (GSTD1), inositol-requiring enzyme (IRE-1), and molecular chaperone-binding immunoglobulin (Bip), while donepezil suppressed these genes and other genes involved in antioxidant and endoplasmic reticulum (ER) stress response, including superoxide dismutase type 1 (SOD1), activating transcription factor 6 (ATF-6), and protein kinase R-like endoplasmic reticulum kinase (PERK). To sum up, the optimized extraction condition reduced extraction time while resulting in higher phytochemicals, antioxidants, and BACE-1 inhibitors.

Angiotensin-(1-12): Does It Exist? A Critical Evaluation in Humans, Rats, and Mice.

Angiotensin-(1-12), measured by a self-developed, polyclonal antibody-based radioimmunoassay, has been suggested to act as an alternative precursor of angiotensin II. A more reliable detection method would be liquid chromatography-tandem mass spectrometry. We set up the quantification of human and murine angiotensin-(1-12) by liquid chromatography-tandem mass spectrometry and then used this method to measure angiotensin-(1-12) in human and mouse blood samples, as well as in mouse brain and kidney. We also verified ex vivo angiotensin-(1-12) generation and metabolism in human blood samples incubated at 37 °C. Stabilization of blood in guanidine hydrochloride was chosen for sample collection since this allowed full recovery of spiked angiotensin-(1-12). Angiotensin-(1-12) was undetectable in human blood samples when incubating nonstabilized plasma at 37 °C, while angiotensin-(1-12) added to nonstabilized human plasma disappeared within 10 minutes. Stabilized human blood samples contained angiotensin II, while angiotensin-(1-12) was undetectable. Blood, hearts, and kidneys, but not brains, of wild-type mice and rats contained detectable levels of angiotensin II, while angiotensin-(1-12) was undetectable. In renin knockout mice, all angiotensins, including angiotensin-(1-12), were undetectable at all sites, despite a 50% rise in angiotensinogen. Angiotensin-(1-12) metabolism in human blood plasma was not affected by renin inhibition. Yet, blockade of angiotensin-converting enzyme and aminopeptidase A, but not of chymase, neutral endopeptidase, or prolyl oligopeptidase, prolonged the half-life of angiotensin-(1-12), and angiotensin-converting enzyme inhibition prevented the formation of angiotensin II. We were unable to detect intact angiotensin-(1-12) in humans or mice, either in blood or tissue, suggesting that this metabolite is an unlikely source of endogenous angiotensins.

A multidimensional study for design functional foods: Chemical profiling, antioxidant potential, enzyme inhibition, and cytotoxic effects of Alkanna tubulosa extracts

This study focuses on the extraction of plant species Alkanna tubulosa growing in Turkey, using solvents of different polarities (ethyl acetate, ethanol, ethanol/water, and water) and determining their chemical composition and biological activity. The extracts were subjected to qualitative LC-MS/MS analyses, which resulted in the identification of even 50 different secondary metabolites in some extracts. The existence of total phenols and flavonoids was determined. of total phenols and flavonoids was determined. The antioxidant capacity was evaluated by various in vitro assays, as well as the enzyme inhibitory capacity against cholinesterases (AChE and BChE), tyrosinase, α-amylase, and α-glucosidase, as well as human isoforms of carbonic anhydrase. In addition, the cytotoxic activity of the extracts was also examined. The results showed that the ethanol/water extract showed the strongest antioxidant activity (225.55 mg TE/g extract in ABTS and 381.14 mg TE/g extract in CUPRAC), probably due to the high total phenol (105.17 mg GAE/g extract) and flavonoids (20.12 mg RE/g extract) content, while the ethanol extract showed the strongest enzyme inhibitory potential. These chemical and biological findings provide valuable insights for potential future products based on the A. tubulosa extracts which could be used in various industries.

Discovery of selective TYK2 inhibitors: Design, synthesis, in vitro and in silico studies of promising hits with triazolopyrimidinone scaffold

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway mediates many cytokine and growth factor signals. Tyrosine kinase 2 (TYK2), one of the members of this pathway and the first described member of the JAK family. TYK2 associates with inflammatory and autoimmune diseases, cancer and diabetes. Here, we present novel compounds as selective inhibitors of the canonical kinase domain of TYK2 enzyme. These compounds were rationally designed and synthesized with appropriate reactions. Molecular modeling techniques were used to design and optimize the candidates for TYK2 inhibition and to determine the estimated binding orientations of them inside JAKs. Designed compounds potently inhibited TYK2 with good selectivity against other JAKs as determined by in vitro assays. In order to verify its selectivity properties, compound A8 was tested against 58 human kinases (KinaseProfiler™ assay). The effects of the selected seven compounds on the protein levels of members of the JAK/STAT family were also detected in THP-1 monocytes although the basal level of these proteins is poorly detectable. Therefore, their expression was induced by lipopolysaccharide treatment and compounds A8, A15, A18, and A19 were found to be potent inhibitors of the TYK2 enzyme, (9.7 nM, 6.0 nM, 5.0 nM and 10.3 nM, respectively), and have high selectivity index for the JAK1, JAK2, and JAK3 enzymes. These findings suggest that triazolo[1,5-a]pyrimidinone derivatives may be lead compounds for developing potent TYK2-selective inhibitors targeting enzymes’ active site.

Functional Model Beverages of Saffron Floral By-Products: Polyphenolic Composition, Inhibition of Digestive Enzymes, and Rheological Characterization

Despite the rapid and dynamic evolution of research into dietary polyphenols, there is still a knowledge gap regarding their bioaccessibility since it could be influenced by the chemical and nutritional compositions of the food matrix. This study aimed to describe the impact of food thickeners (xanthan gum, guar gum, β-glucan, pectin) on the bioactivity of flavonoids from saffron floral by-products in model beverages before and after thermal processing. The different beverage formulas were characterized in terms of polyphenolic composition using HPLC-DAD-ESI-MSn and rheological properties. The impact of food thickeners and thermal processing on the inhibition of digestive enzymes was also determined. The model beverages mainly presented glycosylated flavonols (of kaempferol, quercetin, and isorhamnetin), with a reduced content in some heat-treated samples. The inhibitory effect on α-amylase was only detected in heat-treated beverages, showing the formulation without any thickener to have the greatest inhibitory effect. Finally, the presence of saffron floral by-products in the beverages showed a tendency to decrease the flow consistency index (K) and an increase in the flow behavior index (n), most probably driven by the aggregation of phenolics with thickeners. Therefore, this research provides new insights into the development of flavonoid-rich beverages in order to ensure that they exert the expected beneficial effects after their ingestion.

Exploring enzyme inhibition and comprehensive mechanisms of antioxidant/prooxidative activity of natural furanocoumarin derivatives: A comparative kinetic DFT study

This study aimed to explore the antioxidant and prooxidative activity of two natural furanocoumarin derivatives, Bergaptol (4-Hydroxy-7H-furo [3,2-g] [1]benzopyran-7-one, BER) and Xanthotoxol (9-Hydroxy-7H-furo [3,2-g] [1]benzopyran-7-one, XAN). The collected thermodynamic and kinetic data demonstrate that both compounds possess substantial antiradical activity against HO• and CCl3OO• radicals in physiological conditions. BER exhibited better antiradical activity in comparison to XAN, which can be attributed to the enhanced deprotonation caused by the positioning of the –OH group on the psoralen ring. In contrast to highly reactive radical species, newly formed radical species BER• and XAN• exhibited negligible reactivity towards the chosen constitutive elements of macromolecules (fatty acids, amino acids, nucleobases). Furthermore, in the presence of O2•─, the ability to regenerate newly formed radicals BER• and XAN• was observed. Conversely, in physiological conditions in the presence of Cu(II) ions, both compounds exhibit prooxidative activity. Nevertheless, the prooxidative activity of both compounds is less prominent than their antioxidant activity. Furthermore, it has been demonstrated that anionic species can engage in the creation of a chelate complex, which restricts the reduction of metal ions when reducing agents are present (O2•─ and Asc─). Moreover, studies have demonstrated that these chelating complexes can be coupled with other radical species, hence enhancing their ability to inactivate radicals. Both compounds exhibited substantial inhibitory effects against enzymes involved in the direct or indirect generation of ROS: Xanthine Oxidase (XOD), Lipoxygenase (LOX), Myeloperoxidase (MPO), NADPH oxidase (NOX).

Chemical Constituents and Bioactivities of Nepeta Taxa Essential Oils from Turkey: Principal Component Analysis, Molecular Docking Study, Molecular Dynamics, MM‐PBSA and Drug‐Likeness Estimation

AbstractNepeta taxa are popular plants and sources of traditional Turkish medicine. Chemical constituents in the essential oils (EOs) hydrodistilled from above‐ground parts of Nepeta aristata (NA), N. baytopii (NB), N. italica (NI), N. nuda (NN), and N. stenantha (NS) were determined using GC‐MS. The pharmacological activities of EOs, such as biological activities, were evaluated in vitro. DNA protection activities of NS‐EO were found to be the most effective. The NA‐EO, NI‐EO, and NS‐EO were more potent urease inhibitors, while the NS‐EO exhibited potent AChE inhibitors. Their molecular docking, molecular dynamics and enzyme inhibition results were compatible with the major components. Furthermore, MolDock and binding affinity results were found to be high. Moreover, AChE‐tau‐cadinol, BChE‐tau‐cadinol and tyrosinase‐Caryophyllene oxide complexes showed stability when simulated for 100 ns, with high MM‐PBSA energy values. In addition, the main components′ pharmacokinetic properties were observed to be effective. The present study showed that EOs may be valuable natural products for future pharmacological research, food, and the cosmetic industry according to in vitro and in silico values.