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Kombucha is a fermented tea drink using a symbiotic culture of bacteria and yeast. This drink has been widely used to maintain blood sugar levels. Meanwhile, leaf boiled water of Syzygium polyanthum (Wight) Walp. has been used as an alternative medicine for diabetes mellitus in Indonesia. If this herb is made into kombucha, it may have higher antihyperglycemic activity than kombucha from tea leaves. However, there are no scientific reports of antihyperglycemic activity from S. polyanthum leaf kombucha by inhibiting alpha-glucosidase. This study aims to determine the activity and kinetics inhibition of S. polyanthum leaves kombucha against α-glucosidase. Samples were prepared at varying concentrations (12.5, 25, 37.5, 50 g/L), while phytochemical components in the products were identified, and the inhibitory activity as well as kinetics were comprehensively analyzed. In silico evaluations were conducted to further explore the inhibitory activity. The results showed that the products contained secondary metabolites such as flavonoids, saponins, and tannins. The inhibitory activity against α-glucosidase ranged from 81.05 to 89.41%. The inhibition mechanism was identified as uncompetitive, with a Michaelis-Menten constant (KM) of 0.1357 mM and a vmax value of 27.7008 U/ml minute. Several metabolites showed promising inhibition potential due to their strong binding interactions with α-glucosidase, including hydrogen bonding (H-bond), hydrophobic interactions, van der Waals forces, and electrostatic forces. Additionally, two metabolites, farnesol and α-pinene, were found to interact with other human proteins. These observations showed the potential of S. polyanthum leaves kombucha as a health-promoting beverage that might aid blood sugar control in diabetic individuals. [ABSTRACT FROM AUTHOR]

This article explores the development of glycosyltransferase inhibitors, specifically focusing on FUT8 inhibitors. FUT8 is an enzyme that plays a crucial role in various biological processes. The researchers used diversity-oriented synthesis (DOS) to create compound libraries of FUT8 inhibitors. Through late-stage functionalization and the combination of glycosyl donor and acceptor mimics, they successfully developed a FUT8 inhibitor. The study also discusses the modification of guanine derivatives and the creation of bi-substrate mimics, which are expected to exhibit exceptional selectivity among FUTs. Overall, this article presents an efficient methodology for optimizing the structure of middle molecules. [Extracted from the article]

Introduction: Intestinal colitis, also known as ulcerative colitis, is an inflammatory bowel disease characterized by long-term inflammation and ulcers in the gastrointestinal tract. It has been suggested that the mucosal expression of angiotensin II (AT-II) is increased in colitis. This study aimed to examine the potential therapeutic effects of combination therapy with Enalapril, an angiotensin-converting enzyme inhibitor, and sulfasalazine (SSZ) in a murine colitis model. Methods: Male C57BL/6 mice were divided into five groups: control group (distilled water), dextran sulphate sodium (DSS) group (colitis group) (1% DSS), SSZ group (positive control group) with 100 mg/kg/day, Enalapril alone group with 4 mg/kg/day, and Enalapril (4 mg/kg/day) + SSZ (100 mg/kg/day) group. Results: There was a significant reduction in the disease activity index among the mice receiving the combination of Enalapril and SSZ compared to the colitis group. Enalapril and SSZ treatment was associated with a lower reduction in colon length, decreased colon weight, spleen weight, and spleen-to-body weight in mice with colitis. Following DSS administration, Enalapril and SSZ also significantly decreased MDA levels, an oxidant marker, and increased total thiol, SOD, and CAT levels, as antioxidants. Additionally, mucosal damage, crypt loss, pathological changes, and inflammation scores decreased after treatment with Enalapril and SSZ in comparison with the colitis group. The combination of Enalapril and SSZ reduced colon collagen content and caused a decrease in fibrosis compared to the colitis group. Conclusion: The results of this study indicated that Enalapril alone and in combination with SSZ decreased inflammation and clinical symptoms of colitis induced by DSS. [ABSTRACT FROM AUTHOR]

Methanolic stem bark extracts from ten Mexican Bursera Jacq. ex L. species were evaluated in vitro with regard to their inhibitory activity against two Tenebrio molitor-derived enzymes. Seven extracts (B. bicolor, B. copallifera, B. fagaroides, B. grandifolia, B. lancifolia, B. linanoe, and B. longipes) reduced α-amylase activity by 55.37% to 96.25%, with three samples proving to be particularly potent α-amylase inhibitors (B. grandifolia, B. lancifolia, and B. linanoe; IC50 = 162, 132, and 186 µg/mL, respectively). In contrast, no extract inhibited acetylcholinesterase activity by more than 39.94%. Quantitative HPLC analysis did not reveal any clear correlation between the species-specific flavonoid or phenolic acid profiles and the respective extracts' enzyme inhibitory activity. The findings reported herein do not only contribute to improving the current state of knowledge regarding the enzyme inhibitory potential of the Bursera genus, but could also lead to the development of new sustainable bioinsecticides. [ABSTRACT FROM AUTHOR]

Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected Tropical Diseases affecting millions of people worldwide, mainly in vulnerable territories of tropical and subtropical areas. In general, current treatments against these diseases are old-fashioned, showing adverse effects and loss of efficacy due to misuse or overuse, thus leading to the emergence of resistance. For these reasons, searching for new antitrypanosomatid drugs has become an urgent necessity, and different metabolic pathways have been studied as potential drug targets against these parasites. Considering that trypanosomatids possess a unique redox pathway based on the trypanothione molecule absent in the mammalian host, the key enzymes involved in trypanothione metabolism, trypanothione reductase and trypanothione synthetase, have been studied in detail as druggable targets. In this review, we summarize some of the recent findings on the molecules inhibiting these two essential enzymes for Trypanosoma and Leishmania viability. [ABSTRACT FROM AUTHOR]

The shikimate pathway is crucial for the biosynthesis of aromatic amino acids in plants and represents a promising target for developing new herbicides. This work aimed to identify inhibitors of shikimate dehydrogenase (SDH), a key enzyme of the shikimate pathway that catalyzes the conversion of 3-dehydroshikimate to shikimate. Virtual screening and molecular dynamic simulations were performed on the SDH active site of Arabidopsis thaliana (AtSDH), and 6-nitroquinazoline-2,4-diol (NQD) was identified as a potential inhibitor. In vitro assays showed that NQD decreased the activity of AtSDH by reducing Vmax while keeping KM unchanged, indicating non-competitive inhibition. In vivo, hydroponic experiments revealed that NQD reduced the root length of soybean and maize. Additionally, NQD increased the total protein content and certain amino acids. Soybean roots uptake NQD more efficiently than maize roots. Furthermore, NQD reduced shikimate accumulation in glyphosate-treated soybean roots, suggesting its potential to restrict the flow of metabolites along the shikimate pathway in soybean. The simultaneous treatment of maize seedlings with glyphosate and NQD accumulated gallic acid in the roots, indicating that NQD inhibits SDH in vivo. Overall, the data indicate that NQD inhibits SDH both in vitro and in vivo, providing valuable insights into the potential development of herbicides targeting SDH. [ABSTRACT FROM AUTHOR]

IF1, an inhibitor protein of mitochondrial ATP synthase, suppresses ATP hydrolytic activity of F1. One of the unique features of IF1 is the selective inhibition in mitochondrial F1 (MF1); it inhibits catalysis of MF1 but does not affect F1 with bacterial origin despite high sequence homology between MF1 and bacterial F1. Here, we aimed to engineer thermophilic Bacillus F1 (TF1) to confer the susceptibility to IF1 for elucidating the molecular mechanism of selective inhibition of IF1. We first examined the IF1‐susceptibility of hybrid F1s, composed of each subunit originating from bovine MF1 (bMF1) or TF1. It was clearly shown that only the hybrid with the β subunit of mitochondrial origin has the IF1‐susceptibility. Based on structural analysis and sequence alignment of bMF1 and TF1, the five non‐conserved residues on the C‐terminus of the β subunit were identified as the candidate responsible for the IF1‐susceptibility. These residues in TF1 were substituted with the bMF1 residues. The resultant mutant TF1 showed evident IF1‐susceptibility. Reversely, we examined the bMF1 mutant with TF1 residues at the corresponding sites, which showed significant suppression of IF1‐susceptibility, confirming the critical role of these residues. We also tested additional three substitutions with bMF1 residues in α and γ subunits that further enhanced the IF1‐susceptibility, suggesting the additive role of these residues. We discuss the molecular mechanism by which IF1 specifically recognizes F1 with mitochondrial origin, based on the present result and the structure of F1‐IF1 complex. These findings would help the development of the inhibitors targeting bacterial F1. [ABSTRACT FROM AUTHOR]

While cytochrome P450 (CYP; P450) enzymes are commonly associated with the metabolism of organic xenobiotics and drugs or the biosynthesis of organic signaling molecules, they are also impacted by a variety of inorganic species. Metallic nanoparticles, clusters, ions, and complexes can alter CYP expression, modify enzyme interactions with reductase partners, and serve as direct inhibitors. This commonly overlooked topic is reviewed here, with an emphasis on understanding the structural and physiochemical basis for these interactions. Intriguingly, while both organometallic and coordination compounds can act as potent CYP inhibitors, there is little evidence for the metabolism of inorganic compounds by CYPs, suggesting a potential alternative approach to evading issues associated with rapid modification and elimination of medically useful compounds. [ABSTRACT FROM AUTHOR]

Inhibition of insulin-regulated aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign of approximately 10,000 compounds, identifying novel small-molecule-based compounds acting as inhibitors of the enzymatic activity of IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of 48 imidazo [1,5-α]pyridine-based inhibitors, including delineation of their mode of action as non-competitive inhibitors with a small L-leucine-based IRAP substrate. The best compound displays an IC50 value of 1.0 µM. We elucidate the importance of two chiral sites in these molecules and find they have little impact on the compound's metabolic stability or physicochemical properties. The carbonyl group of a central urea moiety was initially believed to mimic substrate binding to a catalytically important Zn2+ ion in the active site, although the plausibility of this binding hypothesis is challenged by observation of excellent selectivity versus the closely related aminopeptidase N (APN). Taken together with the non-competitive inhibition pattern, we also consider an alternative model of allosteric binding. [ABSTRACT FROM AUTHOR]

Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified several inhibitors with micromolar inhibitory potency. Molecular docking suggests binding of the deprotonated hydrate of the strained cyclobutanone, and thermal shift analysis with the most potent inhibitor (3y, IC50 = 23.1 µM) enabled determination of a Ki value of 10.2 +/− 0.26 µM and observed two separate Tm values for H. influenzae DapE (HiDapE). [ABSTRACT FROM AUTHOR]

Unrestricted use of chemical insecticides, especially at high concentrations, has reduced their efficacy. Plant-based pesticides, due to their relatively high safety levels to humans and environment as well as effective control on insects, have become a suitable alternative to conventional pesticides. The aim of this study was to investigate the biological and physiological effects of the formulated essential oil of Trachyspermum ammi (L.) on the larvae of Helicoverpa armigera Hüb. The obtained essential oil was formulated into an emulsion using Tween 20 as emulsifier. Chemical analysis of the extracted essential oil indicated that Terpinen (14.4%), Cymene (18.5%), and Thymol (61.6%) were the major compounds. The essential oil of T. ammi have a significant repellency rate on third and sixth instar larvae of cotton bollworm at different observed time intervals, with an average repellency rate of 61-76%. Regarding fumigant toxicity, the highest concentration of the essential oil (500 µL/L) resulted in 100% larval mortality. The LC50 value for fumigant toxicity measured as 82.73 µL/L. The duration of larval development significantly increased in treatments compared to control. In EO concentrations of 2.5-1.25 percent an increase was observed respectively in the duration of the larval stage by 9 and 7 days. The pupae and adult’s emergence affected in dose dependent manner. At concentration of 50 µl/l, 89% inhibition of protease enzyme recorded. With regards to the biological and physiological effects observed in the formulated T. ammi essential oil, with complimentary researches, it could be used in integrated management programs of cotton bollworm. [ABSTRACT FROM AUTHOR]

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Aminopeptidase N/CD13, a membrane-bound enzyme upregulated in tumor vasculature and involved in angiogenesis, can be used as a receptor for the targeted delivery of drugs to tumors through ligand-directed targeting approaches. We describe a novel peptide ligand (VGCARRYCS, called “G4”) that recognizes CD13 with high affinity and selectivity. Enzymological and computational studies showed that G4 is a competitive inhibitor that binds to the catalytic pocket of CD13 through its N-terminal region. Fusing the peptide C-terminus to tumor necrosis factor-alpha (TNF) or coupling it to a biotin/avidin complex causes loss of binding and inhibitory activity against different forms of CD13, including natural or recombinant ectoenzyme and a membrane form expressed by HL60 promyelocytic leukemia cells (likely due to steric hindrance), but not binding to a membrane form of CD13 expressed by endothelial cells (ECs). Furthermore, G4-TNF systemically administered to tumor-bearing mice exerted anticancer effects through a CD13-targeting mechanism, indicating the presence of a CD13 form in tumor vessels with an accessible binding site. Biochemical studies showed that most CD13 molecules expressed on the surface of ECs are catalytically inactive. Other functional assays showed that these molecules can promote endothelial cell adhesion to plates coated with G4-avidin complexes, suggesting that the endothelial form of CD13 can exert catalytically independent biological functions. In conclusion, ECs express a catalytically inactive form of CD13 characterized by an accessible conformation that can be selectively targeted by G4-protein conjugates. This form of CD13 may represent a specific target receptor for ligand-directed targeted delivery of therapeutics to tumors. [ABSTRACT FROM AUTHOR]

Boronic acids/esters have recently emerged in the field of medicinal and pharmaceutical research due to their exceptional oxophilicity, low toxicity, and unique structure. They are known as potent enzyme inhibitors, cancer therapy capture agents, and can mimic certain types of antibodies to fight infections. They have been designed and developed into drugs, and this approach has emerged in the last 20 years. Five boronic acid drugs have been approved by the FDA and Health Canada, two of which are used to treat cancer, specifically multiple myeloma. The purpose of this review is to investigate boronic acid/ester derivatives as potential pharmaceutical agents as well as the mechanism of action. It will concentrate on six types of cancer: multiple myeloma, prostate cancer, breast cancer, lung cancer, cervical cancer, and colon cancer. Some newly developed boron-containing compounds have already demonstrated highly promising activities, but further investigation is required before final conclusions can be drawn. [ABSTRACT FROM AUTHOR]

Thirteen novel compounds in a series of dihydrobenzo[h]quinazolin-2-yl thiourea compounds (7a–m) were synthesized and characterized using FT-IR, 1H, 13C NMR spectroscopy, and elemental analysis. Some inhibition parameters including IC50 and inhibition constant values (Ki) were determined for all the compounds. All studied compounds exhibited potent inhibition against carbonic anhydrases (CAs). They inhibited CAs with the IC50 values of 30.45 to 94.00 μM (Ki: 28.27–61.01 μM) for hCA I and 21.80 to 78.00 μM (Ki: 17.84–57.96 μM) for hCA II. The most active compounds were found to be compound 7m for hCA I (Ki: 28.27 μM) and compound 7d for hCA II (Ki : 17.84 μM). The absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) study revealed that all the derivatives had good oral bioavailability with respect to Lipinski's rule of five and Jorgensen's rule of three. All derivatives in the series can be considered as outstanding multitarget inhibitors for further investigations. [ABSTRACT FROM AUTHOR]

Background: Salivary glands from blood-feeding arthropods secrete several molecules that inhibit mammalian hemostasis and facilitate blood feeding and pathogen transmission. The salivary functions from Simulium guianense, the main vector of Onchocerciasis in South America, remain largely understudied. Here, we have characterized a salivary protease inhibitor (Guianensin) from the blackfly Simulium guianense. Materials and methods: A combination of bioinformatic and biophysical analyses, recombinant protein production, in vitro and in vivo experiments were utilized to characterize the molecula mechanism of action of Guianensin. Kinetics of Guianensin interaction with proteases involved in vertebrate inflammation and coagulation were carried out by surface plasmon resonance and isothermal titration calorimetry. Plasma recalcification and coagulometry and tail bleeding assays were performed to understand the role of Guianensin in coagulation. Results: Guianensin was identified in the sialotranscriptome of adult S. guianense flies and belongs to the Kunitz domain of protease inhibitors. It targets various serine proteases involved in hemostasis and inflammation. Binding to these enzymes is highly specific to the catalytic site and is not detectable for their zymogens, the catalytic site-blocked human coagulation factor Xa (FXa), or thrombin. Accordingly, Guianensin significantly increased both PT (Prothrombin time) and aPTT (Activated partial thromboplastin time) in human plasma and consequently increased blood clotting time ex vivo. Guianensin also inhibited prothrombinase activity on endothelial cells. We show that Guianensin acts as a potent anti-inflammatory molecule on FXa-induced paw edema formation in mice. Conclusion: The information generated by this work highlights the biological functionality of Guianensin as an antithrombotic and anti-inflammatory protein that may play significant roles in blood feeding and pathogen transmission. [ABSTRACT FROM AUTHOR]

The effect of pH on microbial, enzyme inactivation, and bioactive retention in ultrasound (US) treated sweet lime (Citrus limetta) juice was studied. The pH of the juice varied at 3.5, 4.0, and 4.5, whereas the US duty cycle (DC) ranged between 75% and 95% (0.07–0.7 W/cm3), and the treatment time varied between 15 and 30 min. More than 5‐log reduction in Saccharomyces cerevisiae and Escherichia coli was achieved at DC 95% (25 min) while Listeria monocytogenes got inactivated at DC 85% (25 min). 95%–99% inactivation of peroxidase and pectin methylesterase was achieved at DC 95% (30 min), while 60% inactivation in polyphenol oxidase (PPO) was observed. The addition of ascorbic acid (1 g/L) as an EI resulted in the complete inactivation of PPO at DC 85% (25 min). A maximum color change (ΔE*) of 2.6 was noticed at the highest US treatment condition (DC 95%, 30 min). Eventually, pH showed a marginal effect (˂5%) on retaining vitamin C and bioactive compounds, but US treatment enhanced them. US treatment at DC 95% (30 min) produced microbially safe (˃5‐log cycle reduction) and enzymatically stable (99% enzyme inactivation) juice. To conclude, optimized US treatment increased total phenolic content (TPC), antioxidant capacity, and vitamin C in sweet lime juice by 16.7%, 10.7%, and 14.1%, respectively. Practical applications: Consumer demand for superior quality sweet lime juice with minimal processing. This explores the opportunity of applying US technology as one of the nonthermal treatments for such a product. Furthermore, the treated juice should be microbially safe and enzymatically stable with better bioactive preservation. Typically, the pH of the fruit juice is one of the main influencing factors controlling microbiological spoilage. The current study explores the consequence of matrix pH and US conditions on the microbial inactivation, enzyme stability, and bioactive compounds of US‐treated sweet lime juice. The hypothesis is that the ultrasonic power required to achieve microbial safety at a lower pH of sweet lime juice should be lower. This will eventually help the industry choose an optimal harvesting condition to obtain the desired pH during processing. [ABSTRACT FROM AUTHOR]

Polygoni Cuspidati Rhizoma et Radix (PCR), the rhizome and root of Polygonum cuspidatum Sieb. et Zucc., has been used as an herbal medicine for a long time. In this study, the ultrafiltration combined with high performance liquid chromatography (UF-HPLC) method was developed to screen tyrosinase (TYR), α-glucosidase (α-GLU), and xanthine oxidase (XOD) inhibitors from PCR. Firstly, the inhibitory activity of 50% methanol PCR extract on TYR, α-GLU, XOD, and acetylcholinesterase (ACHE) was tested. The extract showed a good inhibition on the enzymes, except for ACHE. Therefore, UF-HPLC experiments were carried out to screen TYR, α-GLU, and XOD inhibitors from PCR extract. Seven potential bioactive components were discovered, including methylgallate (1), 1,6-di-O-galloyl-D-glucose (2), polydatin-4′-O-D-glucoside (3), resveratrol-4′-O-D-glucoside (4), polydatin (5), malonyl glucoside resveratrol (6), and resveratrol-5-O-D-glucoside (7). Most of them were found as enzyme inhibitors from PCR for the first time, except polydatin (5), which had been reported as an α-GLUI in PCR in the literature. Finally, molecular docking analysis was applied to validate the interactions of these seven potential active components with the enzymes. Compounds 1–7 were proven as TYR inhibitors, compounds 2, 4–7 were identified as XOD inhibitors, and compounds 4–6 were confirmed as α-GLU inhibitors. In short, the current study provides a good reference for the screening of enzyme inhibitors through UF-HPLC, and provides scientific data for future studies of PCR. [ABSTRACT FROM AUTHOR]

BACKGROUND: Euryale ferox is an important cash crop and valuable tonic in traditional medicine. The seeds of E. ferox are rich in starch, which is hard to digest, and the digestion speed is significantly slower than that of rice starch. The goal of this study was to evaluate the effects of E. ferox seed‐coat phenolics (EFCPs) on the digestion of E. ferox seed starch. RESULTS: EFCPs were extracted and identified by ultra‐high performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry. We optimized the extraction parameters, and the final extraction yield was about 1.49%. We identified seven phenolics from the E. ferox seed‐coat extracts: gallic acid, digalloylhexoside, catechin, procyanidin B2, epicatechin, ellagic acid, and epicatechin gallate. Quantitative analysis results showed that the E. ferox seed phenolics mainly distributed in the seed coat and the gallic acid, digalloylhexoside, and epicatechin gallate were three main phenolic compounds. The phenolics displayed strong inhibitory activities on α‐glucosidase and α‐amylase with an IC50 of 3.25 μg mL−1 and 1.36 mg mL−1 respectively. Furthermore, these phenolics could interact with starch by hydrogen bonds, which might make its starch more difficult to digest. CONCLUSION: Our investigation suggests that the EFCPs can strongly inhibit the digestion of E. ferox seed starch by inhibiting the α‐amylase and α‐glucosidase activities and interacting with starch by hydrogen bonds; therefore, E. ferox seeds have a promising application prospect in foods for hypoglycemia. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The reuse of food by-products is crucial for the well-being of the planet. Considering the high content of nutrients and other bioactive compounds in many of them, investigating their suitability for use as human food ingredients is an interesting challenge. In this study, in addition to the proximate composition, phenol content and antioxidant activity (AOA = 3.2 mmol Trolox equivalent (TE)/100 g, db) of orange juice powder by-product (CoP), different in vitro properties related to carbohydrate metabolism have been characterised. Specifically, the glycaemic index (GI), the glycaemic load (GL), the glucose dialysis retardation index (GDRI = 13.6%), the glucose adsorption capacity (GAC = 22.5 mM) and the inhibition capacity of α-amylase (α-A = 46.9%) and α-glucosidase (α-G = 93.3%) of powdered orange juice waste have been determined and related to fibre and phenolics composition. Taking advantage of the high fibre content of the by-product (36.67%), its GL was calculated for a CoP dose that allows labelling the food to which it is added as a source of fibre. The low GI value (24.4%) and the low GL (0.918 g available carbohydrates per serving) allowed us to conclude that the product studied could be an interesting opportunity for the food industry to offer it as a healthy food ingredient to be included in the diet, especially for those suffering from type 2 diabetes mellitus. Of the total phenolic compounds (TP = 509 mg equivalent of gallic acid (GAE)/100 g, db), 68% were found in free fraction (FP), and their contribution to the total AOA was 40.6%, while this was 54.9% for the 32% of phenols bound to plant tissues (BP). [ABSTRACT FROM AUTHOR]

The landscape of viral strains and lineages of SARS-CoV-2 keeps changing and is currently dominated by Delta and Omicron variants. Members of the latest Omicron variants, including BA.1, are showing a high level of immune evasion, and Omicron has become a prominent variant circulating globally. In our search for versatile medicinal chemistry scaffolds, we prepared a library of substituted ɑ-aminocyclobutanones from an ɑ-aminocyclobutanone synthon (11). We performed an in silico screen of this actual chemical library as well as other virtual 2-aminocyclobutanone analogs against seven SARS-CoV-2 nonstructural proteins to identify potential drug leads against SARS-CoV-2, and more broadly against coronavirus antiviral targets. Several of these analogs were initially identified as in silico hits against SARS-CoV-2 nonstructural protein 13 (Nsp13) helicase through molecular docking and dynamics simulations. Antiviral activity of the original hits as well as ɑ-aminocyclobutanone analogs that were predicted to bind more tightly to SARS-CoV-2 Nsp13 helicase are reported. We now report cyclobutanone derivatives that exhibit anti-SARS-CoV-2 activity. Furthermore, the Nsp13 helicase enzyme has been the target of relatively few target-based drug discovery efforts, in part due to a very late release of a high-resolution structure accompanied by a limited understanding of its protein biochemistry. In general, antiviral agents initially efficacious against wild-type SARS-CoV-2 strains have lower activities against variants due to heavy viral loads and greater turnover rates, but the inhibitors we are reporting have higher activities against the later variants than the wild-type (10–20X). We speculate this could be due to Nsp13 helicase being a critical bottleneck in faster replication rates of the new variants, so targeting this enzyme affects these variants to an even greater extent. This work calls attention to cyclobutanones as a useful medicinal chemistry scaffold, and the need for additional focus on the discovery of Nsp13 helicase inhibitors to combat the aggressive and immune-evading variants of concern (VOCs). [ABSTRACT FROM AUTHOR]

Planar chromatography has recently been combined with six different effect-directed assays for three golden root (Rhodiola rosea L.) samples. However, the profiles obtained showed an intense tailing, making zone differentiation impossible. The profiling was therefore improved to allow for the detection of individual bioactive compounds, and the range of samples was extended to 15 commercial golden root products. Further effect-directed assays were studied providing information on 15 different effect mechanisms, i.e., (1) tyrosinase, (2) acetylcholinesterase, (3) butyrylcholinesterase, (4) β-glucuronidase, and (5) α-amylase inhibition, as well as endocrine activity via the triplex planar yeast antagonist-verified (6–8) estrogen or (9–11) androgen screen, (12) genotoxicity via the planar SOS-Umu-C bioassay, antimicrobial activity against (13) Gram-negative Aliivibrio fischeri and (14) Gram-positive Bacillus subtilis bacteria, and (15) antioxidative activity (DPPH• radical scavengers). Most of the golden root profiles obtained were characteristic, but some samples differed substantially. The United States Pharmacopeia reference product showed medium activity in most of the assays. The six most active compound zones were further characterized using high-resolution mass spectrometry, and the mass signals obtained were tentatively assigned to molecular formulae. In addition to confirming the known activities, this study is the first to report that golden root constituents inhibit butyrylcholinesterase (rosin was tentatively assigned), β-glucuronidase (rosavin, rosarin, rosiridin, viridoside, and salidroside were tentatively assigned), and α-amylase (stearic acid and palmitic acid were tentatively assigned) and that they are genotoxic (hydroquinone was tentatively assigned) and are both agonistic and antagonistic endocrine active. [ABSTRACT FROM AUTHOR]

Xanthomonas spp. are important plant pathogens that seriously endanger crop yields and food security. RpfF is a key enzyme that is involved in the synthesis of diffusible signal factor (DSF) signals and predominates in the signaling pathway regulating quorum sensing (QS) in Xanthomonas. Currently, novel RpfF enzyme-based quorum sensing agents have been proposed as a promising strategy for the development of new pesticides. However, few reports are available that comprehensively summarize the progress in this field. Therefore, we provide a comprehensive review of the recent advances in DSF-mediated QS and recently reported inhibitors that are proposed as bactericide candidates to target the RpfF enzyme and control plant bacterial diseases. [ABSTRACT FROM AUTHOR]

A new triterpene glycoside, silviridoside, was isolated from the aerial parts of Silene viridiflora (Caryophyllaceae) using different chromatographic techniques. The structure of silviridoside was comprehensively elucidated as 3-O-β-D-galacturonopyranosyl-quillaic acid 28-O-β-D-glucopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→3)]-β-D-fucopyranosyl ester by one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS). Silviridoside showed promising antioxidant activity in different antioxidant assays such as 2,2-diphenyl-1-picrylhydrazyl (DPPH) (2.32 mg TE/g), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) (1.24 mg TE/g), cupric-reducing antioxidant capacity (CUPRAC) (9.59 mg TE/g), ferric-reducing antioxidant power (FRAP) (5.13 mg TE/g), phosphomolybdenum (PHD) (0.28 mmol TE/g), and metal-chelating (MCA) (6.62 mg EDTA/g) assays. It exhibited a good inhibitory potential on acetylcholinesterase (AChE) (2.52 mg GALAE/g), butyrylcholinesterase (BChE) (7.16 mg GALAE/g), α-amylase (0.19 mmol ACAE/g), α-glucosidase (1.21 mmol ACAE/g), and tyrosinase (38.83 mg KAE/g). An in silico evaluation of the pharmacodynamic, pharmacokinetic, and toxicity properties of silviridoside showed that the new compound exhibited reasonable pharmacodynamic and pharmacokinetic properties without any mutagenic effect, but slight toxicity. Thus, it could be concluded that silviridoside could act as a promising lead drug for pharmaceutical and nutraceutical developments to combat oxidative stress and various disorders, but a future optimization is necessary. [ABSTRACT FROM AUTHOR]

Carbonic anhydrases (EC 4.2.1.1) catalyse the reversible hydration of CO2 into bicarbonate and protons. As a hypoxia-sensitive and tumour-associated isoform, isoform CA IX, is significantly overexpressed in various malignancies, being a validated target for new anticancer/antimetastatic drugs. A multitude of studies has shown that CA IX inhibition decreases cancer cell proliferation and metastasis through pHe/pHi modulation and enhancement of ferroptosis among others. Numerous studies demonstrated increased efficacy of cytotoxic drugs combined with CA inhibitors (CAIs) in various cancer types. We tested the inhibitory effect of boric acid (BA), an inorganic Lewis acid, on CA IX as well as other isoforms (CA I, II, and XII). BA acted as a millimolar in vitro CAI, decreased proliferation of two cancer cell lines, although not strong correlations between the in vitro inhibition and in vivo effects were observed. The mechanism of antiproliferative action of BA should be investigated in more detail. [ABSTRACT FROM AUTHOR]

Calcineurin (CN) controls the immune response by regulating nuclear factor of activated T cells (NFAT). Inhibition of CN function is an effective treatment for immune diseases. The PVIVIT peptide is an artificial peptide based on the NFAT-PxIxIT motif, which exhibits stronger binding to CN. A bioactive peptide (named pep4) that inhibits the CN/NFAT interaction was designed. Pep4 contains a segment of A238L as the linker and the LxVP motif and PVIVIT motif as CN binding sites. Pep4 has strong binding capacity to CN and inhibits CN activity competitively. 11-arginine-modified pep4 (11 R-pep4) inhibits the nuclear trans-location of NFAT and reduces the expression of IL-2. 11 R-pep4 improves the pathological characteristics of asthmatic mice to a certain extent. The above results indicated that pep4 is a high-affinity CN inhibitor. These findings will contribute to the discovery of new CN inhibitors and promising immunosuppressive drugs. [ABSTRACT FROM AUTHOR]

Context: Brassica incana Ten. (Brassicaceae) is an edible plant with very limited available information. Previous studies have demonstrated the polyphenolic profile and the antioxidant and cytotoxic properties of the leaf and flowering top hydroalcoholic extracts. Objective: The volatile composition and the antidiabetic and anti-obesity potential of B. incana leaf and flowering top extracts have been investigated. Material and methods: The volatile characterization of the extracts was attained by HS-SPME-GC/MS analysis. The antidiabetic and anti-obesity potential was investigated spectrophotometrically in vitro by the ability to modulate pancreatic lipase and α-glucosidase at different concentrations using orlistat and acarbose as reference drugs. The inhibition of advanced glycation end-products (AGEs) was measured with aminoguanidine as reference and the antioxidant activity with the xanthine/xanthine oxidase system and Trolox for comparative purposes. Results: Several volatiles belonging to different chemical classes were identified, being sulphur compounds the most abundant in both leaf and flowering top extracts (56.33% and 64.40% of all volatiles). Although the leaf extract showed lower IC50 values in most of the assays (0.968 and 1.921 mg/mL for α-glucosidase; 0.192 and 0.262 mg/mL for AGEs; 0.022 and 0.038 mg/mL for superoxide scavenging), there were no statistically significant differences between both samples. These extracts showed a similar behaviour to Trolox in the xanthine oxidase assay (IC50 values of 0.022 mg/mL for leaf extract; 0.038 mg/mL for flowering top and 0.028 for Trolox). Conclusions: Leaves and flowering tops from B. incana can be used as sources of functional compounds that could act as antidiabetic and anti-obesogenic agents. [ABSTRACT FROM AUTHOR]

Inhibition profiles of synthesized 4‐methyl benzene sulfonamide derivatives on carbonic anhydrase I (CA I) and II (CA II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were investigated in this study. All sulfonamide based compounds showed the inhibition profiles with KI values in the range 0.39–2.46 nM for CA I, 4.81–14.43 nM for CA II, 52.10–58.83 nM AChE and 50.78–57.38 nM for BChE, respectively. CA Isoenzymes are essential therapeutic targets and their inhibitors have been used for pharmacological purposes particularly in the remedy of diseases such as glaucoma, edema, cancer, etc. Cholinesterase inhibitors are important compounds that can be used in many diverse therapeutic applications, especially Alzheimer's disease (AD). The 4‐methyl benzene sulfonamides examined here and acetazolamide, the clinically used CA Inhibitor, showed similar results for CA I and II. Similarly, synthesized compounds demonstrated close inhibition ranges with neostigmine, a cholinesterase inhibitor, on AChE and BChE enzymes. These results indicate that these molecules can be used as potential inhibitors for these esterase enzymes. In addition, molecular docking studies were carried out to elucidate the mechanism of the observed activities of the potent compounds. [ABSTRACT FROM AUTHOR]

Aristotelia chilensis is a plant whose fruit is considered a powerful natural antioxidant. During the last years, some investigations of the fruit have been carried out, finding antioxidant properties in the juice or the phenolic fraction. The antioxidant properties of the plant are useful in the inhibition of enzymes related to diabetes such as pancreatic aldose reductase and alpha-amylase. Because many synthetic drugs used today have limitations and potentially harmful side effects, the use of naturally occurring compounds, such as flavonoids, is clinically attractive. In this study, the characterization of aqueous extracts of fruits and in vitro plants of A. chilensis was carried out based on their content of anthocyanins and total phenols, the antioxidant capacity by the antiradical activity 2,2-diphenyl-1-picrilhydrazil (DPPH), and the profile of anthocyanins and other phenolic compounds by liquid chromatography coupled to mass spectrometry (LC-MS/MS). Subsequently, the effect of these extracts on the inhibition of bovine aldose reductase and pancreatic alpha-amylase enzymes was determined. According to our results, extracts of fruits and in vitro plants of A. chilensis achieved inhibition of the bovine aldose reductase enzyme of 85.54 ± 1.86% and 75.67 ± 1.21%, respectively. Likewise, the percentage of inhibition of the pancreatic alpha-amylase enzyme for fruit extracts was 29.64 ± 0.63%, while for in vitro plant extracts it was 47.66 ± 0.66%. The antioxidant and enzymatic inhibition activity of the extracts were related to the content of anthocyanins, such as delphinidin and cyanidin glycosides as well as the phenols derived from quercetin, myricetin, and kaempferol. The results obtained allow us to suggest that the in vitro culture of plants of A. chilensis represents a viable biotechnological alternative to obtain phenolic compounds for the inhibition of aldose reductase and pancreatic alpha-amylase enzymes. [ABSTRACT FROM AUTHOR]

Background: Quercetin is a food supplement with multiple biological activities including antihypertensive, vasodilator effects, antiobesity, antihypercholesterolemic, antiatherosclerotic and other activities, it is available in wide range of dietary supplement and daily food intake, after oral ingestion, quercetin is metabolized by intestinal enzymes and absorbed by the duodenum, then be transported to the liver where is transformed into its glucuronidated, methylated and sulfo-substituted metabolites. Aim of Study: Boosting the bioavailability of Quercetin by enzyme inhibitor effect of ketoconazole. Method: 10 apparently healthy adult, male (5) and female (5) were grouped A and B, with a 1-week wash-period, Group A received Quercetin 1000 mg, group B received Quercetin 1000 mg and Ketoconazole 400 mg, and 15 blood samples are collected on the following timing 0, 0.5 - 12.5 by 1 hour interval and other by hour 24 for HPLC Assay. Results: Concurrent ketoconazole administration with Quercetin significantly improves the mean plasma concentration under the curve from zero time to infinity (AUC0-8) by 176% (403.41 ± 62.28 vs. 228.51 ± 28.67 µg.h/mL; P <0.0001) and prolonged time to complete elimination (44.66 ± 9.17 vs. 12.93 ± 1.4 hr.; P <0.0000) compared with Quercetin alone. Conclusion: Bioavailability of Quercetin will be increased by its administration together with ketoconazole, due to enzyme inhibiting effect of ketoconazole which delay elimination and increase the AUC of Quercetin. [ABSTRACT FROM AUTHOR]

By the importance of exploring novel compounds for inhibiting the cancerous enzymes activities, this work was performed to recognize advantages of employing 4-amino modified derivatives of cytidine for participating in more efficient interactions with the methyltransferase (MTN) cancerous enzyme target. To this aim, four groups of modified models of cytidine were investigated in addition the original models to recognize the structural features and the corresponding activities. The 4-amino site of cytidine was functionalized by different carbon-based groups in linear and cyclic modes through a bridging peptide linkage. The models were optimized to reach the minimized energy structures by performing quantum chemical calculations and their interactions with the target were analyzed by performing molecular docking simulations. The obtained results of 4-amino modified derivatives of cytidine showed advantages of employing structural modifications to find structures with better molecular orbital based features. Formations of interacting complexes indicated that the additional of carbon-based groups helped to improve possibility of interactions between the substances in both of chemical and physical modes. As a remarkable achievement of this work, the model of cytidine with a phenyl group showed the best advantage of participating in interactions with the MTN target among all twenty five models of the investigated cytidine compounds. [ABSTRACT FROM AUTHOR]

This paper discusses a complex nonlinear fractional model of enzyme inhibitor reaction where reaction memory is taken into account. Analytical expressions of the concentrations of enzyme, substrate, inhibitor, product, and other complex intermediate species are derived using Laplace decomposition and differential transformation methods. Since different rate constants, large initial concentrations, and large time domains are unavoidable in biochemical reactions, different dynamics will result; hence, the convergence of the approximate concentrations may be lost. In this case, the proposed analytical methods will be coupled with Padé approximation. The validity and accuracy of the derived analytical solutions will be established by direct comparison with numerical simulations. [ABSTRACT FROM AUTHOR]

Methionine is an essential amino acid involved in many physiological and pathological processes. Methionine starvation caused by methionine decarboxylase (MetDC) degradation becomes a promising strategy for cancer treatment. Multistep colorimetric method, the present approach to monitor the MetDC activity, possesses drawbacks of the complicated process, low accuracy, and poor anti‐interference due to indirect detection. Herein, we report a facile and easy‐to‐use supramolecular tandem assay (STA) with the cucurbit[7]uril and acridine orange reporter pair for the direct and real‐time monitoring of MetDC activity. This strategy not only provides a feasible method for enzymatic activity detection but also establishes the capability of inhibitor screening. [ABSTRACT FROM AUTHOR]

In insects, melanism plays important roles in defense, immunoreactions, and body color. The underlying molecular mechanisms of melanism in different insects are diverse and remain elusive. In contrast to another silkworm, Bombyx mori , the Chinese oak silkworm, Antheraea pernyi , produces melanic pupae under natural environmental conditions. DOPA and dopamine synthesis are crucial for melanin formation. Disruption of these processes reportedly influences body colors in many insects. Most research focuses on newly emerged pupae, and the larval process preceding pupation remains unknown. Due to the large size and long pupation period in A. pernyi , the entire process was studied at least every 12 h. The expression patterns of tyrosine hydroxylase (TH) and DOPA decarboxylase (DDC), which are involved in DOPA and dopamine synthesis in the epidermis, were evaluated during larval–pupal metamorphosis. We also performed RNA interference (RNAi) and used enzyme inhibitors to examine morphological changes. The amino acid sequences of TH and DDC share 90.91% and 86.64% identity with those of B. mori. TH and DDC expression was upregulated during the 48–72 h period prior to pupal emergence, especially at 60 h. RNAi of TH and DDC induced partial melanism in some pupae. The inhibitors 3-iodo-tyrosine (3-IT) and L-α-methyl-DOPA (L-DOPA) influenced pupal melanization. Different concentrations of inhibitors led to pupal deformity and even mortality. Four different monoamines, only DOPA and Dopamine synthezed from Tyrosine will be influenced by TH and DDC inhibitor. These results indicate that TH and DDC are key genes associated with pupal melanization during larval–pupal transformation in A. pernyi. Overall, our results suggest that TH and DDC expression alterations in a particular stage can affect body color, setting the molecular basis for artificial control of pupal melanization. [ABSTRACT FROM AUTHOR]

The enzyme phenoloxidase (PO) plays an essential role in insect immune defense. Phenolic compounds sharing structural homology with PO substrates could act as substrate analogues, and may interfere with insect physiological process, thus, leading to their control. Herein, the bioinformatic molecular docking was used to predict the interaction of the crystal 3D structure of the insect Manduca sexta PO (PDB: 3HHS) with the antiseptic 4 hexylresorcinol (4‐Hr). The method was firstly validated using phenylthiourea (PTU) as reference ligand. Data demonstrated the ability of the 4‐Hr to bind to M. sexta PO with binding energy score ΔG = −372,285 Kcal/mol indicative of a plausible affinity to active site of the enzyme, nevertheless, the affinity of PTU was stronger with a binding energy of ΔG = −462.173 Kcal/mol. Furthermore, biochemical in vitro assays confirmed the behavior of 4‐Hr as substrate‐analog when binding to the active site of the insect PO leading to its competitive inhibition. This is the first report demonstrating the molecular bases of the usefulness of hexylresorcinol as a promising insecticide. Further investigations could emphasize synergistic effects of 4‐Hr with other insecticides in integrated pest management (IPM) programs. [ABSTRACT FROM AUTHOR]

Antibiotic resistance is a challenge for the control of bacterial infections. In an effort to explore unconventional avenues for antibacterial drug development, we focused on the FMN‐transferase activity of the enzyme Ftp from the syphilis spirochete, Treponema pallidum (Ftp_Tp). This enzyme, which is only found in prokaryotes and trypanosomatids, post‐translationally modifies proteins in the periplasm, covalently linking FMN (from FAD) to proteins that typically are important for establishing an essential electrochemical gradient across the cytoplasmic membrane. As such, Ftp inhibitors potentially represent a new class of antimicrobials. Previously, we showed that AMP is both a product of the Ftp_tp‐catalyzed reaction and an inhibitor of the enzyme. As a preliminary step in exploiting this property to develop a novel Ftp_Tp inhibitor, we have used structural and solution studies to examine the inhibitory and enzyme‐binding properties of several adenine‐based nucleosides, with particular focus on the 2‐position of the purine ring. Implications for future drug design are discussed. PDB Code(s): 7MGT; [ABSTRACT FROM AUTHOR]

Antibiotic resistance is a continually growing challenge in the treatment of various bacterial infections worldwide. New drugs and new drug targets are necessary to curb the threat of infectious diseases caused by multidrug‐resistant pathogens. The tryptophan biosynthesis pathway is essential for bacterial growth but is absent in higher animals and humans. Drugs that can inhibit the bacterial biosynthesis of tryptophan offer a new class of antibiotics. In this work, we combined a structure‐based strategy using in silico docking screening and molecular dynamics (MD) simulations to identify compounds targeting the α subunit of tryptophan synthase with experimental methods involving the whole‐cell minimum inhibitory concentration (MIC) test, solution state NMR, and crystallography to confirm the inhibition of L‐tryptophan biosynthesis. Screening 1,800 compounds from the National Cancer Institute Diversity Set I against α subunit revealed 28 compounds for experimental validation; four of the 28 hit compounds showed promising activity in MIC testing. We performed solution state NMR experiments to demonstrate that a one successful inhibitor, 3‐amino‐3‐imino‐2‐phenyldiazenylpropanamide (Compound 1) binds to the α subunit. We also report a crystal structure of Salmonella enterica serotype Typhimurium tryptophan synthase in complex with Compound 1 which revealed a binding site at the αβ interface of the dimeric enzyme. MD simulations were carried out to examine two binding sites for the compound. Our results show that this small molecule inhibitor could be a promising lead for future drug development. PDB Code(s): 6XIN; [ABSTRACT FROM AUTHOR]

Psephellus appendicigerus, is a plant endemic to Turkey, belonging to the Asteraceae family, which is traditionally used in folk medicine in Turkey. The aim of this study is to reveal for the first time the biological activities of this plant and evaluate its potential use as a natural product. For this reason, different extracts (ethanol, methanol, ethyl acetate, and hexane) of the plant's aerial parts were used in determining the antioxidant (2,20-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid and 1,1-diphenyl-2-picrylhydrazyl assays), antimicrobial (disc diffusion and microdilution methods), and enzyme inhibition activity (calorimetric methods) related to diabetes (α-amylase and α-glucosidase). Moreover, the phenolic constituents were analysed by high performance liquid chromatography. Methanol extract of the plant exhibited significant biological activity compared to other extracts. This extract had the highest amount of chlorogenic acid as phenolic compound. In addition, all extracts showed inhibition against at least one test microorganism. According to the results, P. appendicigerus has the potential to be used as a natural antioxidant, antimicrobial and enzyme inhibitor. [ABSTRACT FROM AUTHOR]

Staphylococcus xylosus (S. xylosus) has become an emerging opportunistic pathogen due to its strong biofilm formation ability. Simultaneously, the biofilm of bacteria plays an important role in antibiotic resistance and chronic infection. Here, we confirmed that rutin can effectively inhibit biofilm formation in S. xylosus , of which the inhibition mechanism involves its ability to interact with imidazole glycerol phosphate dehydratase (IGPD), a key enzyme in the process of biofilm formation. We designed experiments to target IGPD and inhibited its activities against S. xylosus. Our results indicated that the activity of IGPD and the amount of histidine decreased significantly under the condition of 0.8 mg/ml rutin. Moreover, the expression of IGPD mRNA (hisB) and IGPD protein was significantly down-regulated. Meanwhile, the results from molecular dynamic simulation and Bio-layer interferometry (BLI) technique showed that rutin could bind to IGPD strongly. Additionally, in vivo studies demonstrated that rutin treatment reduced inflammation and protect mice from acute mastitis caused by S. xylosus. In summary, our findings provide new insights into the treatment of biofilm mediated persistent infections and chronic bacterial infections. It could be helpful to design next generation antibiotics to against resistant bacteria. [ABSTRACT FROM AUTHOR]

Purpose: A neuropathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with Aβ aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic. Procedures: Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[18F]. IC50 values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor. Results: Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman's assay gave an IC50 value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K1 = 32.9 nM). Conclusions: The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with 18F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield. [ABSTRACT FROM AUTHOR]

Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) and has been regarded as the main therapeutic target for AD. However, most of the Aβ-targeted clinical trials have not succeeded. Therefore, the Aβ-targeted therapeutic strategy on treating this complex disease needs to be re-evaluated. In this review, we analyzed the challenges and critical points of the current anti-Aβ therapeutic strategies. In addition to Aβ, multiple pathological events such as tau hyperphosphorylation, oxidative stress, and neuroinflammation, which are involved in AD pathogenesis and synergistically drive disease progression, could be important targets for AD treatment. Tertiary prevention strategies are needed for the successful management of AD due to its complex and dynamic pathogenesis. Systemic perspective addressing the disease pathogenesis within and outside the brain, as well as the multidomain intervention targeting risk factors and comorbidities, are important approaches for the therapeutic solutions of AD. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Pesticide Science / Nongyaoxue Xuebao is the property of Chinese Journal of Pesticide Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Glyceric acid (GA) is an oxidative product of glycerol, and its d-isomer is obtained as a phytochemical from tobacco leaves and fruits of some plants. However, the production and applications of GA have not yet been fully investigated. In this review, recent developments in the microbial production of GA and its application to bio-related materials are summarized. The sodium salt of diacylated GA showed superior surface tension-lowering activity and antitrypsin activity. GA and its glucosyl derivative had positive effects on the viability and collagen production of skin cells in vitro, respectively. Glucosyl derivatives of GA showed protective effects against heat-induced protein aggregation. In addition, the microbial production of GA using raw glycerol as the starting material was investigated. The effect of methanol, a major impurity in raw glycerol, on GA production was investigated, and mutant strains to tolerate methanol in the culture were constructed. Enantioselective production of GA using newly isolated microbial strains has also been developed. [ABSTRACT FROM AUTHOR]

In Anatolia, the tubers of Dactylorhiza romana subsp. georgica orchid are consumed as food and frequently used in folk medicine to alleviate the symptoms of some disorders. However, these properties have not been scientifically studied until the present day. In this research, we aimed to identify phenolic profile of the orchid tubers and determine their several features and functions. Among these, there are the antioxidant and antimicrobial effects and the inhibitory effect against diabetes related enzymes (α-amylase and α-glucosidase). In this sense, total phenolic content (Folin–Cicalteu assay), total antioxidant capacity (Phosphomolybdate method), antioxidant (ABTS and DPPH assays) and enzyme inhibition effects of tuber extracts obtained with different solvents (chloroform, ethyl acetate, methanol, ethanol, or hexane) were determined by using spectrophotometric methods, and the phenolic profile was also analysed by HPLC. In addition, antimicrobial activity of the extracts against 3 g (+) and 3 g (−) bacteria and 2 forms of yeasts was determined by disc diffusion and micro dilution methods. Based on our findings, the total phenolic content and antioxidant properties of ethyl acetate extract were considerably higher than the others. The most abundant among the screened phenolic standards was found to be benzoic acid. The highest α-amylase and α-glucosidase enzyme inhibition was measured in methanol and chloroform extracts, respectively. The highest antibacterial (B. cereus) and anticandidal (C. tropicalis and C. albicans) activities were detected in the chloroform and ethyl acetate extracts, respectively. In short, it was clearly seen that the D. romana subsp. georgica tuber had a great potential for being used in food and drug industries as a source of bioactive compounds. [ABSTRACT FROM AUTHOR]

The strategy of reducing carbohydrate digestibility by controlling the activity of two hydrolyzing enzymes (α‐amylase and α‐glucosidase) to control postprandial hyperglycemia is considered as a viable prophylactic treatment of type 2 diabetes mellitus (T2DM). Thus, the consumption of foods rich in hydrolyzing enzyme inhibitors is recommended for diet therapy of diabetes. Whole cereal products have gained increasing interests for plasma glucose‐reducing effects. However, the mechanisms for whole cereal benefits in relation to T2DM are not yet fully understood, but most likely involve bioactive components. Cereal‐derived phenolic compounds, peptides, nonstarch polysaccharides, and lipids have been shown to inhibit α‐amylase and α‐glucosidase activities. These hydrolyzing enzyme inhibitors seem to make whole cereals become nutritional strategies in managing postmeal glucose for T2DM. This review presents an updated overview on the effects provided by cereal‐derived ingredients on carbohydrate digestibility. It suggests that there is some evidence for whole cereal intake to be beneficial in amelioration of T2DM through inhibiting α‐glucosidase and α‐amylase activities. [ABSTRACT FROM AUTHOR]

A fluorescence method for the determination of inorganic pyrophosphatase (PPase) activity has been established based on copper nanoclusters (CuNCs). The polythymine of 40 mer (T40) acts as a template for the reduction reaction from Cu2+ to Cu0 by ascorbic acid (AA). This reaction leads to the formation of fluorescent CuNCs with excitation/emission peaks at 340/640 nm. However, the higher binding affinity between inorganic pyrophosphate (PPi) and Cu2+ hinders the effective formation of CuNCs. This shows low fluorescence intensity. PPase catalyzes the hydrolysis of PPi into Pi during which free Cu2+ ions are produced. This facilitates the formation of fluorescent CuNCs. Thus, the fluorescence intensity was restored. The fluorescence enhancement of the system has a linear relationship with PPase activity in the range 0.3 to 20 mU·mL−1, and the detection limit is0.2 mU·mL−1. The relative intensity (I/I0) at 640 nm for the analytical solution versus system is also employed to screen the inhibitor for PPase with high efficiency. [ABSTRACT FROM AUTHOR]

Human carbonic anhydrase I and II isoenzymes (hCA I and II) are important metabolic enzymes. In this study, a new series of thiazol‐(2(3H)‐ylideneamino)benzenesulfonamide derivatives were synthesized and also some inhibition parameters including IC50 (hydratese) and inhibition constant values (Ki, esterase) were determined. All studied compounds exhibited potent inhibition against these enzymes. They inhibited carbonic anhydrases (CAs) with the IC50 values of 113 to 395.8 nM (Ki = 77.38‐319.59 nM) for hCA I and 91.9 to 516 nM (Ki = 62.79‐425.89 nM) for hCA II. Among the compounds, 5c was found to be the most active one (Ki: 77.38 nM) for hCA I and 5g was found for hCA II with the value of 62.79 nM. [ABSTRACT FROM AUTHOR]

Copyright of Erzincan University Journal of Science & Technology is the property of Erzincan Binali Yildirim Universitesi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Barnyardgrass (Echinochloa crus-galli (L.) P. Beauv.) is one of the most yield-limiting weeds in rice in Turkey. Barnyardgrass resistance to common herbicides has been reported worldwide; however, such information is largely lacking in the country. The objective of this study was to determine the resistance spectrum of different barnyardgrass populations to the most commonly-used herbicides in rice in Turkey. The susceptibility of 40 barnyardgrass populations was evaluated. The samples were collected from fields with intensive rice cultivation in Balıkesir and Çanakkale provinces. Seeds were picked from barnyardgrass plants suspected to be herbicide-resistant because of their survival in the rice fields after herbicides application. A total of 38 populations were resistant to penoxsulam, and the resistance index of these populations ranged from 2 to 39. A total of 24 out of the 38 barnyardgrass populations showed a GR50 (herbicide dose causing a 50% reduction in plant dry matter) value higher than the recommended penoxsulam dose (20.2 g a.i./ha) in rice. Among these 24 barnyardgrass populations, 25, 29.2 and 45.8% populations exhibited high, moderate and low level of penoxsulam resistance, respectively. From the penoxsulam-resistant populations (38), the response of 14 populations (low to high resistance to penoxsulam) to six commonly-used herbicides for barnyardgrass control in rice was evaluated. The selected 14 populations showed resistance to almost all herbicides tested, with the lowest average resistance being determined against profoxydim and the highest average resistance against molinate herbicide. Resistance levels against six commonly-used herbicides in rice ranged from 2 to 34. [ABSTRACT FROM AUTHOR]

BACKGROUND: In this investigation, the chemical and biological profiles of three Turkish Crataegus species (Crataegus orientalis, Crataegus szovitsii and Crataegus tanacetifolia) were studied in order to provide the first comprehensive characterization and their health‐promoting potential. In this respect, polyphenolic profiles were evaluated using ultrahigh‐performance liquid chromatography–quadrupole time‐of‐flight mass spectrometry. The in vitro antioxidant activities of the Crataegus samples were evaluated by using free‐radical scavenging, phosphomolybdenum, ferrous‐ion chelating, and reducing power assays. The inhibitory activities against α‐glucosidase, amylase, cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)), and tyrosinase were also established. RESULTS: The untargeted metabolomic approach highlighted the effect of both extraction types and species on the phenolic profiles of different Crateagus tissues (i.e. leaves and twigs). The methanolic extracts showed the maximum radical scavenging and reducing activity in all test systems, whereas for ferrous‐ion chelating assays the decocted and infused extracts showed the highest activity. Only the methanolic extracts were effective against AChE and BChE. The extract tested showed remarkable inhibitory effects against tyrosinase and α‐glucosidase, whereas all the extracts exhibited modest inhibition against α‐amylase. Overall, the twig extracts of the three species studied showed superior antioxidant and enzyme inhibitory activities. CONCLUSION: On the basis of these results, the three Crataegus species can be classified as potent bioresources for high‐value phytochemicals, which warrant further investigations for developing novel nutraceuticals. © 2019 Society of Chemical Industry [ABSTRACT FROM AUTHOR]