Search Results (68)

In this study, the ranking of the multifaceted activity of rutin (Ru), quercetin (Q), and quercetin’s glucosides (Q3G, Q4′G and Q3,4′G) was addressed. The antioxidant potency was determined by electrochemical methods, whereas the ability of these compounds to inhibit angiotensin-converting enzyme (ACE) activity, acetylcholinesterase (AChE) activity, and advanced glycation endproduct (AGE) formation was examined in bovine serum albumin (BSA)/glucose and BSA/methylglyoxal (MGO) model systems to show their importance against hypertension, Alzheimer-type dementia, and diabetic complication, respectively. Then, the relationship between the biological activities of these compounds and their antioxidant potential provided by the cyclic voltammetry (CV) method was evaluated. The ranking of the ACE inhibitory activity was Q > Q3,4′G > Ru > Q3G > Q4′G. The correlation coefficient between ACE enzyme inhibitory activities and antioxidant potentials had a value of r = −0.68, thus clearly indicating the impact of antioxidant potential and chemical structure on ACE inhibitory activity. The ranking of the AChE enzyme inhibitory activity was Q ≈ Q3G ≈ Q4′G ≈ Ru > Q3,4′G, and the correlation between their antioxidant potentials and AChE inhibitory activities (r = −0.77) also indicated the impact of chemical structure. The quercetin glucosides displayed strong inhibitory capacity on AGE formation, as the ranking of anti-AGE activity in the BSA/MGO model system was Q3,4′G ≈ Q4′G ≈ Q3G > Ru ≈ Q > AG. The anti-AGE activity of rutin, quercetin, and quercetin’s glucosides was negatively correlated with their IC₅₀ values for ACE inhibition (r = −0.67) and AChE inhibition (r = −0.81), whereas no correlation was found between their ACE and AChE inhibition activities. These effects of rutin, quercetin, and quercetin’s glucosides expand our knowledge of the multifunctional activity of biologically active compounds of plant origin. Full article

Essential oils (EOs), which are complex mixtures of plant-derived volatile compounds, have been utilized for centuries in the medical, food, and pharmaceutical industries because of their diverse biological properties. In recent years, there has been growing interest in elucidating the bioactivities of essential oils and their underlying mechanisms of action. This study aimed to investigate the antioxidant, antimicrobial, and cytotoxic characteristics of Laurus nobilis, Eucalyptus camaldulensis, Rosmarinus officinalis, and Mentha suaveolens oils and relate them to their volatile compound content. The volatile compounds of the essential oils were characterized and quantified by gas chromatography, the antioxidant activity was quantified using the ABTS assay, the antibacterial activity was quantified using broth microdilution and agar diffusion techniques, and the MTT assay was used to establish the cytotoxic potential. This study revealed a significant antioxidant capacity, which correlated with the proportion of terpenes known for their antioxidant properties. The antioxidant potency was ranked in descending order: R. officinalis, M. suaveolens, E. camaldulensis, and L. nobilis. Antimicrobial testing demonstrated that all the examined essential oils were effective against the evaluated microbial species, including both Gram-positive (Listeria innocua) and Gram-negative (Escherichia coli) bacteria. Additionally, all the tested essential oils triggered cell death in the human epithelioid cervical carcinoma (HeLa) cell line. Collectively, this article highlights the promising therapeutic and alimentary potential of essential oils and underscores the need for further research to fully harness their benefits in industrial settings. Full article

Dipeptidyl peptidase III (DPP III) is a zinc-dependent enzyme that hydrolyses biologically active peptides by cleaving dipeptides from their amino terminus. While the fundamental role of this metallopeptidase remains incompletely understood, human DPP III (hDPP III) has been linked to several pathophysiological processes relevant to drug development. In this study, thirty-six amidino-substituted benzimidazole derivatives, including seven newly synthesized compounds, were examined for their activity against hDPP III by combining in vitro tests, in silico quantitative structure–activity relationship (QSAR) modelling, and molecular docking approaches. The experiments demonstrate that all compounds display inhibitory activity at a 30 µM concentration. A biochemical assay revealed that 2,2′-bithiophene, 4-trifluoromethylphenyl, 4-(N,N-diethylamino)phenyl, and 2,3,4-trihydroxyphenyl as substituents at position 2 of the benzimidazole core enhance inhibitor potency. Additionally, the type of substituent at positions 5(6) of the benzimidazole core influences enzyme inhibition, with effectiveness ranked as follows: 2-imidazolinyl > unsubstituted amidine > 2-tetrahydropyrimidine. A multiple linear regression QSAR model for hDPP III inhibition was developed using four Dragon descriptors (Rww, Mats3e, BELe4, and nCs), which can explain 82% of the inhibitory activity. Docking analysis of the semi-closed form of hDPP III in a complex with the most potent compounds indicates the structural features of the benzimidazole derivatives important for the binding at the hDPP III active site. Full article

It is well established that certain carboxylic acid compounds can effectively inhibit tyrosinase activity. This study investigated the mechanisms by which four carboxylic acid compounds—3-phenyllactic acid, lactic acid, L-pyroglutamic acid, and malic acid—inhibit tyrosinase and melanogenesis. IC₅₀ values for mushroom tyrosinase inhibition ranged from 3.38 to 5.42 mM, with 3-phenyllactic acid (3.50 mM), lactic acid (5.42 mM), and malic acid (3.91 mM) exhibiting mixed-type inhibition, while L-pyroglutamic acid (3.38 mM) showed competitive inhibition, as determined by enzymatic kinetic analysis. Additionally, the acidification effects of lactic acid, L-pyroglutamic acid, and malic acid contributed to the reduction in tyrosinase activity. Furthermore, all four carboxylic acid compounds effectively inhibited DOPA auto-oxidation (IC₅₀ = 0.38–0.66 mM), ranking in potency as follows: malic acid (0.38 mM) > lactic acid (0.57 mM) > 3-phenyllactic acid (0.63 mM) > L-pyroglutamic acid (0.66 mM). These compounds also demonstrated a dose-dependent reduction in melanin production in B16-F10 cells. Proteomic analysis further revealed that these compounds not only inhibit key proteins involved in melanin synthesis, such as tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2, but also potentially modulate other genes associated with melanogenesis and metabolism, including Pmel, Slc45a2, Ctns, Oca2, and Bace2. Network toxicology analysis indicated that these four compounds exhibit a low risk of inducing dermatitis. These findings suggest that these compounds may indirectly regulate melanin-related pathways through multiple mechanisms, highlighting their potential for further applications in cosmetics and pharmaceuticals. Full article

This study aims to design improved inhibitors targeting the thymidylate kinase (TMK) of Mycobacterium tuberculosis (Mtb), the causative agent of infectious disease tuberculosis that is associated with high morbidity and mortality in developing countries. TMK is an essential enzyme for the synthesis of bacterial DNA. We have performed computer-aided molecular design of MtbTMK inhibitors by modification of the reference crystal structures of the lead micromolar inhibitor TKI1 1-(1-((4-(3-Chlorophenoxy)quinolin-2-yl)methyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione bound to TMK of Mtb strain H37Rv (PDB entries: 5NRN and 5NR7) using the computational approach MM-PBSA. A QSAR model was prepared for a training set of 31 MtbTMK inhibitors with published inhibitory potencies (${\mathrm{I}\mathrm{C}}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$) and showed a significant correlation between the calculated relative Gibbs free energies of the MtbTMK–TKIx complex formation and the observed potencies. This model was able to explain approximately 95% of the variation in the in vitro inhibition data and validated our molecular model of MtbTMK inhibition for the subsequent design of new TKI analogs. Furthermore, we have confirmed the predictive capacity of this complexation QSAR model by generating a 3D QSAR PH4 pharmacophore-based model. A satisfactory correlation was also obtained for the validation PH4 model of MtbTMK inhibition (R² = 0.84). We have extended the hydrophobic m-chloro-phenoxyquinolin-2-yl group of TKI1 that can occupy the entry into the thymidine binding cleft of MtbTMK by alternative larger hydrophobic groups. Analysis of residue interactions at the enzyme binding site made it possible to select suitable building blocks to be used in the preparation of a virtual combinatorial library of 28,900 analogs of TKI1. Structural information derived from the complexation model and the PH4 pharmacophore guided the in silico screening of the library of analogs and led to the identification of new potential MtbTMK inhibitors that were predicted to be effective in the low nanomolar concentration range. The QSAR complexation model predicted an inhibitory concentration ${\mathrm{I}\mathrm{C}}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}$ of 9.5 nM for the best new virtual inhibitor candidate TKI 13_1, which represents a significant improvement in estimated inhibitory potency compared to TKI1. Finally, the stability of the MtbTMK–inhibitor complexes and the flexibility of the active conformation of the inhibitors were assessed by molecular dynamics for five top-ranking analogs. This computational study resulted in the discovery of new MtbTMK inhibitors with predicted enhanced inhibitory potencies, which also showed favorable predicted pharmacokinetic profiles. Full article

Deoxynivalenol (DON), fumonisin B₁ (FB₁), and zearalenone (ZEN) are typical fusarium mycotoxins that occur worldwide in foodstuffs, posing significant health hazards to humans and animals. Single and combined exposure of DON, FB₁, and ZEN leads to intestinal toxicity but the toxicology mechanism research is still limited. In this study, we explored the cytotoxicity effects of DON, FB₁, ZEN, and their combination in rat intestinal epithelial cell line 6 (IEC-6) cells. Cell viability results showed that the cytotoxicity potency ranking was DON > ZEN > FB₁. Furthermore, both DON + FB₁ and DON + ZEN presented synergism to antagonism effects based on a combination index (CI)-isobologram equation model. Integrated metabolomics and lipidomics was adopted to explore cell metabolism disorders induced by fusarium mycotoxin exposure. A total of 2011 metabolites and 670 lipids were identified. An overlap of 37 and 62 differential compounds was confirmed after single and combined mycotoxin exposure by multivariate analysis, respectively. Some of the differential compounds were endocellular antioxidants and were significantly downregulated in mycotoxin exposure groups, indicating metabolic disorders as well as antioxidant capacity damage in cells. Pathway enrichment analysis annotated ethanol metabolism production of ROS by CYP2E1 was mainly involved in the disturbance of DON, FB₁, and ZEN. The results obtained in this study help to define the toxicity effects of DON, FB₁, and ZEN singly and in co-existence, providing an important scientific basis for combined risk recognition of mycotoxin contamination. Full article

Background: Cervical cancer ranks as the fourth most common cancer affecting women globally, with HPV as the primary etiology agent. Prophylactic HPV vaccines have substantially reduced the incidence of cervical cancer. Methods: This study assessed the immunogenicity of SCT1000, a 14-valent recombinant virus-like particle (VLP) vaccine developed by Sinocelltech, Ltd. using pseudovirion-based neutralization assays (PBNAs) and total IgG Luminex immunoassays (LIAs). Currently in phase III clinical trials in China, SCT1000 targets the same HPV types as Gardasil 9^®, plus five additional high-risk types, thereby covering twelve high-risk HPV types implicated in 96.4% of cervical cancer cases. Results: In murine models, a dose of 1.85 μg per mouse was identified as optimal for evaluating SCT1000’s immunogenicity in a three-dose regimen, as measured by PBNA and total IgG LIA across all 14 HPV types. SCT1000 induced high levels of protective antibodies, which were sustained for at least four months following the third dose. The vaccine also demonstrated stable and consistent immunogenicity in mouse potency assays under both long-term and accelerated conditions. Additionally, our studies revealed a strong correlation between the two serological tests used. Conclusions: SCT1000 elicited robust, durable, and consistent humoral immune responses across all 14 HPV types, indicating its potential as a broad-spectrum vaccine candidate against HPV types 6/11/16/18/31/33/35/39/45/51/52/56/58/59. The significant correlations observed between PBNA and total IgG LIA support the use of the Luminex-based total IgG method as a reliable and effective alternative for immunogenicity assessment in preclinical and future clinical vaccine development. Full article

Breast cancer ranks first in incidence and second in deaths worldwide, presenting alarmingly rising mortality rates. Imaging methodologies and/or invasive biopsies are routinely used for screening and detection, although not always with high sensitivity/specificity. MicroRNAs (miRNAs) could serve as diagnostic and prognostic biomarkers for breast cancer. We have designed a computational approach combining transcriptome profiling, survival analyses, and diagnostic power calculations from 1165 patients with breast invasive carcinoma from The Cancer Genome Atlas (TCGA-BRCA). Our strategy yielded two separate miRNA signatures consisting of four up-regulated and five down-regulated miRNAs in breast tumors, with cumulative diagnostic strength of AUC 0.93 and 0.92, respectively. We provide direct evidence regarding the breast cancer-specific expression of both signatures through a multicancer comparison of >7000 biopsies representing 19 solid cancer types, challenging their diagnostic potency beyond any of the current diagnostic methods. Our signatures are functionally implicated in cancer-related processes with statistically significant effects on overall survival and lymph-node invasion in breast cancer patients, which underlie their strong prognostic implication. Collectively, we propose two novel miRNA signatures with significantly elevated diagnostic and prognostic power as a functionally resolved tool for binary and accurate detection of breast cancer and other tumors of the female reproductive system. Full article

The passion fruit, Passiflora edulis, recognized for its rich nutritional properties, has long been used for its varied ethnobotanical applications. This study investigates the therapeutic potential of P. edulis var. Tainung No. 1 rind extracts by examining their polyphenolic content (TPC), total flavonoid content (TFC), anti-skin aging activities against key enzymes such as elastase, tyrosinase, and hyaluronidase, and their ability to inhibit bacterial growth, single-stranded DNA-binding protein (SSB), and their cytotoxic effects on oral carcinoma cells. The acetone extract from the rind exhibited the highest levels of TPC, TFC, anti-SSB, and antibacterial activities. The antibacterial effectiveness of the acetone-extracted rind was ranked as follows: Escherichia coli > Pseudomonas aeruginosa > Staphylococcus aureus. A titration curve for SSB inhibition showed an IC₅₀ value of 313.2 μg/mL, indicating the potency of the acetone extract in inhibiting SSB. It also significantly reduced the activity of enzymes associated with skin aging, particularly tyrosinase, with a 54.5% inhibition at a concentration of 100 μg/mL. Gas chromatography–mass spectrometry (GC–MS) analysis tentatively identified several major bioactive compounds in the acetone extract, including stigmast-5-en-3-ol, vitamin E, palmitic acid, stigmasterol, linoleic acid, campesterol, and octadecanoic acid. Molecular docking studies suggested some of these compounds as potential inhibitors of tyrosinase and SSB. Furthermore, the extract demonstrated anticancer potential against Ca9-22 oral carcinoma cells by inhibiting cell survival, migration, and proliferation and inducing apoptosis. These results underscore the potential of P. edulis (Tainung No. 1) rind as a promising candidate for anti-skin aging, antibacterial, and anticancer applications, meriting further therapeutic investigation. Full article

Natural polyphenols may be very effective lipid antioxidants; however, the studies pertaining to specific commodities, such as refined olive kernel oil (OKO), are extremely limited, and thus there is a lack of relevant information. To provide coverage for this gap in the literature, this study was performed with the view of testing structurally related natural hydroxycinnamates, namely caffeic acid (CA), ferulic acid (FA), and p-coumaric acid (CouA), as effective OKO antioxidants, and establishing concentration–activity relationships. First, a ranking concerning the antioxidant potency of the three polyphenols was attempted using the radical probe DPPH, and then the compounds were assayed using OKO as the lipid substrate. Employing a concentration–activity model, the potency of the three polyphenols to stabilize OKO, based on Rancimat measurements, was CA > CouA ≈ FA. A further simulated long-term trial revealed that all three polyphenols may be equally effective in inhibiting peroxide onset over a period of 40 days, but the determination of thiobarbituric acid reactive substances (TBARS) formation evidenced that FA may be a more efficient antioxidant. The outcome was that all three polyphenols tested may behave as very effective agents against oxidative OKO rancidity, and the prospect of producing such compounds from agri-food wastes may provide unprecedented opportunities for replacing the controversial synthetic antioxidants. Full article

Synthetic cathinones have gained increasing popularity in the illicit drug market, yet their abuse potential remains poorly understood. In this study, zebrafish were used to compare the addictive potential of three cathinone analogs, namely pentylone, eutylone, and N-ethylpentylone (NEP). The zebrafish received various doses (0 to 60 mg/kg) of the cathinone analogs by oral gavage over two sessions per day for two consecutive days to induce conditioned place preference (CPP). Pentylone, eutylone, and NEP dose-dependently induced CPP, with NEP showing significantly higher CPP than pentylone and eutylone at the dose of 20 mg/kg. The fish that received 60 mg/kg of cathinones underwent extinction, followed by reinstatement triggered by drug priming. NEP required six sessions to meet the criteria of extinction, followed by eutylone, which required four sessions, and pentylone, which required three sessions. Furthermore, NEP and eutylone at a dose of 40 mg/kg could reinstate the extinguished CPP, while 60 mg/kg of pentylone was necessary for CPP reinstatement. The persistence of susceptibility to reinstatement was also assessed at 7 and 14 days after the initial reinstatement. The CPP induced by all three cathinone analogs could be reinstated 7 days after the initial reinstatement, whereas only CPP induced by NEP, but not pentylone and eutylone, could be reinstated again after 14 days. Considering the potency to induce CPP, resistance to extinction, and the propensity for reinstatement, the abuse liability rank order of the cathinone analogs might be as follows: NEP > eutylone > pentylone. These findings suggest that the zebrafish CPP paradigm can serve as a viable model for assessing the relative abuse liability of substances. Full article

Computer-aided design usually gives inspirations and has become a vital strategy to develop novel pesticides through reconstructing natural lead compounds. Patulin, an unsaturated heterocyclic lactone mycotoxin, is a new natural PSII inhibitor and shows significant herbicidal activity to various weeds. However, some evidence, especially the health concern, prevents it from developing as a bioherbicide. In this work, molecular docking and toxicity risk prediction are combined to construct interaction models between the ligand and acceptor, and design and screen novel derivatives. Based on the analysis of a constructed patulin–Arabidopsis D1 protein docking model, in total, 81 derivatives are designed and ranked according to quantitative estimates of drug-likeness (QED) values and free energies. Among the newly designed derivatives, forty-five derivatives with better affinities than patulin are screened to further evaluate their toxicology. Finally, it is indicated that four patulin derivatives, D3, D6, D34, and D67, with higher binding affinity but lower toxicity than patulin have a great potential to develop as new herbicides with improved potency. Full article

Bacillus cereus (Bc) is a wide group of Gram-positive and spore-forming bacteria, known to be the etiological agents of various human infections, primarily food poisoning. The Bc group includes enteropathogenic strains able to germinate in the digestive tract and to produce enterotoxins such as Nhe, Hbl, and CytK. One species of the group, Bacillus thuringiensis (Bt), has the unique feature of producing insecticidal crystals during sporulation, making it an important alternative to chemical pesticides to protect crops from insect pest larvae. Nevertheless, several studies have suggested a link between the ingestion of pesticide strains and human cases of food poisoning, calling their safety into question. Consequently, reliable tools for virulence assessment are worth developing to aid decision making in pesticide regulation. Here, we propose complementary approaches based on two biological models, the human intestinal Caco-2 cell line and the insect Drosophila melanogaster, to assess and rank the enteric virulence potency of Bt strains in comparison with other Bc group members. Using a dataset of 48 Bacillus spp. strains, we showed that some Bc group strains, including Bt, were able to induce cytotoxicity in Caco-2 cells with concomitant release of IL-8 cytokine, a landmark of pro-inflammatory response. In the D. melanogaster model, we were able to sort a panel of 39 strains into four different classes of virulence, ranging from no virulence to strong virulence. Importantly, for the most virulent strains, mortality was associated with a loss of intestinal barrier integrity. Interestingly, although strains can share a common toxinotype, they display different degrees of virulence, suggesting the existence of specific mechanisms of virulence expression in vivo in the intestine. Full article

Effective data reduction must retain the greatest possible amount of informative content of the data under examination. Feature selection is the default for dimensionality reduction, as the relevant features of a dataset are usually retained through this method. In this study, we used unsupervised learning to discover the top-k discriminative features present in the large multivariate IoT dataset used. We used the statistics of principal component analysis to filter the relevant features based on the ranks of the features along the principal directions while also considering the coefficients of the components. The selected number of principal components was used to decide the number of features to be selected in the SVD process. A number of experiments were conducted using different benchmark datasets, and the effectiveness of the proposed method was evaluated based on the reconstruction error. The potency of the results was verified by subjecting the algorithm to a large IoT dataset, and we compared the performance based on accuracy and reconstruction error to the results of the benchmark datasets. The performance evaluation showed consistency with the results obtained with the benchmark datasets, which were of high accuracy and low reconstruction error. Full article

We tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 µg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT. Full article