BACKGROUND: Human neutrophil elastase (HNE) is an important contributor to lung diseases such as acute lung injury (ALI) or acute respiratory distress syndrome. Therefore, this study aimed to identify natural HNE inhibitors with anti-inflammatory activity through machine learning algorithms, in vitro assays, molecular dynamic simulation, and an in vivo ALI assay.
METHODS: Based on the optimized Discovery Studio two-dimensional molecular descriptors, combined with different molecular fingerprints, six machine learning models were established using the Naïve Bayesian (NB) method to identify HNE inhibitors. Subsequently, the optimal model was utilized to screen 6,925 drug-like compounds obtained from the Traditional Chinese Medicine Systems Pharmacy Database and Analysis Platform (TCMSP), followed by ADMET analysis. Finally, 10 compounds with reported anti-inflammatory activity were selected to determine their inhibitory activities against HNE in vitro, and the compounds with the best activity were selected for a 100 ns molecular dynamics simulation and its anti-inflammatory effect was evaluated using Poly(I:C)-induced ALI model.
RESULTS: The evaluation of the in vitro HNE inhibition efficiency of the 10 selected compounds showed that the flavonoid tricetin had the strongest inhibitory effect on HNE. The molecular dynamics simulation indicated that the binding of tricetin to HNE was relatively stable throughout the simulation. Importantly, in vivo experiments indicated that tricetin treatment substantially improved the Poly(I:C)-induced ALI.
CONCLUSIONS: The proposed NB model was proved valuable for exploring novel HNE inhibitors, and natural tricetin was screened out as a novel HNE inhibitor, which was confirmed by in vitro and in vivo assays for its inhibitory activities.

BACKGROUND: AH Plus, an epoxy resin-based sealer, is widely used in endodontic practice, owing to its good physical properties that confers longstanding dimensional stability and good adhesion to dentin. Nevertheless, its propensity to trigger inflammation, especially in its freshly mixed state, has been extensively documented. Phytochemicals such as Petasin, Pachymic acid, Curcumin, and Shilajit are known for their anti-inflammatory and analgesic effects. This study aimed to analyze and determine the effect of these natural products on the physical properties of AH Plus sealer when incorporated with the sealer.
METHODS: AH Plus (AHR) sealer was mixed with 10% petasin, 0.75% pachymic, 0.5% and 6%shilajit to obtain AHP, AHA, AHC and AHS in the ratio of 10:1 and 5:1 respectively. Five samples of each material were assessed for setting time, solubility, flow, and dimensional stability in accordance with the ISO 6876:2012 standardization. Sealers were characterized through scanning electron microscopy (SEM), X-ray energy dispersive spectroscopy, X-ray diffraction (XRD), and Fourier transform infrared (FTIR) spectroscopy. Statistical evaluation involved the Kolmogorov-Smirnov and Shapiro-Wilks tests for normality and the one-way ANOVA test for analysis.
RESULTS: In this investigation, the characterisation analysis revealed a relatively similar microstructure in all the experimental root canal sealers. All experimental groups, excluding the control group, exhibited an increase in flow ranging from 11.9 to 31.4% at a 10:1 ratio. Similarly, for the 5:1 ratio, the increase ranged from 12.02 to 31.83%. In terms of dimensional stability, all groups at the 10:1 ratio showed a decrease compared to the control group. The addition of natural agents to AHR in 10:1 ratio led to a reduction in setting time by 8.9-31.6%, and at a 5:1 ratio, the reduction ranged from 8.1 to 31.5%. However, regarding solubility, the addition of natural agents did not induce any significant alterations.
CONCLUSIONS: Based on the results of this study, it can be concluded that all tested root canal sealers exhibited properties that met the acceptable criteria outlined in the ISO 6876:2012 standardization.

This study aimed to obtain optimized mixture with three essential oils (EOs) for maximum antioxidant activity through the augmented simplex-centroid mixture design and evaluate the effect of this optimized blend on total aerobic psychrotrophic count (TAPC), lipid and protein oxidation, instrumental color parameters and texture profile in rainbow trout fillets at refrigerated storage for nine days. Considering the DPPH and FRAP assays, the ideal EO blend was 66% lemongrass and 34% oregano. During refrigerated storage, this blend at 2000 ppm was equally effective as BHT (100 ppm) (p > 0.05), mitigating the discoloration (a* and b*), lipid, and protein oxidation in 38.83%, 12.95%, 76.13%, and 35.13%, respectively, besides shows greater effectiveness for preserving texture changes (p < 0.05) and extending the shelf life in 13 h. The lemongrass + oregano EO blend reveals a promising natural alternative to enhance the quality of rainbow trout fillets under refrigerated storage. Furthermore, the multiresponse optimization showed to be a strong ally in enabling the use of these EOs by food industries.

The meadow spittlebug Philaenus spumarius (Hemiptera: Aphrophoridae) is distributed in several habitats worldwide and has been recently recognized as the main vector of Xylella fastidiosa subsp. pauca. This bacterium has been associated with olive quick decline syndrome (OQDS) in the Salento Peninsula (Italy) and is responsible for extensive desiccation and die-off of olive trees. Current OQDS management strategies include the control of P. spumarius populations, mainly through the removal of weed hosts and insecticide treatments. In addition to the mandatory phytosanitary measures, the demand for new strategies compatible with integrated pest management is increasing. In this study, laboratory biological assays were performed to assess the potential toxic effect of vegetal formulations against P. spumarius adults. Two formulations were tested at different concentrations: Form A, an emulsion of 10% hot pepper-infused oil (Capsicum annuum subspecies Cayenna in olive oil) and Arabic gum in an aqueous solution of extracts of Salvia guaranitica, and Form B, an aqueous solution of extracts of Taxus baccata. Both Form A and B showed to be toxic against P. spumarius compared to the water control. The mean percentage of spittlebug mortality obtained with Form A one hour after treatments was dose-dependent; the lethal dose values were 0.13% (LD25), 0.36% (LD50), and 0.85% (LD75). At the same time, no significant differences in mortality rate were observed between the 0.75% treatment and the treatments with deltamethrin (about 90%). The mean percentage of spittlebug mortality obtained with Form B ranged from 21% to 53% one hour after treatment, but these values were significantly lower than those obtained with deltamethrin. The effectiveness of Form A on the P. spumarius population was also evaluated in the field. The averages of captures in the three experimental blocks were 1.8/trap for treated and 7.7/trap for untreated plots, and the spittlebug populations significantly decreased after treatments. Based on these results and the literature data, we hypothesize that the effectiveness of Form A is the result of the synergistic effect of all its components. No symptoms of phytotoxicity were recorded on olive trees treated with Form A, and the number of P. spumarius specimens collected on these plants was much lower than on untreated plants. These results suggest the potential use of Form A in the protection of olive trees. This vegetal formulation can thus be considered as a valid alternative to chemical insecticides for the control of the main vector of X. fastidiosa and could be integrated into a sustainable management system for OQDS.

Androgenic alopecia (AGA) is a dermatological disease with psychosocial consequences for those who experience hair loss. AGA is linked to an increase in androgen levels caused by an excess of dihydrotestosterone in blood capillaries produced from testosterone by 5α-reductase type II (5αR2), which is expressed in scalp hair follicles; 5αR2 activity and dihydrotestosterone levels are elevated in balding scalps. The diverse health benefits of flavonoids have been widely reported in epidemiological studies, and research interest continues to increase. In this study, a virtual screening approach was used to identify compounds that interact with active site residues of 5αR2 by screening a library containing 241 flavonoid compounds. Here, we report two potent flavonoid compounds, eriocitrin and silymarin, that interacted strongly with 5αR2, with binding energies of -12.1 and -11.7 kcal/mol, respectively, which were more significant than those of the control, finasteride (-11.2 kcal/mol). Molecular dynamic simulations (200 ns) were used to optimize the interactions between compounds and 5αR2 and revealed that the interaction of eriocitrin and silymarin with 5αR2 was stable. The study shows that eriocitrin and silymarin provide developmental bases for novel 5αR2 inhibitors for the management of AGA.

Natural products have successfully treated several diseases using a multi-component, multi-target mechanism. However, a precise mechanism of action (MOA) has not been identified. Systems pharmacology methods have been used to overcome these challenges. However, there is a limitation as those similar mechanisms of similar components cannot be identified. In this study, comparisons of physicochemical descriptors, molecular docking analysis and RNA-seq analysis were performed to compare the MOA of similar compounds and to confirm the changes observed when similar compounds were mixed and used. Various analyses have confirmed that compounds with similar structures share similar MOA. We propose an advanced method for in silico experiments in herbal medicine research based on the results. Our study has three novel findings. First, an advanced network pharmacology research method was suggested by partially presenting a solution to the difficulty in identifying multi-component mechanisms. Second, a new natural product analysis method was proposed using large-scale molecular docking analysis. Finally, various biological data and analysis methods were used, such as in silico system pharmacology, docking analysis and drug response RNA-seq. The results of this study are meaningful in that they suggest an analysis strategy that can improve existing systems pharmacology research analysis methods by showing that natural product-derived compounds with the same scaffold have the same mechanism.

The Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) has become a global health crisis, and the urgent need for effective treatments is evident. One potential target for COVID-19 therapeutics is the main protease (Mpro) of SARS‑CoV‑2, an essential enzyme for viral replication. Natural compounds have been explored as a source of potential inhibitors for Mpro due to their safety and availability. In this study, we employed a computational approach to screen a library of phytoconstituents and identified potential Mpro inhibitors based on their binding affinities and molecular interactions. The top-ranking compounds were further validated through molecular dynamics simulations (MDS) and free energy calculations. As a result of the above procedures, we identified two phytoconstituents, Khelmarin B and Neogitogenin, with appreciable binding affinity and specificity towards the Mpro binding pocket. Our results suggest that Khelmarin B and Neogitogenin could potentially serve as Mpro inhibitors and have the potential to be developed as COVID-19 therapeutics. Further experimental studies are required to confirm the efficacy and safety of these compounds.Communicated by Ramaswamy H. Sarma.

A neurodegenerative disorder (ND) refers to Huntington\'s disease (HD) which affects memory loss, weight loss, and movement dysfunctions such as chorea and dystonia. In the striatum and brain, HD most typically impacts medium-spiny neurons. Molecular genetics, excitotoxicity, oxidative stress (OS), mitochondrial, and metabolic dysfunction are a few of the theories advanced to explicit the pathophysiology of neuronal damage and cell death. Numerous in-depth studies of the literature have supported the therapeutic advantages of natural products in HD experimental models and other treatment approaches. This article briefly discusses the neuroprotective impacts of natural compounds against HD models. The ability of the discovered natural compounds to suppress HD was tested using either in vitro or in vivo models. Many bioactive compounds considerably lessened the memory loss and motor coordination brought on by 3-nitropropionic acid (3-NP). Reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and enhanced mitochondrial energy generation have profoundly decreased the biochemical change. It is significant since histology showed that therapy with particular natural compounds lessened damage to the striatum caused by 3-NP. Moreover, natural products displayed varying degrees of neuroprotection in preclinical HD studies because of their antioxidant and anti-inflammatory properties, maintenance of mitochondrial function, activation of autophagy, and inhibition of apoptosis. This study highlighted about the importance of bioactive compounds and their semi-synthetic molecules in the treatment and prevention of HD.

BACKGROUND: Cancer remains the major cause of morbidity and mortality. The nuclear factor kappa-B (NF- κB) plays an indispensable role in cancer cell proliferation and drug resistance. The role of NF-κB is not only limited to tumor cell proliferation and suppression of apoptotic genes but it also induces EMT transition responsible for metastasis. Inhibition of the NF-κB pathway in cancer cells by herbal derivatives makes it a favorable yet promising target for cancer therapeutics.
OBJECTIVE: The purpose of the study is to explore the inhibition potential of Nimbin and its analogs against NF-κB subunits p50 and p65.
METHODS: In the present study, an herbal compound Nimbin and its derivative analogs were investigated to examine their impact on the p50 and p65 subunits of the NF-κB signaling pathway using in silico tools, namely molecular docking and simulation.
RESULTS: The molecular docking analysis revealed that Nimbin and its analogs may bind to p50 and p65 subunits with dG bind values ranging from -33.23 to -50.49 Kcal/mol. Interestingly, molecular dynamic simulation for the NO5-p65 complex displayed a stable conformation and convergence when compared to the NO4-p50 complex.
CONCLUSIONS: These results indicate that NO5 may have a potential inhibitory effect against NF-κB subunit p65, which needs to be further validated in in vitro and in vivo systems. Also, the results obtained emphasize and pave the way for exploring the Nimbin scaffold against NF-κB inhibition for cancer therapeutics.

Myostatin is a widely recognized inhibitory factor of skeletal muscle growth and significantly influences muscle development and metabolism. In mice, myostatin inhibition improves insulin sensitivity, increases glucose uptake by skeletal muscle, and reduces body fat. Furthermore, Mss51 is downregulated in response to myostatin inhibition, and its deletion appears to improve the metabolic state of skeletal muscle and reduce adipose tissue, which makes Mss51 a potential target for the treatment of obesity and type 2 diabetes. Here, we report a computationally predicted and validated three-dimensional structure of Mss51. Computational screening was used to identify naturally occurring compounds from the Herbal and Specs chemical database that might inhibit Mss51, based on binding affinities and physiochemical and ADMET properties. ZINC00338371, ZINC95099599 and ZINC08214878 were found to bind to Mss51 with high binding affinity and specificity. In addition, 100 ns molecular dynamics simulations were conducted to assess the stabilities of the interactions between the three compounds and Mss51. MD simulation demonstrated that all three compounds bind to the active pocket site of Mss51 stably and cause conformation changes. ZINC00338371 was found to bind most stably with binding free energy -229.022 ± 13.776 kJ/mol to Mss51, suggesting that it has therapeutic potential as a treatment option for obesity and type 2 diabetes.Communicated by Ramaswamy H. Sarma.