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In this study, the initial focus was on exploring the simultaneous impact of the oil-based food matrix and the polarity of rosmarinic acid derivatives on the antioxidant properties. Rosmarinic acid (RA) showed remarkable DPPH, FRAP, and ABTS radical scavenging activities, followed by methyl rosmarinate (MR) and ethyl rosmarinate (ER). In bulk oil, both conjugated dienes and p-AnV values reached a peak in the following order after 30 days: ER > MR > RA = BHT > control (no antioxidant). In the oil structured using monoacylglycerol, MR was more effective than ER and RA. For ethyl cellulose oleogel, emulsion, and gelled emulsion systems, RA was more effective. Additionally, after confirming the importance of the food matrix on the antioxidant activity of RA derivatives, the lipophilization of RA with ethanol was optimized as a model with Lipozyme 435 in hexane. A conversion yield of as high as 85.59% for ER was achieved, as quantified by HPLC-UV and confirmed by HPLC-DAD-ESI-qTOFMS., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The SARS-CoV-2 coronavirus is characterized by high mutation rates and significant infectivity, posing ongoing challenges for therapeutic intervention. To address potential challenges in the future, the continued development of effective drugs targeting SARS-CoV-2 remains an important task for the scientific as well as the pharmaceutical community. The main protease (M pro ) of SARS-CoV-2 is an ideal therapeutic target for COVID-19 drug development, leading to the introduction of various inhibitors, both covalent and non-covalent, each characterized by unique mechanisms of action and possessing inherent strengths and limitations. Natural products, being compounds naturally present in the environment, offer advantages such as low toxicity and diverse activities, presenting a viable source for antiviral drug development. Here, we identified a natural compound, rosmarinic acid, which exhibits significant inhibitory effects on the M pro of the SARS-CoV-2. Through detailed structural biology analysis, we elucidated the precise crystal structure of the complex formed between rosmarinic acid and SARS-CoV-2 M pro , revealing the molecular basis of its inhibitory mechanism. These findings not only enhance our understanding of the antiviral action of rosmarinic acid, but also provide valuable structural information and mechanistic insights for the further development of therapeutic strategies against SARS-CoV-2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aβ-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aβ toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aβ deposition in Aβ 1-42 -injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Molecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new N-acyl-cinnamoyl-hydrazone hybrid molecular architecture. Twenty-eight new compounds were synthesized and evaluated for multifunctional activities related to Parkinson's disease (PD), including neuroprotection, antioxidant, metal chelating ability, and Keap1/Nrf2 pathway activation. Compounds 3b (PQM-161) and 3e (PQM-164) were highlighted for their significant antioxidant profile, acting directly as induced free radical stabilizers by DPPH and indirectly by modulating intracellular inhibition of t-BOOH-induced ROS formation in neuronal cells. The mechanism of action was determined as a result of Keap1/Nrf2 pathway activation by both compounds and confirmed by different experiments. Furthermore, compound 3e (PQM-164) exhibited a significant effect on the accumulation of α-synuclein and anti-inflammatory activity, leading to an expressive decrease in gene expression of iNOS, IL-1β, and TNF-α. Overall, these results highlighted compound 3e as a promising and innovative multifunctional drug prototype candidate for PD treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hyperpigmentation disorders may result from inappropriate melanin deposition and/or excessive melanin synthesis. They are classified mainly as aesthetic problems, but they can significantly affect human health by decreasing self-esteem. There are available only limited treatment options for hyperpigmentation disorder, among others, cosmetic products applied topically. Depigmenting ingredients were found to be ineffective and characterized by various side effects. As a result, many efforts are made to discover novel, potent, and safe melanogenesis inhibitors for possible use in topical cosmetic depigmenting formulations. Cinnamic acid derivatives constitute a widely tested group for that purpose. This article reports research in the group of N-alkyl cinnamamide derivatives (un)substituted in phenyl ring. Among tested series, (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide (compound 21) showed the most promising inhibitory properties in mushroom tyrosinase assay (IC 50  = 36.98 ± 1.07 µM for monophenolase activity, IC 50  = 146.71 ± 16.82 µM for diphenolase activity) and melanin production inhibition in B16F10 mouse melanoma cell line at concentration 6.25 µM resulting probably from decreasing of Tyr, Mitf, Tyrp-1, and Tyrp-2 genes expression. This compound also showed melanin production inhibitory properties in pigmented reconstructed human epidermis when used in 1 % and 2 % solutions in 50 % PEG400. In vitro evaluation of its safety profile showed no cytotoxicity to human keratinocytes HaCaT, human skin fibroblasts BJ, and human primary epidermal melanocytes HEMa, no mutagenicity in the Ames test, no genotoxicity in micronucleus test, no phototoxicity, as well as no skin irritation potential tested in PEG400 solution. This compound was also shown to penetrate across the epidermis to reach the possible site of action. The performed research led to classify (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide as a novel potential depigmenting cosmetic ingredient., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Antimicrobial resistance has emerged as a significant danger to global health, and the need for more effective antimicrobial resistance (AMR) control has been highlighted. Cinnamic acid is abundant in plant products and is a potential starting material for further modification, focusing on the development of new antimicrobial compounds. In the following review, we describe the classification of critical antibacterial-guided reactions applied to the main skeleton structure of cinnamic acid derivatives over the last decade. Of all of the main parts of cinnamic acids, the phenyl ring and the carboxylic group significantly affect antibacterial activity. The results presented in the following review can provide valuable insights into considerable features in the organic modification of cinnamic acids related to antibacterial medication development and the food industry.

Danggui-Jianzhong decoction (DGJZ) is a famous classical traditional Chinese medicine formula, which ingredients are complex and the quality is difficult to control. Our study aimed to identify the overall chemical profile of DGJZ qualitatively by ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and UPLC. A total of 77 components, including terpenoids, flavonoids, phenolic acids, gingerols and other components, were firstly detected and characterized by UPLC-Q-TOF-MS and 18 peaks marked after analyzing the UPLC fingerprint. Finally, paeoniflorin, liquiritin, ferulic acid, cinnamic acid, glycyrrhizic acid and 6-gingerol were quantified, which was validated in terms of linearity, precision, accuracy, repeatability and recovery. Taken together, the chemical constitutes of DGJZ were systematically identified and a reliable quantitative method coupled with fingerprint analysis was successfully employed for evaluating the holistic quality, which will provide a robust foundation for the quality control of DGJZ., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This study introduces a novel cheminformatic read-across approach designed to identify potential environmental obesogens, substances capable of disrupting metabolism and inducing obesity by mainly influencing nuclear hormone receptors (NRs). Leveraging real-valued two-dimensional features derived from chemical fingerprints of 8435 Tox21 compounds, cluster analysis and subsequent statistical testing revealed 385 clusters enriched with compounds associated with specific NR targets. Notably, one cluster exhibited selective enrichment in peroxisome proliferator-activated receptor γ (PPARγ) agonist activity, prominently featuring methoxy cinnamate ultraviolet (UV) filters and obesogen-related compounds. Experimental validation confirmed that 2-ethoxyethyl 4-methoxycinnamate, an organic UV filter cinoxate, could selectively bind to PPARγ ( K i = 18.0 μM), eliciting an obesogenic phenotype in human bone marrow-derived mesenchymal stem cells during adipogenic differentiation. Molecular docking and further experiments identified cinoxate as a potent PPARγ full agonist, demonstrating a preference for coactivator SRC3 recruitment. Moreover, cinoxate upregulated transcription levels of genes encoding lipid metabolic enzymes in normal human epidermal keratinocytes as primary cells exposed during clinical usage. This study provides compelling evidence for the efficacy of cheminformatic read-across analysis in prioritizing potential obesogens, showcasing its utility in unveiling cinoxate as an obesogenic PPARγ agonist.

Aim : To synthesize new hybrid cinnamic acids ( 10a , 10b and 11 ) and ester derivatives ( 7 , 8 and 9 ) and investigate their anti-breast cancer activities. Materials & methods: Compounds 7-11 were evaluated ( in vitro ) for their cytotoxic activities against the MCF-7 cell line. A flow cytometry examination was performed. Protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), topoisomerase II and caspase-9 were measured by qRT-PCR. Molecular docking studies were conducted. Results : Several components were discovered to be active, mainly component 11 , which induced arrest in the cell cycle at phase S, greatly decreased the expression of Nrf2 and topoisomerase II; and upregulated the expression of caspase-9. Conclusion: The newly thiohydantoin-cinnamic acid hybrids can contribute to creating promising candidates for cancer drugs.

This study aimed to determine the effect of the administration dose, combinations with co-antioxidants (vitamin C, caffeic acid, chlorogenic acid, catechin, rutin), and different food matrices (cooked and lyophilized hen eggs, chicken breast, soybean seeds, potatoes) on the potential bioaccessibility of rosmarinic acid (RA) in simulated digestion conditions, depending on the digestion stage (gastric and intestinal) and the contribution of physicochemical and biochemical digestion factors. The in vitro bioaccessibility of RA depended on the digestion stage and conditions. The physicochemical factors were mainly responsible for the bioaccessibility of RA applied alone. The higher RA doses improved its bioaccessibility, especially at the intestinal stage of digestion. Furthermore, the addition of vitamin C and protein-rich food matrices resulted in enhanced intestinal bioaccessibility of RA. In the future, the knowledge of factors influencing the bioaccessibility of RA can help enhance its favorable biological effects and therapeutic potential., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Degenerative conditions, such as neurodegenerative disorders (Alzheimer's disease (AD), Parkinson's disease (PD)) and cardiovascular diseases, are complex, multifactorial disorders whose pathophysiology has not been fully elucidated yet. As a result, the available treatment options cannot eliminate these diseases radically, but only alleviate the symptoms. Both inflammatory processes and oxidation are key factors in the development and evolution of neurodegeneration, while acetylcholinesterase inhibitors are the most used therapeutic options against AD. In this work, following the multi-targeting compound approach, we designed and synthesized a series of proline and gamma-aminobutyric acid (GABA) amides with various acidic moieties that possess an antioxidant and/or anti-inflammatory potency. Proline is the pharmacophore of nootropic drugs (e.g., piracetam) used for memory improvement, while GABA is the main inhibitory neurotransmitter in the central nervous system. The designed molecules were subjected to a preliminary screening of their bioactivity in antioxidant and anti-inflammatory assays, as well as against acetylcholinesterase. Most of the synthesized compounds could inhibit lipid peroxidation (IC 50 as low as 8 μΜ) and oxidative protein glycation (inhibition of up to 48%) and reduce the 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH). In addition, all of the compounds were moderate inhibitors of lipoxygenase (LOX) (up to 46% at 100 μΜ) and could decrease carrageenan-induced paw edema in rats by up to 55%. Finally, some of the compounds were moderate acetylcholinesterase inhibitors (IC 50 as low as 219 μΜ). The results confirmed the design rationale, indicating that the compounds could be further optimized as multi-targeting molecules directed against degenerative conditions.

Cinnamomum tamala leaf (CTL), also known as Indian bay leaf, is used all over the world for seasoning, flavoring, and medicinal purposes. These characteristics could be explained by the presence of several essential bioactive substances and lipid derivatives. In this work, rapid screening and identification of the chemical compounds in supercritical (SC)-CO 2 extracts of CTL by use of UPLC-Q-TOF-MSE with a multivariate statistical analysis approach was established in both negative and positive mode. A total of 166 metabolites, including 66 monocarboxylic fatty acids, 52 dicarboxylic fatty acids, 27 fatty acid amides, and 21 cinnamic acid derivatives, were tentatively identified based on accurate mass and the mass spectrometric fragmentation pattern, out of which 142 compounds were common in all SC-CO 2 extracts of CTL. Further, PCA and cluster hierarchical analysis clearly discriminated the chemical profile of analyzed extracts and allowed the selection of SC-CO 2 extract rich in fatty acids, fatty acid amides, and other bioactive constituents. The result showed that the higher number of compounds was detected in CTL4 (300 bar/55 °C) extract than the other CTL extracts. The mono- and di-carboxylic fatty acids, fatty acid amides, and cinnamic acid derivatives were identified in CTL for the first time. UPLC-Q-TOF-MS E combined with chemometric analysis is a powerful method to rapidly screen the metabolite profiling to justify the quality of CTL as a flavoring agent and in functional foods.

Introduction: Pseudomonas aeruginosa is a ubiquitous pathogen that causes various infectious diseases through the regulation of quorum sensing (QS). The strategy of interfering with the QS systems of P. aeruginosa , coupled with a reduction in the dosage of conventional antibiotics, presents a potential solution to treating infection and mitigating antibiotic resistance. In this study, seven cinnamoyl hydroxamates were synthesized to evaluate their inhibitory effects on QS of P. aeruginosa . Among these cinnamic acid derivatives, we found cinnamoyl hydroxamic acid (CHA) and 3-methoxy-cinnamoyl hydroxamic acid (MCHA) were the two most effective candidates. Furtherly, the effect of CHA and MCHA on the production of virulence factors and biofilm of P. aeruginosa were evaluated. Ultimately, our study may offer promising potential for treating P. aeruginosa infections and reducing its virulence., Methods: The disc diffusion test were conducted to evaluate inhibitory effects on QS of seven cinnamoyl hydroxamates. The influence of CHA and MCHA on the production of virulence and flagellar motility of P. aeruginosa was furtherly explored. Scanning electron microscopy (SEM) experiment were conducted to evaluate the suppression of CHA and MCHA on the formed biofilm of P. aeruginosa . RT-qPCR was used to detect rhlI, lasA, lasB, rhlA, rhlB, and oprL genes in P. aeruginosa . In silico docking study was performed to explore the molecular mechanism of CHA and MCHA. The synergistic effects of CHA with gentamicin were detected on biofilm cell dispersal., Result: After treatment of CHA or MCHA, the production of multiple virulence factors, including pyocyanin, proteases, rhamnolipid, and siderophore, and swimming and swarming motilities in P. aeruginosa were inhibited significantly. And our results showed CHA and MCHA could eliminate the formed biofilm of P. aeruginosa . RT-qPCR revealed that CHA and MCHA inhibited the expression of QS related genes in P. aeruginosa . Molecular docking indicated that CHA and MCHA primarily inhibited the RhlI/R system in P. aeruginosa by competing with the cognate signaling molecule C4-HSL.Additionally, CHA exhibited potent synergistic effects with gentamicin on biofilm cell dispersal., Discussion: P. aeruginosa is one of the most clinically and epidemiologically important bacteria and a primary cause of catheter-related urinary tract infections and ventilator-associated pneumonia. This study aims to explore whether cinnamoyl hydroxamates have inhibitory effects on QS. And our results indicate that CHA and MCHA, as two novel QSIs, offer promising potential for treating P. aeruginosa infections and reducing its virulence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pan, Wu, Li, Wang and Jia.)

Magnetic drug delivery systems using nanoparticles present a promising opportunity for clinical treatment. This study explored the potential anti-inflammatory properties of RosA- CrFe2O4 nanoparticles. These nanoparticles were developed through rosmarinic acid (RosA) co-precipitation via a photo-mediated extraction technique. XRD, FTIR, and TEM techniques were employed to characterize the nanoparticles, and the results indicated that they had a cubic spinel ferrite (FCC) structure with an average particle size of 25nm. The anti-inflammatory and antioxidant properties of RosA- CrFe2O4 nanoparticles were evaluated by using LPS-induced raw 264.7 macrophages and a hydrogen peroxide scavenging assay, respectively. The results showed that RosA- CrFe2O4 nanoparticles had moderate DPPH scavenging effects with an IC50 value of 59.61±4.52μg/ml. Notably, these nanoparticles effectively suppressed the expression of pro-inflammatory genes (IL-1β, TNF-α, IL-6, and iNOS) in LPS-stimulated cells. Additionally, the anti-inflammatory activity of RosA- CrFe2O4 nanoparticles was confirmed by reducing the release of secretory pro-inflammatory cytokines (IL-6 and TNF-α) in LPS-stimulated macrophages. This investigation highlights the promising potential of Phyto-mediated CrFe2O4-RosA as an anti-inflammatory and antioxidant agent in biomedical applications., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Al-Hunaiti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Isoamyl 4-methoxycinnamate (IMC) is widely used in various fields because of its exceptional UV-filter properties. However, due to its cytotoxicity and anti-microbial degradability, the potential eco-environmental toxicity of IMC has become a focus of attention. In this study, we propose a host-guest supramolecule approach to enhance the functionality of IMC, resulting in a more environmentally friendly and high-performance materials. Sulfobutyl-β-cyclodextrin sodium salt (SBE-β-CD) was used as the host molecule. IMC-SBE-β-CD supramolecular substances were prepared through the "saturated solution method", and their properties and biosecurity were evaluated. Meanwhile, we conducted the AOS tree evaluation system that surpasses existing evaluation approaches based on apoptosis, oxidative stress system, and signaling pathways to investigate the toxicological mechanisms of IMC-SBE-β-CD within human hepatoma SMMC-7721 cells as model organisms. The AOS tree evaluation system aims to offer the comprehensive analysis of the cytotoxic effects of IMC-SBE-β-CD. Our findings showed that IMC-SBE-β-CD had an encapsulation rate of 84.45% and optimal stability at 30 °C. Further, IMC-SBE-β-CD promoted cell growth and reproduction without compromising the integrity of mitochondria and nucleus or disrupting oxidative stress and apoptosis-related pathways. Compared to IMC, IMC-SBE-β-CD is biologically safe and has improved water solubility with the UV absorption property maintained. Our study provides the foundation for the encapsulation of hydrophobic, low-toxicity organic compounds using cyclodextrins and offers valuable insights for future research in this field.

The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics., (© 2024 Wiley Periodicals LLC.)

Gentiopicroside (Gp) and swertiamarin (Sm), secoiridoid glycosides commonly found in plants of the Gentianaceae family, differ in one functional group. They exhibit promising cytotoxic effects in cancer cell lines and overall protective outcomes, marking them as promising molecules for developing novel pharmaceuticals. To investigate potential variations in cellular sensitivity to compounds of similar molecular structures, we analyzed the mode of Gp and Sm induced cell death in human peripheral blood mononuclear cells (PBMCs) after 48 h of treatment. The lowest tested concentration that significantly reduces cell viability, 50 μM, was applied. Oxidative stress parameters were estimated by measuring the levels of prooxidative/antioxidative balance, lipid peroxidation products, and 8-oxo-7,8-dihydro-2-deoxyguanosine, while gene expression of DNA repair enzymes was evaluated by employing quantitative real-time PCR. Cellular morphology was analyzed by fluorescent microscopy, and immunoblot analysis of apoptosis and necroptosis-related proteins was used to assess the type of cell death induced by the treatments. The discriminatory impact of Gp/Sm treatments on apoptosis and necroptosis-induced cell death was evaluated by monitoring the cell survival in co-treatment with specific cell death inhibitors. Obtained results show greater cytotoxicity of Gp than Sm suggesting that variations in the molecular structures of the tested compounds can substantially affect their biological effects. Gp/Sm co-treatment with apoptosis and necroptosis inhibitors revealed a distinct, albeit non-specific mechanism of PBMCs cell death. Although the therapeutic may not directly cause a specific type of cell death, its extent can be pivotal in assessing the safety of therapeutic application and developing phytopharmaceuticals with improved features. Since phytopharmaceuticals affect all exposed cells, identification of cytotoxic mechanisms on PBMCs after Gp and Sm treatment is important for addressing the formulation and dosage of potential phytopharmaceuticals., Competing Interests: Declaration of Competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The transformation of salvianolic acid B brought on by heat treatment recovery of ethanol eluent, which is a difficult problem in pharmaceutical technology, affects the purity of raw material when the medicinal raw material salvianolic acid B is purified by resin. Ultrasonic-assisted nanofiltration separation (UANS) was first employed to improve efficiency of resource utilization by regulating rejection and separating salvianolic acid B and rosmarinic acid from organic pharmaceutical wastewater. The rejection was related to three variables: ultrasonic power, pH, and ethanol concentration. But there were differences in the effects of variables on the rejections of salvianolic acid B and rosmarinic acid. The rejections of rosmarinic acid and salvianolic acid B showed a decreasing trend with an increase in ultrasonic power or a decrease in pH; however, when the concentration of ethanol was increased from 5 % to 35 %, the salvianolic acid B rejection increased from 84.96 % to 96.60 % and the rosmarinic acid rejection decreased from 35.09 % to 17.51 %. On the basis of response surface methodology (RSM), the optimal UANS parameters for solution conditions involving different ethanol concentrations are as follows: 10 % ethanol solution (ultrasonic power 500 W and pH 6.15), 20 % ethanol solution (ultrasonic power 500 W and pH 6.54), and 30 % ethanol solution (ultrasonic power 460 W and pH 6.34). The molecular proportions of salvianolic acid B were 10.75 %, 7.13 %, and 8.27 % in 10 %, 20 %, and 30 % ethanol wastewater, while the molecular proportions of rosmarinic acid were 40.52 %, 33.83 %, and 69.87 %, respectively. And the recoveries of salvianolic acid B in 10 %, 20 %, and 30 % ethanol wastewater were 93.56 %, 95.04 %, and 97.30 %, respectively, while the recoveries of rosmarinic acid were 3.19 %, 2.27 %, and 0.56 %. The molecular proportion and the rejection are correlated exponentially. In comparison with conventional nanofiltration separation (CNS), UANS is able to resolve the conflict between rosmarinic acid and salvianolic acid B in pharmaceutical wastewater, as well as enhance resource recycling and separation efficiency to prevent pollution of the environment from pharmaceutical wastewater. Experiments using UANS at different power intensities suggest that the ultrasonic at a power intensity of 46-50 W/L and the power density of 0.92-1.00 W/cm 2 may resolve the separation conflict between rosmarinic acid and salvianolic acid B. This work suggests that UANS may be a significant advancement in the field of ultrasonic separation and has several potential uses in the water treatment industry., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Various wound dressings have been developed so far for wound healing, but most of them are ineffective in properly reestablishing the skin's structure, which increases infection risks and dehydration. Electrospun membranes are particularly interesting for wound dressing applications because they mimic the extracellular matrix of healthy skin. In this study, a potential wound healing platform capable of inducing synergistic antibacterial and antioxidation activities was developed by incorporating bio-active rosmarinic acid-hydroxyapatite hybrid (HAP-RA) with different contents (0.5, 1, and 1.5 wt.%) into the electrospun polyamide 6 (PA6) nanofibers. Then, polyethylene glycol (PEG) was introduced to the nanofibrous composite to improve the biocompatibility and biodegradability of the dressing. The results indicated that the hydrophilicity, water uptake, biodegradability, and mechanical properties of the obtained PA6/PEG/HAP-RA nanofibrous composite enhanced at 1 wt.% of HAP-RA. The nanofibrous composite had excellent antibacterial activity. The antioxidation potential of the samples was assessed in vitro. The MTT assay performed on the L929 cell line confirmed the positive effects of the nanofibrous scaffold on cell viability and proliferation. According to the results, the PA6/PEG/HAP-RA nanofibrous composite showed the desirable physiochemical and biological properties besides antibacterial and antioxidative capabilities, making it a promising candidate for further studies in wound healing applications., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

The species Bathysa gymnocarpa K.Schum is a tree belonging to the Rubiaceae family, endemic in Brazil. So far, there are reports neither of phytochemical work nor of biological evaluation of it. The analysis by High Performance Liquid Chromatography coupled to a Diode Array Detector and a tandem Mass Spectrometer with an Electrospray Ionization source (HPLC-DAD-ESI-MS/MS) of its crude extract allowed to characterize in a complex mixture, without isolation, fourteen compounds, being two as cinnamic acid derivatives, and the others as mono-, di- and triglycosilated derivatives of the flavonols quercetin and kaempferol. These compounds are reported for the first time in Bathysa spp.

Lamellar gel networks (LGNs) in personal care or pharmaceutical lotions and creams provide an opaque cream appearance and a creamy texture to these products. Within the LGNs, the lamellar gel (L β ) phase composed of regularly spaced bilayers of surfactants and long-chain fatty alcohols is predominately responsible for the unique rheological properties of the LGNs. To extend the shelf life of LGN-containing products, bioactive compounds with antimicrobial properties are often incorporated into the formulation. However, how the protonation state of the bioactive compounds regulates their release from the L β -phase bilayers is currently unknown. Using molecular dynamics simulations, we found that the protonated (neutral) form of cinnamic acid, a common antimicrobial food additive, has a retention ratio higher than that of its deprotonated (charged) counterpart in the L β -phase bilayer. From free energy calculations, we determined that not only is the protonated molecule more stable in the hydrophobic interior of the bilayer but also the formation of hydrogen-bonded dimers significantly enhances its stability within the bilayer. Thus, the protonation state has a profound impact on bioavailability of the compounds. Our results also highlight the importance of considering possible oligomeric states of molecules when performing calculations to estimate the permeability of molecules within various bilayers.

Chemotherapeutic drugs and radiotherapy are fundamental treatments to combat cancer, but, often, the doses in these treatments are restricted by their non-selective toxicities, which affect healthy tissues surrounding tumors. On the other hand, drug resistance is recognized as the main cause of chemotherapeutic treatment failure. Rosmarinic acid (RA) is a polyphenol of the phenylpropanoid family that is widely distributed in plants and vegetables, including medicinal aromatic herbs, consumption of which has demonstrated beneficial activities as antioxidants and anti-inflammatories and reduced the risks of cancers. Recently, several studies have shown that RA is able to reverse cancer resistance to first-line chemotherapeutics, as well as play a protective role against toxicity induced by chemotherapy and radiotherapy, mainly due to its scavenger capacity. This review compiles information from 56 articles from Google Scholar, PubMed, and ClinicalTrials.gov aimed at addressing the role of RA as a complementary therapy in cancer treatment.

Hyaluronidase possesses the capacity to degrade high-molecular-weight hyaluronic acid into smaller fragments, subsequently initiating a cascade of inflammatory responses and activating dendritic cells. In cases of bacterial infections, substantial quantities of HAase are generated, potentially leading to severe conditions such as cellulitis. Inhibiting hyaluronidase activity may offer anti-inflammatory benefits. Salvia miltiorrhiza Bunge, a traditional Chinese medicine, has anti-inflammatory properties. However, its effects on skin inflammation are not well understood. This study screened and evaluated the active components of S. miltiorrhiza that inhibit skin inflammation, using ligand fishing, enzyme activity assays, drug combination analysis, and molecular docking. By combining magnetic nanomaterials with hyaluronidase functional groups, we immobilized hyaluronidase on magnetic nanomaterials for the first time in the literature. We then utilized an immobilized enzyme to specifically adsorb the ligand; two ligands were identified as salvianolic acid B and rosmarinic acid by HPLC analysis after desorption of the dangling ligands, to complete the rapid screening of potential anti-inflammatory active ingredients in S. miltiorrhiza roots. The median-effect equation and combination index results indicated that their synergistic inhibition of hyaluronidase at a fixed 3:2 ratio was enhanced with increasing concentrations. Kinetic studies revealed that they acted as mixed-type inhibitors of hyaluronidase. Salvianolic acid B had K i and K is values of 0.22 and 0.96 μM, respectively, while rosmarinic acid had values of 0.54 and 4.60 μM. Molecular docking revealed that salvianolic acid B had a higher affinity for hyaluronidase than rosmarinic acid. In addition, we observed that a 3:2 combination of SAB and RA significantly decreased the secretion of TNF-α, IL-1, and IL-6 inflammatory cytokines in UVB-irradiated HaCaT cells. These findings identify salvianolic acid B and rosmarinic acid as key components with the potential to inhibit skin inflammation, as found in S. miltiorrhiza . This research is significant for developing skin inflammation treatments. It demonstrates the effectiveness and broad applicability of the magnetic nanoparticle-based ligand fishing approach for screening enzyme inhibitors derived from herbal extracts.

Nanoparticles (NPs) are important in regulating plant tolerance to salt stress. Peppermint is one of the most widely used aromatic plants, with a high sensitivity to salt stress. The present study investigated physiological and biochemical factors to understand better the behavior of cinnamic acid (CA) and cinnamic acid nanocomposite in salinity control in peppermint plants. The first factor was salt stress with different salt concentrations, including 0, 50, 100, and 150 mg/L, the second factor was 50 μM CA, and the third factor was 50 μM CA nanocomposite based on carboxymethyl cellulose (CMC-CA NC). Results showed that stress markers increased with increasing salinity levels. On the contrary, plants treated with salinity showed a decrease in physiological and photosynthetic parameters, while the application of CA and CMC CA NC increased these critical parameters. Under salinity, compared to the control, malondialdehyde and hydrogen peroxide contents decreased by 11.3% and 70.4%, respectively. Furthermore, CA and CMC-CA NC enhanced peppermint tolerance to salinity by increasing compatible solute content such as proline, free amino acids, protein content, and soluble carbohydrates, increasing antioxidant enzymes, and decreasing stress markers in plant tissues. Compared to the control, chlorophyll fluorescence and proline content increased by 1.1% and 172.1%, respectively. Salinity stress negatively affected all physiological and biochemical parameters, but CA and CMC-CA NC treatments improved them. We concluded that the nanocomposite, a biostimulant, significantly enhances mint tolerance under salinity conditions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Noncovalent interactions of 4 selected phenolic acids, including gallic acid (GA), caffeic acid (CA), chlorogenic acid (CGA), and rosmarinic acid (RA) with lactoferrin (LF) were investigated. Compound combined with LF in the binding constant of CA > GA > RA > CGA, driven by van der Waals and hydrogen bonding for GA, and hydrophobic forces for others. Conformation of LF was affected at secondary and ternary structure levels. Molecular docking indicated that GA and CA located in the same site near the iron of the C-lobe, whereas RA and CGA bound to the C2 and N-lobe, respectively. Significantly enhanced antioxidant activity of complexes was found compared with pure LF, as demonstrated by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis(2-ethylbenzothiazoline-6-sulfonate) (ABTS), and ferric reducing antioxidant power (FRAP) models. Caffeic acid, CGA, and RA significantly decreased the emulsifying stability index and improved foam ability of LF, and the effect of CA and RA was the most remarkable, respectively., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC 50 : 1.52±0.19 μmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72±93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the C Brain /C Serum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Myotoxicity caused by snakebite envenoming emerges as one of the main problems of ophidic accidents as it is not well neutralized by the current serum therapy. A promising alternative is to search for efficient small molecule inhibitors that can act against multiple venom components. Phospholipase A 2 (PLA 2 ) is frequently found in snake venom and is usually associated with myotoxicity. Thus it represents an excellent target for the search of new treatments. This work reports the effect of temperature in the inhibition of catalytic properties of PLA 2 from Bothrops brazili venom by Rosmarinic (RSM) and Chlorogenic (CHL) acids through experimental and computational approaches. Three temperatures were evaluated (25, 37 and 50 °C). In the experimental section, enzymatic assays showed that RSM is a better inhibitor in all three temperatures. At 50 °C, the inhibition efficiency decayed significantly for both acids. Docking studies revealed that both ligands bind to the hydrophobic channel of the protein dimer where the phospholipid binds in the catalytic process, interacting with several functional residues. In this context, RSM presents better interaction energies due to stronger interactions with chain B of the dimer. Molecular dynamics simulations showed that RSM can establish selective interactions with ARG112B of PLA 2 , which is located next to residues of the putative Membrane Disruption Site in PLA2-like structures. The affinity of RSM and CHL acids towards PLA 2 is mainly driven by electrostatic interactions, especially salt bridge interactions established with residues ARG33B (for CHL) and ARG112B (RSM) and hydrogen bonds with residue ASP89A. The inability of CHL to establish a stable interaction with ARG112B was identified as the reason for its lower inhibition efficiency compared to RSM at the three temperatures. Furthermore, extensive structural analysis was performed to explain the lower inhibition efficiency at 50 °C for both ligands. The analysis performed in this work provides important information for the future design of new inhibitors.Communicated by Ramaswamy H. Sarma.

Cinnamic acids are aromatic acids primarily found in plants and plant-derived food. Phenolic cinnamic acids, with one or more hydroxyl groups in the aromatic ring, often contribute to the biological activities attributed to these compounds. The presence of hydroxyl groups and a carboxyl group makes cinnamic acids very hydrophilic, preventing them from crossing biological membranes and exerting their biological activities. To alleviate this condition, a panel of synthetic modifications have been made leading to a diverse set of phenolic cinnamic structures. In this review, an overview of the natural phenolic cinnamic acid derivatives and their plant sources (more than 200) is described. The synthetic approaches to obtain the referred derivatives (more than 200) namely esters and amides are reviewed. Further, their anti-inflammatory activity (more than 70 compounds) is scrutinized. Finally, future directions will be indicated to translate the research on phenolic cinnamic derivatives into potentially effective anti-inflammatory drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

This work aimed to explore an alternative to the use of antibiotics for prevention and treatment of wounds infection caused by two common bacterial pathogens Staphylococcus aureus and Pseudomonas aeruginosa. For this purpose, three different essential oil components (EOCs), namely carvacrol, citronellol and cinnamic acid, were loaded into electrospun fibers of poly-ε-caprolactone (PCL) aided by alpha-cyclodextrin (αCD) and hydroxypropyl-β-cyclodextrin (HPβCD). Electrospun-fibers prepared with each EOC and their mixtures were screened for antimicrobial capability and characterized regarding morphological, mechanical, thermal, surface polarity, antibiofilm and antioxidant properties. αCD formed poly(pseudo)rotaxanes with PCL and weakly interacted with EOCs, while HPβCD facilitated EOC encapsulation and formation of homogeneous fibers (500-1000 nm diameter) without beads. PCL/HPβCD fibers with high concentration of EOCs (mainly carvacrol and cinnamic acid) showed strong antibiofilm (>3 log CFU reduction) and antioxidant activity (10-50% DPPH scavenging effects). Different performances were recorded for the EOCs and their mixtures; cinnamic acid migrated to fiber surface and was released faster. Fibers biocompatibility was verified using hemolysis tests and in ovo tissue integration and angiogenesis assays. Overall, HPβCD facilitates complete release of EOCs from the fibers to the aqueous medium, being an environment-friendly and cost-effective strategy for the treatment of infected wounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, and the therapeutic is focused on several approaches including the inhibition of fibril formation by small compounds, avoiding the formation of cytotoxic oligomers. Thus, we decided to explore the capacity of compounds carrying catechol moieties to inhibit the progression of α-synuclein. Overall, the compounds rosmarinic acid (1), carnosic acid (2), carnosol (3), epiisorosmanol (4), and rosmanol (5) avoid the progression of fibril formation assessed by Thiofavine T (ThT), and atomic force microscopy images showed that morphology is influenced for the actions of compounds over fibrillization. Moreover, ITC experiments showed a K d varying from 28 to 51 µM, the ΔG showed that the reaction between compounds and α-syn is spontaneous, and ΔH is associated with an exothermic reaction, suggesting the interactions of hydrogen bonds among compounds and α-syn. Docking experiments reinforce this idea showing the intermolecular interactions are mostly hydrogen bonding within the sites 2, 9, and 3/13 of α-synuclein, and compounds 1 and 5. Thus, compound 1, rosmarinic acid, interestingly interacts better with site 9 through catechol and Lysines. In cultured Raw 264. 7 cells, the presence of compounds showed that most of them can promote cell differentiation, especially rosmarinic acid, and rosmanol, both preserving tubulin cytoskeleton. However, once we evaluated whether or not the aggregates pre-treated with compounds could prevent the disruption of microtubules of Raw 264.7 cells, only pre-treated aggregates with rosmarinic acid prevented the disruption of the cytoskeleton. Altogether, we showed that especially rosmarinic acid not only inhibits α-syn but stabilizes the remaining aggregates turning them into not-toxic to Raw 264.7 cells suggesting a main role in cell survival and antigen processing in response to external α-syn aggregates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) is a potential drug target for diabetes. The DYRK1A inhibitor can promote β cells proliferation, increase insulin secretion and reduce blood sugar in diabetes. In this paper, a series β-carboline-cinnamic acid skeletal derivatives were designed, synthesized and evaluated to inhibit the activity of DYRK1A and promote pancreatic islet β cell proliferation. Pharmacological activity showed that all of the compounds could effectively promote pancreatic islet β cell proliferation at a concentration of 1 μM, and the cell viability of compound A1, A4 and B4 reached to 381.5 %, 380.2 % and 378.5 %, respectively. Compound A1, A4 and B4 could also inhibit the expression of DYRK1A better than positive drug harmine. Further mechanistic studies showed that compound A1, A4 and B4 could inhibit DYRK1A protein expression via promoting its degradation and thus enhancing the expression of proliferative proteins PCNA and Ki67. Molecular docking showed that β-carboline scaffold of these three compounds was fully inserted into the ATP binding site and formed hydrophobic interactions with the active pocket. Besides, these three compounds were predicted to possess better drug-likeness properties using SwissADME. In conclusion, compounds A1, A4 and B4 were potent pancreatic β cell proliferative agents as DYRK1A inhibitors and might serve as promising candidates for the treatment of diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Drug repurposing and rescuing have been widely explored as cost-effective approaches to expand the portfolio of chemotherapeutic agents. Based on the reported antitumor properties of both trans-cinnamic acids and quinacrine, an antimalarial aminoacridine, we explored the antiproliferative properties of two series of N-cinnamoyl-aminoacridines recently identified as multi-stage antiplasmodial leads. The compounds were evaluated in vitro against three cancer cell lines (MKN-28, Huh-7, and HepG2), and human primary dermal fibroblasts. One of the series displayed highly selective antiproliferative activity in the micromolar range against the three cancer cell lines tested, without any toxicity to non-carcinogenic cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Phenolic acids still gain significant attention due to their potential antimicrobial and cytotoxic properties. In this study, we have investigated the antimicrobial of six phenolic acids, namely chlorogenic, caffeic, p-coumaric, rosmarinic, gallic and tannic acids in the concentration range 0.5-500 μM, against Escherichia coli and Lactobacillus rhamnosus. The antimicrobial activity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Additionally, the cytotoxic effects of these phenolic acids on two cancer cell lines, the colorectal adenocarcinoma Caco-2 cell line and Dukes' type C colorectal adenocarcinoma DLD-1 cell line was examined. To further understand the molecular properties of these phenolic acids, quantum chemical calculations were performed using the Gaussian 09W program. Parameters such as ionization potential, electron affinity, electronegativity, chemical hardness, chemical softness, dipole moment, and electrophilicity index were obtained. The lipophilicity properties represented by logP parameter was also discussed. This study provides a comprehensive evaluation of the antimicrobial and cytotoxic activity of six phenolic acids, compounds deliberately selected due to their chemical structure. They are derivatives of benzoic or cinnamic acids with the increasing number of hydroxyl groups in the aromatic ring. The integration of experimental and computational methodologies provides a knowledge of the molecular characteristics of bioactive compounds and partial explanation of the relationship between the molecular structure and biological properties. This knowledge aids in guiding the development of bioactive components for use in dietary supplements, functional foods and pharmaceutical drugs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kalinowska et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The emphasis on sustainable sources of drug development seems imminent with phytochemicals emerging as promising candidates due to their minimal probability of adverse effects. This study focuses on utilizing simple cinnamic acid and nicotinic acid derivatives as starting materials, employing an efficient synthetic protocol to obtain methyl 5-((cinnamoyloxy)methyl)picolinate targeting CVD mediated by multiple enzymes such as MAPK, PCSK9, MPO, SIRT1 and TNF-α. Comprehensive characterization of synthesized molecule is achieved through 1 H, 13 C, FT-IR, and HRMS methods. Additionally, the crystal structure was established via SC-XRD. Comparative analysis with the DFT-optimized structure identifies key nucleophilic and electrophilic regions for determining interactions with bio-targets. Notably, Compound 5 adheres to all drug-likeness criteria, further validated through screening similar pharmacophoric drugs from databases. Targeting bio-relevant areas with a specific focus on CVD drug development. The molecular docking studies elucidate ligand-protein interactions for better binding connectivity. This investigation further underscores the importance of sustainable practices, simple chemical synthesis, and computational approaches, contributing to the pursuit of eco-friendly drug development with enhanced safety profiles (MTT assay)., (© 2024. The Author(s).)

Callus cultures of the Iranian medicinal plant Salvia atropatana were initiated from three-week-old seedlings on Murashige and Skoog (MS) medium supplemented with α-naphthaleneacetic acid (NAA) and various cytokinins. Although all tested hormonal variants of the medium and explant enabled callus induction, the most promising growth was noted for N -(2-chloro-4-pyridyl)- N '-phenylurea (CPPU)-induced calli. Three lines obtained on this medium (cotyledon line-CL, hypocotyl line-HL, and root line-RL) were preselected for further studies. Phenolic compounds in the callus tissues were identified using UPLC-MS (ultra-performance liquid chromatography-mass spectrometry) and quantified with HPLC (high-performance liquid chromatography). All lines exhibited intensive growth and contained twelve phenolic acid derivatives, with rosmarinic acid predominating. The cotyledon-derived callus line displayed the highest growth index values and polyphenol content; this was exposed to different light-emitting diodes (LED) for improving biomass accumulation and secondary metabolite yield. Under LED treatments, all callus lines exhibited enhanced RA and total phenolic content compared to fluorescent light, with the highest levels observed for white (48.5-50.2 mg/g dry weight) and blue (51.4-53.9 mg/g dry weight) LEDs. The selected callus demonstrated strong antioxidant potential in vitro based on the 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) tests. Our findings confirm that the S. atropatana callus system is suitable for enhanced rosmarinic acid production; the selected optimized culture provide high-quality plant-derived products.

Abdominal wall defects are common clinical diseases, and mesh repair is the standard treatment method. The most commonly used polypropylene (PP) mesh in clinical practice has the advantages of good mechanical properties, stable performance, and effective tissue integration effect. However, direct contact between abdominal viscera and PP mesh can lead to severe abdominal adhesions. To prevent this, the development of a hydrogel-PP composite mesh with anti-adhesive properties may be an effective measure. Herein, biofunctional hydrogel loaded with rosmarinic acid is developed by modifying chitosan and Pluronic F127, which possesses suitable physical and chemical properties and commendable in vitro biocompatibility. In the repair of full-thickness abdominal wall defects in rats, hydrogels are injected onto the surface of PP mesh and applied to intraperitoneal repair. The results indicate that the use of hydrogel-PP composite mesh can alleviate abdominal adhesions resulting from traditional PP mesh implantation by decreasing local inflammatory response, reducing oxidative stress, and regulating the fibrinolytic system. Combined with the tissue integration ability of PP mesh, hydrogel-PP composite mesh has great potential for repairing full-thickness abdominal wall defects., (© 2024 Wiley‐VCH GmbH.)

Investigation of a novel thermophilic esterase gene from Geobacillus subterraneus DSMZ 13552 indicated a high amino acid sequence similarity of 25.9% to a reported esterase from Geobacillus sp. A strategy that integrated computer-aided rational design tools was developed to select mutation sites. Six mutants were selected from four criteria based on the simulated saturation mutation (including 19 amino acid residues) results. Of these, the mutants Q78Y and G119A were found to retain 87% and 27% activity after incubation at 70 °C for 20 min, compared with the 19% activity for the wild type. Subsequently, a double-point mutant (Q78Y/G119A) was obtained and identified with optimal temperature increase from 65 to 70 °C and a 41.51% decrease in K m . The obtained T 1/2 values of 42.2 min (70 °C) and 16.9 min (75 °C) for Q78Y/G119A showed increases of 340% and 412% compared with that in the wild type. Q78Y/G119A was then employed as a biocatalyst to synthesize cinnamyl acetate, for which the conversion rate reached 99.40% with 0.3 M cinnamyl alcohol at 60 °C. The results validated the enhanced enzymatic properties of the mutant and indicated better prospects for industrial application as compared to that in the wild type. This study reported a method by which an enzyme could evolve to achieve enhanced thermostability, thereby increasing its potential for industrial applications, which could also be expanded to other esterases., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Human skin is the first line of photoprotection against UV radiation. However, despite having its defence mechanisms, the photoprotection that the skin exerts is not enough. To protect human skin, the inclusion of UV filters in the cosmetic industry has grown significantly as a photoprotection strategy. Octylmethoxycinnamate, also designated by octinoxate, or 2-ethylhexyl-4-methoxycinnamate (CAS number: 5466-77-3) is one of the most widely used UV-B filter in the cosmetic industry. The toxic effects of OMC have alarmed the public, but there is still no consensus in the scientific community about its use. This article aims to provide an overview of the UV filters' photoprotection, emphasizing the OMC and the possible negative effects it may have on the public health. Moreover, the current legislation will be addressed. In summary, the recommendations should be rethought to assess their risk-benefit, since the existing literature warns us to endocrine-disrupting effects of OMC. Further studies should be focus on the toxicity of OMC alone, in mixture and should consider its degradation products, to improve the knowledge of its risk assessment as EDC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Ischemic stroke (IS) is a serious cerebrovascular disease characterized by significantly elevated mortality and disability rates, and the treatments available for this disease are limited. Neuroinflammation and oxidative stress are deemed the major causes of cerebral ischemic injury. N-Cinnamoylpyrrole alkaloids form a small group of natural products from the genus Piper and have not been extensively analyzed pharmacologically. Thus, identifying the effect and mechanism of N-cinnamoylpyrrole-derived alkaloids on IS is worthwhile., Purpose: The present research aimed to explore the antineuroinflammatory and antioxidative stress effects of N-cinnamoylpyrrole-derived alkaloids isolated from the genus Piper and to explain the effects and mechanism on IS., Methods: N-cinnamoylpyrrole-derived alkaloids were isolated from Piper boehmeriaefolium var. tonkinense and Piper sarmentosum and identified by various chromatographic methods. Lipopolysaccharide (LPS)-induced BV-2 microglia and a mouse model intracerebroventricularly injected with LPS were used to evaluate the antineuroinflammatory and antioxidative stress effects. Oxygen‒glucose deprivation/reperfusion (OGD/R) and transient middle cerebral artery occlusion (tMCAO) models were used to evaluate the effect of PB-1 on IS. To elucidate the fundamental mechanism, the functional target of PB-1 was identified by affinity-based protein profiling (ABPP) strategy and verified by cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and circular dichroism (CD) analyses. The effect of PB-1 on the NF-κB and NRF2 signaling pathways was subsequently evaluated via western blotting and immunofluorescence staining., Results: The results showed that N-cinnamoylpyrrole-derived alkaloids significantly affected neuroinflammation and oxidative stress. The representative compound, PB-1 not only inhibited neuroinflammation and oxidative stress induced by LPS or OGD/R insult, but also alleviated cerebral ischemic injury induced by tMCAO. Further molecular mechanism research found that PB-1 promoted antineuroinflammatory and antioxidative stress activities via the NF-κB and NRF2 signaling pathways by targeting eEF1A1., Conclusion: Our research initially unveiled that the therapeutic impact of PB-1 on cerebral ischemic injury might rely on its ability to target eEF1A1, leading to antineuroinflammatory and antioxidative stress effects. The novel discovery highlights eEF1A1 as a potential target for IS treatment and shows that PB-1, as a lead compound that targets eEF1A1, may be a promising therapeutic agent for IS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Most biosynthetic gene clusters (BGCs) are functionally inaccessible by using fermentation methods. Bioinformatic-coupled total synthesis provides an alternative approach for accessing BGC-encoded bioactivities. To date, synthetic bioinformatic natural product (synBNP) methods have focused on lipopeptides containing simple lipids. Here we increase the bioinformatic and synthetic complexity of the synBNP approach by targeting BGCs that encode N -cinnamoyl lipids. This led to our synthesis of cinnamosyn, a 10-mer N -cinnamoyl-containing peptide that is cytotoxic to human cells.

Perilla frutescens var. acuta (Lamiaceae) is widely used not only as an oil or a spice, but also as a traditional medicine to treat colds, coughs, fever, and indigestion. As an ongoing effort, luteolin-7- O -diglucuronide ( 1 ), apigenin-7- O -diglucuronide ( 2 ), and rosmarinic acid ( 3 ) isolated from P. frutescens var. acuta were investigated for their anti-adipogenic and thermogenic activities in 3T3-L1 cells. Compound 1 exhibited a strong inhibition against adipocyte differentiation by suppressing the expression of Pparg and Cebpa over 52.0% and 45.0%, respectively. Moreover, 2 inhibited the expression of those genes in a dose-dependent manner [ Pparg : 41.7% (5 µM), 62.0% (10 µM), and 81.6% (50 µM); Cebpa : 13.8% (5 µM), 18.4% (10 µM), and 37.2% (50 µM)]. On the other hand, the P. frutescens var. acuta water extract showed moderate thermogenic activities. Compounds 1 and 3 also induced thermogenesis in a dose-dependent manner by stimulating the mRNA expressions of Ucp1 , Pgc1a , and Prdm16 . Moreover, an LC-MS/MS chromatogram of the extract was acquired using UHPLC-MS 2 and it was analyzed by feature-based molecular networking (FBMN) and the Progenesis QI software (version 3.0). The chemical profiling of the extract demonstrated that flavonoids and their glycoside derivatives, including those isolated earlier as well as rosmarinic acid, are present in P. frutescens var. acuta .

This review presents an overview of the biological applications of coordinative compounds based on unsaturated carboxylates accompanied by other ligands, usually N-based heterocyclic species. The interest in these compounds arises from the valuable antimicrobial and antitumor activities evidenced by some species, as well as from their ability to generate metal-containing polymers suitable for various medical purposes. Therefore, we describe the recently discovered aspects related to the synthesis, structure, and biological activity of a wide range of unsaturated carboxylate-containing species and metal ions, originating mostly from 3d series. The unsaturated carboxylates encountered in coordinative compounds are acrylate, methacrylate, fumarate, maleate, cinnamate, ferulate, coumarate, and itaconate. Regarding the properties of the investigated compounds, it is worth mentioning the good ability of some to inhibit the development of resistant strains or microbial biofilms on inert surfaces or, even more, exert antitumor activity against resistant cells. The ability of some species to intercalate into DNA strands as well as to scavenge ROS species is also addressed.

Newly, green metallic-nanoparticles (NPs) have received scientists' interest due to their wide variable medicinal applications owned to their economical synthesis and biologically compatible nature. In this study, we used rosmarinic acid (RosA) to prepare Cu 0.5 Zn 0.5 FeO 4 NPs and later encapsulated them using PEG polymer. Characterization of NPs was done using the XRD method and SEM imaging. Further, we explored the encapsulated NPs for anti-inflammatory properties by downregulating the expression of pro-inflammatory cytokines mRNA in LPS-stimulated Raw 264.7 cells. Besides, employing DPPH, NO and ABTS radical scavenging assays to examine the antioxidant activity of the synthesized Cu 0.5 Zn 0.5 FeO 4 NPs. Cu0.5Zn0.5FeO4 NPs revealed moderate antioxidant activity by scavenging DPPH and nitric oxide. We demonstrated that the NPs showed high potential anti-inflammatory activity by suppressing the mRNA and protein levels of pro-inflammatory cytokines in a dose-dependent manner, in LPS-induced Raw 264.7 cells. To our best knowledge, this is the first report where RosA was found to be a suitable phyto source for the green synthesis of Cu0.5Zn0.5FeO4 NPs and their in vitro anti-inflammatory and antioxidant effects. Taken together, our findings suggest that the RosA is a green resource for the eco-friendly synthesis of Cu0.5Zn0.5FeO4/PEG NPs, which further can be employed as a novel anti-inflammatory therapeutic agent., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The current investigation encompasses the structural planning, synthesis, and evaluation of the urease inhibitory activity of a series of molecular hybrids of hydroxamic acids and Michael acceptors, delineated from the structure of cinnamic acids. The synthesized compounds exhibited potent urease inhibitory effects, with IC 50 values ranging from 3.8 to 12.8 µM. Kinetic experiments unveiled that the majority of the synthesized hybrids display characteristics of mixed inhibitors. Generally, derivatives containing electron-withdrawing groups on the aromatic ring demonstrate heightened activity, indicating that the increased electrophilicity of the beta carbon in the Michael Acceptor moiety positively influences the antiureolytic properties of this compounds class. Biophysical and theoretical investigations further corroborated the findings obtained from kinetic assays. These studies suggest that the hydroxamic acid core interacts with the urease active site, while the Michael acceptor moiety binds to one or more allosteric sites adjacent to the active site., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this study, cinnamic acid modified acid-ethanol hydrolyzed starch (CAES) with different degrees of substitution (DS) was fabricated to stabilize Pickering emulsions and probed their application for encapsulating curcumin (Cur). Successful preparation of CAES (with DS from 0.016 to 0.191) was confirmed by 1 H NMR and FT-IR, and their physicochemical properties were characterized by XRD, SEM, and TGA. The biosafety evaluations and surface wettability confirmed the excellent safety and amphiphilic character of CAES. CAES-stabilized Pickering emulsion (CS-PE) exhibited different emulsion stability at different DS, with CS-PE (0.031) showing the highest stability. CLSM revealed that the CAES (0.031) formed a dense barrier on the surface of the oil droplets, preventing them from coalescing. The CS-PE (0.031) achieved effective encapsulation of Cur (up to 96.2 %). Compared with free Cur, CS-PE (0.031) exhibited better photochemical stability, higher free fatty acids (FFA) release, and enhanced bioaccessibility. These studies suggested that CAES may serve as a promising emulsifier for stabilizing Pickering emulsions to encapsulate and deliver hydrophobic bioactive compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Severe acute respiratory syndrome-related Coronavirus 2 (SARS-CoV-2) has infected more than 762 million people to date and has caused approximately 7 million deaths all around the world, involving more than 187 countries. Although currently available vaccines show high efficacy in preventing severe respiratory complications in infected patients, the high number of mutations in the S proteins of the current variants is responsible for the high level of immune evasion and transmissibility of the virus and the reduced effectiveness of acquired immunity. In this scenario, the development of safe and effective drugs of synthetic or natural origin to suppress viral replication and treat acute forms of COVID-19 remains a valid therapeutic challenge. Given the successful history of flavonoids-based drug discovery, we developed esters of substituted cinnamic acids with quercetin to evaluate their in vitro activity against a broad spectrum of Coronaviruses. Interestingly, two derivatives, the 3,4-methylenedioxy 6 and the ester of acid 7, have proved to be effective in reducing OC43-induced cytopathogenicity, showing interesting EC50s profiles. The ester of synaptic acid 7 in particular, which is not endowed with relevant cytotoxicity under any of the tested conditions, turned out to be active against OC43 and SARS-CoV-2, showing a promising EC 50 . Therefore, said compound was selected as the lead object of further analysis. When tested in a yield reduction, assay 7 produced a significant dose-dependent reduction in viral titer. However, the compound was not virucidal, as exposure to high concentrations of it did not affect viral infectivity, nor did it affect hCoV-OC43 penetration into pre-treated host cells. Additional studies on the action mechanism have suggested that our derivative may inhibit viral endocytosis by reducing viral attachment to host cells.

An excessive inflammatory response of the gastrointestinal tract is recognized as one of the major contributors to ulcerative colitis (UC). Despite this, effective preventive approaches for UC remain limited. Rosmarinic acid (RA), an enriched fraction from Perilla frutescens , has been shown to exert beneficial effects on disease-related inflammatory disorders. However, RA-enriched perilla seed meal (RAPSM) and perilla seed (RAPS) extracts have not been investigated in dextran sulfate sodium (DSS)-induced UC in mice. RAPSM and RAPS were extracted using the solvent-partitioning method and analyzed with high-pressure liquid chromatography (HPLC). Mice with UC induced using 2.5% DSS for 7 days were pretreated with RAPSM and RAPS (50, 250, 500 mg/kg). Then, the clinical manifestation, colonic histopathology, and serum proinflammatory cytokines were determined. Indeed, DSS-induced UC mice exhibited colonic pathological defects including an impaired colon structure, colon length shortening, and increased serum proinflammatory cytokines. However, RAPSM and RAPS had a protective effect at all doses by attenuating colonic pathology in DSS-induced UC mice, potentially through the suppression of proinflammatory cytokines. Concentrations of 50 mg/kg of RAPSM and RAPS were sufficient to achieve a beneficial effect in UC mice. This suggests that RAPSM and RAPS have a preventive effect against DSS-induced UC, potentially through alleviating inflammatory responses and relieving severe inflammation in the colon.