Polyphenols Research Articles

Construction of core@double-shell structured energetic composites with simultaneously enhanced thermal stability and safety performance

The poor thermal stability and high sensitivity severely hinder the practical application of hexanitrohexaazaisowurtzitane (CL-20). Herein, a kind of novel core@double-shell CL-20 based energetic composites were fabricated to address the above issues. The coordination complexes which consist of natural polyphenol tannic acid (TA) and FeIII were chosen to construct the inner shell, while the graphene sheets were used to build the outer shell. The resulting CL-20/TA-FeIII/graphene composites exhibited simultaneously improved thermal stability and safety performance with only 1 wt% double-shell content, which should be ascribed to the intense physical encapsulation effect from inner shell combined with the desensitization effect of carbon nano-materials from outer shell. The phase transition (ε to γ) temperature increased from 173.70 °C of pure CL-20 to 191.87 °C of CL-20/TA-FeIII/graphene composites. Meanwhile, the characteristic drop height (H50) dramatically increased from 14.7 cm of pure CL-20 to 112.8 cm of CL-20/TA-FeIII/graphene composites, indicating much superior safety performance after the construction of the double-shell structure. In general, this work has provided an effective and versatile strategy to conquer the thermal stability and safety issues of CL-20 and contributes to the future application of high energy density energetic materials.

Construction and Properties of High-Toughness Soft-Soft Interfaces Based on the Adhesion of Natural Polyphenols.

Artificial joint replacement is the most effective way to treat osteoarthritis. However, these artificial joints are too stiff with high interfacial contact stress and poor surface lubrication, resulting in stress shielding and severe wear and tear lead to an extremely high failure rate. At present, hydrogels are considered the most promising substitute for artificial joint prostheses owing to their good biocompatibility, adjustable mechanical properties, and excellent flexibility. Nevertheless, a traditional single-layer hydrogel has poor bearing capacity and lubrication, which are far from the properties of natural articular cartilage. The high strength and low friction properties of natural articular cartilage are based on its own multilayer fibrous structure. Therefore, by simulating the multilayer structure of natural cartilage, a bilayer bionic cartilage hydrogel was prepared; that is, the upper hydrogel realized excellent lubrication and the lower hydrogel realized high load-bearing capacity. However, the interface binding of bilayer hydrogels is a challenge at present. Therefore, the interfacial adhesion of the bilayer hydrogel is improved by adding tannic acid (TA) based on the adhesion of the natural polyphenol structure. The average interfacial toughness reaches 3650 J/m2, and the average interfacial shear force reaches 800 kPa. In the preparation of the bilayer hydrogel, taking advantage of the coordination reaction between TA and metal cations, Fe3+ is further added to endow the bilayer hydrogel with excellent mechanical properties and good sliding friction performance. Therefore, this work opens up a new way to construct cartilage-like materials with high toughness and a soft-soft interface.

Natural Polyphenols From Moringa and Centella Extracts as Collagen Cross-Linkers and Matrix Metalloproteinase (MMP) Inhibitors in Dentin Preservation: An In Vitro Study

Natural Polyphenols From Moringa and Centella Extracts as Collagen Cross-Linkers and Matrix Metalloproteinase (MMP) Inhibitors in Dentin Preservation: An In Vitro Study

Grape seed proanthocyanidin improves intestinal inflammation in canine through regulating gut microbiota and bile acid compositions.

Although certain progress has been made in treating canine inflammatory bowel disease (IBD), a large proportion of dogs have a poor prognosis and may develop resistance and side effects. Therefore, it is of great significance to prevent or alleviate canine IBD through nutritional intervention. Plant polyphenol can interact with intestinal bacteria and has important prospects in the intestinal health improvement. This study evaluated the effect of grape seed proanthocyanidin (GSP), a plant-derived natural polyphenol, on Labrador Retrievers with mild IBD. In Experiment 1 of this study, GSP alleviated persistent intestinal inflammation in canines by improving inflammatory indexes and reducing intestinal permeability. Moreover, GSP treatment increased the abundance of bacteria with potential anti-inflammatory properties and engaging bile acid metabolism, including Ruminococcaceae, Faecalibacterium, Ruminococcus_torques_group, and Lachnospiraceae_NK4A136_group. Notably, targeted metabolomic analysis identified elevated productions of fecal chenodeoxycholic acid and its microbial transformation product lithocholic acid, which might contribute to relieving canine intestinal inflammation. Further, in Experiment 2, fecal microbiota transplantation was used to determine whether gut microbiota is a potential mechanism for GSP efficacy. Dogs with mild IBD received the fecal microbiota from the group administered GSP and mirrored the improvement effects of GSP, which results verified that gut microbial alteration could be an underlying mechanism for GSP efficiency on canine IBD. Our findings highlight that the mechanism of the GSP function on canine IBD is mediated by altering gut microbial composition and improving bile acid metabolism. This study proposes a natural polyphenol-based dietary strategy for improving canine intestinal health.

Utilization of rice production residues as a reinforcing agent in bioadhesives based on polyphenols extracted from the bark of trees from the Brazilian Cerrado biome

The scarcity of nonrenewable resources and the increase in environmental pollution have intensified the search for materials that exhibit specific characteristics and are nontoxic, renewable, and sustainable. Thus, the objective of this work was to produce natural polyphenol adhesives reinforced with rice husk and its ash to increase the mechanical resistance and moisture resistance of the glue line in wood bonded joints. Polyphenols were extracted from the bark of Stryphnodendron adstringens (Mart.) Coville (barbatimão). Adhesives were produced with a 50 % solid and 50 % liquid composition. Rice husk and husk ash underwent X-ray fluorescence analysis (XRF). Adhesives and reinforcement material were characterized by Fourier transform infrared (FTIR) and thermogravimetric analyses (TGA). The adhesives were glued in a mechanical press in specimens made of Pinus elliottii, which were subjected to shear testing of the wet and dry glue line. As a result, the chemical components present in rice husk and its ash positively influenced the properties of the adhesives. The mechanical glue line shear test showed that the adhesive reinforced with rice husk ash did not show a statistically significant difference. However, natural adhesives based on polyphenols from barbatimão strengthened with rice husk and ash showed improved properties, demonstrating how much it pays to use the residue of rice production to reinforce the matrix of tannin adhesives. Thus, it can be determined that reinforcement with rice husk and ash is efficient in improving some properties of natural adhesives based on polyphenols.

Metal-Phenolic Networks for Chronic Wounds Therapy.

Chronic wounds are recalcitrant complications of a variety of diseases, with pathologic features including bacterial infection, persistent inflammation, and proliferation of reactive oxygen species (ROS) levels in the wound microenvironment. Currently, the use of antimicrobial drugs, debridement, hyperbaric oxygen therapy, and other methods in clinical for chronic wound treatment is prone to problems such as bacterial resistance, wound expansion, and even exacerbation. In recent years, researchers have proposed many novel materials for the treatment of chronic wounds targeting the disease characteristics, among which metal-phenolic networks (MPNs) are supramolecular network structures that utilize multivalent metal ions and natural polyphenols complexed through ligand bonds. They have a flexible and versatile combination of structural forms and a variety of formations (nanoparticles, coatings, hydrogels, etc.) that can be constructed. Functionally, MPNs combine the chemocatalytic and bactericidal properties of metal ions as well as the anti-inflammatory and antioxidant properties of polyphenol compounds. Together with the excellent properties of rapid synthesis and negligible cytotoxicity, MPNs have attracted researchers' great attention in biomedical fields such as anti-tumor, anti-bacterial, and anti-inflammatory. This paper will focus on the composition of MPNs, the mechanisms of MPNs for the treatment of chronic wounds, and the application of MPNs in novel chronic wound therapies.

Polyphenolic natural products as photosensitizers for antimicrobial photodynamic therapy: recent advances and future prospects.

Antimicrobial photodynamic therapy (aPDT) has become a potent contender in the fight against microbial infections, especially in the context of the rising antibiotic resistance crisis. Recently, there has been significant interest in polyphenolic natural products as potential photosensitizers (PSs) in aPDT, given their unique chemical structures and inherent antimicrobial properties. Polyphenolic natural products, abundant and readily obtainable from natural sources, are generally regarded as safe and highly compatible with the human body. This comprehensive review focuses on the latest developments and future implications of using natural polyphenols as PSs in aPDT. Paramount polyphenolic compounds, including curcumin, hypericin, quercetin, hypocrellin, celastrol, riboflavin, resveratrol, gallic acid, and aloe emodin, are elaborated upon with respect to their structural characteristics, absorption properties, and antimicrobial effects. Furthermore, the aPDT mechanism, specifically its targeted action on microbial cells and biofilms, is also discussed. Polyphenolic natural products demonstrate immense potential as PSs in aPDT, representing a promising alternate approach to counteract antibiotic-resistant bacteria and biofilm-related infections.

Metal-free multifunctional nanozymes mimicking endogenous antioxidant system for acute kidney injury alleviation

Cellular redox homeostasis is highly dependent on endogenous antioxidant systems, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). The nanozymes mimicking the catalytic activities of natural antioxidant systems serve as potential candidates for the therapy of reactive oxygen species (ROS)-related diseases. However, previously reported metal-containing nanozymes possessed unsatisfactory catalytic activity and inevitable peroxidase activity, limiting their translational applications. Therefore, inspired by the superior ROS scavenging activities of natural polyphenols and metal-free carbon dots (CDs) with ultra-small size, phenol-functionalized CDs that mimic endogenous antioxidant system have been fabricated. The SOD activity was determined at an extremely high level (18187 U/mg), which was substantially comparable to natural SOD. Notably, this study reveals for the first time that CDs, as selenium-free nanomaterials, show robust GPx activity in vitro. The theory calculation suggests that the bond dissociation of phenols on CDs is considerably lower than selenocysteine of natural GPx, which facilitates the formation of peroxide intermediate to initiate GPx-like reactions. Furthermore, the kidney-targeting and intracellular antioxidant mimicking properties contribute to the effective alleviating cisplatin-induced acute kidney injury via suppressing oxidative stress-mediated ferroptosis in vivo. These results provide an effective polyphenol-functionalized strategy for synthesizing metal-free multifunctional antioxidant nanozyme to treat ROS-related diseases.

Quality and shelf life of strawberry fruit as affected by edible coating by moringa leaf extract, aloe vera gel, oxalic acid, and ascorbic acid

ABSTRACT In the current study, the most effective concentrations of moringa leaf extract (MLE), aloe vera gel (AV gel), ascorbic acid (1 mM) and oxalic acid (5 mM) were used. Physically mature fruits harvested from a commercial orchard were dipped in aqueous solutions of different edible coatings and kept at ambient conditions (25±2ºC & 55-60% RH) for evaluation of the quality and enzymatic parameters on daily basis till marketability. Current results revealed that 5 mM ascorbic acid treatment resulted in 57% reduced fruit weight loss; while 20% AV gel coating increased firmness by 60% over a 5-day ambient storage period. Application 6% MLE exhibited 50.7% and 49.7% reduced respiration rate and ethylene production respectively. Fruit biochemical quality parameters were also improved with the lowest accumulation of total soluble solids as a result of slow respiration, higher titratable acidity, ascorbic acid contents, carotenoids and anthocyanin contents in all treated fruit. While, total phenolic contents and total antioxidants along with superoxide dismutase, catalase, peroxidase, and anthocyanins were higher in ascorbic acid treated fruits. The activity of poly phenol oxidase enzyme was lowest in fruits treated with 5 mM ascorbic acid solution. Conclusively, the application of different edible coatings was proved to be beneficial as numerous fruit biochemical and antioxidative attributes were improved by ascorbic acid treatment; furthermore, MLE, AV gel and oxalic acid treatments were also helpful in maintaining fruit quality of strawberry fruits over a 5-days ambient storage period.

Recent Advances in Functional Cellulose-based Films with Antimicrobial and Antioxidant Properties for Food Packaging.

The packaging of food plays a crucial role in food preservation worldwide. However, traditional packaging systems are passive layers with weak efficiency in protecting the food quality. Therefore, packaged foods are gradually spoiled due to the oxidation and growth of microorganisms. Additionally, most of the commercial packaging films are made of petroleum-based materials which raise environmental concerns. Accordingly, the development of eco-friendly natural-derived active packaging systems has increased the attention of scientists. Cellulose as the most abundant polysaccharide on earth with high biocompatibility, no toxicity, and high biodegradability has extensively been applied for the fabrication of packaging films. However, neat cellulose-based films lack antioxidant and antimicrobial activities. Therefore, neat cellulose-based films are passive films with weak food preservation performance. Active films have been developed by incorporating antioxidants and antimicrobial agents into the films. In this review, we have explored the latest research on the fabrication of antimicrobial/antioxidant cellulose-based active packaging films by incorporating natural extracts, natural polyphenols, nanoparticles, and microparticles into the cellulose-based film formulations. We categorized these types of packaging films into two main groups: (i) blend films which are obtained by mixing solutions of cellulose with other soluble antimicrobial/antioxidant agents such as natural extracts and polyphenols; and (ii) composite films which are fabricated by dispersing antimicrobial/antioxidant nano- or microfillers into the cellulose solution. The effect of these additives on the antioxidant and antimicrobial properties of the films has been explained. Additionally, the changes in the other properties of the films such as hydrophilicity, water evaporation rate, and mechanical properties have also been briefly addressed.

Fabrication of Robust Superhydrophobic Polyester Fabrics with Photothermal Conversion and Oil-Water Separation Performance through Deposition of Natural Polyphenols.

Superhydrophobic polyester (PET) fabrics were created by increasing fabric surface roughness and decreasing surface energy through interactions between natural polyphenols, ferrous sulfate heptahydrate, and hexadecyltrimethoxysilane. The superhydrophobic fabric can be obtained with different natural polyphenols, including tannic acid, ferulic acid, gallic acid, guaiacol, and caffeic acid. Durability tests were carried out on the superhydrophobic PET fabric, investigating resistance to washing, rubbing, UV aging, acids, alkalis, and organic reagents. The results demonstrate the stability and versatility of modified PET in complex environments. The modified superhydrophobic PET fabric exhibited exceptional oil-water separation and self-cleaning properties, exhibiting a water contact angle of 161.3° and a sliding angle of 4°. In addition, the modified fabric demonstrated a remarkable photothermal conversion efficiency, with the surface temperature increasing from 29.1 to 72 °C in 300 s, and it maintained a degree of photothermal conversion capability even upon completion of four cycles. This study offers novel perspectives on extending the utilization of natural polyphenols for constructing durable, robust, and multifunctional superhydrophobic fabrics.

Resveratrol and beyond: The Effect of Natural Polyphenols on the Cardiovascular System: A Narrative Review.

Cardiovascular diseases (CVDs) are among the leading causes of morbidity and mortality worldwide. Unhealthy dietary habits have clearly been shown to contribute to the development of CVDs. Beyond the primary nutrients, a healthy diet is also rich in plant-derived compounds. Natural polyphenols, found in fruits, vegetables, and red wine, have a clear role in improving cardiovascular health. In this review, we strive to summarize the results of the relevant pre-clinical and clinical trials that focused on some of the most important natural polyphenols, such as resveratrol and relevant flavonoids. In addition, we aim to identify their common sources, biosynthesis, and describe their mechanism of action including their regulatory effect on signal transduction pathways. Finally, we provide scientific evidence regarding the cardiovascular benefits of moderate, long-term red wine consumption.

Demethylation of ethanol organosolv lignin by Na2SO3 for enhancing antioxidant performance

Natural polyphenol antioxidants have excellent antioxidant activity and degradability which are considered as one of the possible alternatives to chemical synthetic antioxidants. Here, lignin-based polyphenols were prepared from poplar lignin, pine lignin and rice husk lignin by demethylation, and no toxic reagents were used in the preparation process. The phenolic hydroxyl groups of all three lignin were increased and the methoxyl content was significantly reduced after the demethylation without degradation or structural changes in the lignin as shown by GPC and 2D HSQC analyses. Furthermore, the antioxidant activity of the modified lignin was significantly increased. In this paper, a green and efficient strategy was developed to prepare lignin-based polyphenols with high phenolic hydroxyl content, low molecular weight, strong antioxidant activity and low cytotoxicity, which have a promising future in the field of antioxidant applications.

Nature-inspired construction of multifunctional composited membrane by in situ formation TA-APTES NPs for selective adsorption of tetrabromobisphenol a and oil-water separation

In this work, a novel in-situ synthetic TA-APTES NPs multifunctional imprinted membrane was fabricated by tanning-inspired coating for selective adsorption of tetrabromobisphenol a (TBBPA) and oil-water emulsion separation. Tannic acid (TA) from natural plants can be cross-linked with 3-aminopropyltriethoxysilane (APTES) by a simple green method to form nanosphere structures with secondary reaction sites. With TA-APTES coating, the membrane can be quickly converted from hydrophobic to super-hydrophilic. TEOS is not only used as a cross-linking agent in imprinting process，but also can be used for TA-APTES hybridization on the membrane surface to introduce stable silicone hydroxyl groups to the membrane surface. The modified membranes showed good hydrophilicity with a water flux of 27,272Lm−2 h−1 at 0.1Mpa, which was 18 times higher than that of pure PVDF membranes. In addition, the separation efficiency of four different types of oil-water emulsions (n-hexane, petroleum ether, dichloromethane and kerosene) reached 99.6%, 98.3%, 95.6%, and 98.7%, respectively. Among them, the oil water emulsion flux of dichloromethane could reach 1000.1. what's more, the prepared membranes also maintained relatively high selective separation efficiencies of TBBPA in oil-water mixtures. To better explain the mechanism of the TBBPA reaction process, the active sites in the TBBPA reaction process were calculated and predicted by density generalization theory (DFT). The Br and phenolic hydroxyl groups on the benzene ring of TBBPA showed higher activity and might be the main reaction sites. In addition, the imprinted composite membranes can be easily regenerated and reused without performance loss through a simple cleaning process. The coating process inspired by natural polyphenol chemistry has the advantage of being green, cost-effective and low energy, showing real potential in multifunctional membrane applications.

Resveratrol can improve spinal cord injury by activating Nrf2/HO-1 signaling pathway

Spinal cord injury (SCI) often induces severe sensory and motor dysfunction. Oxidative stress is an important pathophysiological process of secondary SCI, and its inhibition could facilitate the alleviation of the injury. Resveratrol is a natural plant polyphenol compound that has significant antioxidant and anti-inflammatory effects. It can inhibit oxidative stress by activating the Nrf2/HO-1 signal pathway. In this report, we analyze the antioxidant effect of resveratrol in SCI, clarify the specific mechanism of action and provide a theoretical basis for the clinical employment of resveratrol for SCI.

Protocatechuic aldehyde increases pericyte coverage and mitigates pericyte damage to enhance the atherosclerotic plaque stability

Pericyte dysfunction and loss contribute substantially to the destabilization and rupture of atherosclerotic plaques. Protocatechuic aldehyde (PCAD), a natural polyphenol, exerts anti-atherosclerotic effects. However, the effects and mechanisms of this polyphenol on pericyte recruitment, coverage, and pericyte function remain unknown. We here treated apolipoprotein E-deficient mice having high-fat diet-induced atherosclerosis with PCAD. PCAD achieved therapeutic effects similar to rosuvastatin in lowering lipid levels and thus preventing atherosclerosis progression. With PCAD administration, plaque phenotype exhibited higher stability with markedly reduced lesion vulnerability, which is characterized by reduced lipid content and macrophage accumulation, and a consequent increase in collagen deposition. PCAD therapy increased pericyte coverage in the plaques, reduced VEGF-A production, and inhibited intraplaque neovascularization. PCAD promoted pericyte proliferation, adhesion, and migration to mitigate ox-LDL-induced pericyte dysfunction, which thus maintained the capillary network structure and stability. Furthermore, TGFBR1 silencing partially reversed the protective effect exerted by PCAD on human microvascular pericytes. PCAD increased pericyte coverage and impeded ox-LDL-induced damages through TGF-β1/TGFBR1/Smad2/3 signaling. All these novel findings indicated that PCAD increases pericyte coverage and alleviates pericyte damage to improve the stability of atherosclerotic plaques, which is accomplished by regulating TGF-β1/TGFBR1/Smad2/3 signaling in pericytes.

Magnetic phosphazene porous organic polymer for efficient and selective recovery of rare earth elements from acidic wastewater

Efficient recovery of rare earth elements (REEs) from secondary resources is highly recommended to meet industrial production demand and maximize resource utilization. Herein, a magnetic porous organic polymer, termed MTAP, was developed by choosing natural polyphenol tannic acid as a monomer and hexachlorocyclotriphosphazene as a crosslinker. The integration of magnetic nanoparticles further enhanced its advantages since it can be rapidly isolated using an external magnetic field, simplifying the overall operation. Batch adsorption experimental results showed that MTAP can quickly capture REEs including Ce, Nd, Eu, and Gd, achieving the adsorption equilibrium just in 2 min. Furthermore, the adsorption isotherms exhibited an excellent fit with the Langmuir model with the maximum adsorption capacities ranging from 145.5 to 164.2 mg/g at 25 °C. What’s more, MTAP was successfully applied to recycle REEs in industrial wastewater with high recovery efficiencies. These characteristics including low cost, easy preparation, rapid adsorption kinetics, and high adsorption capacities highlight the outstanding application prospects of MTAP for the recovery of REEs.

Resveratrol may dose-dependently modulate nephrin and OTULIN levels in a doxorubicin-induced nephrotoxicity model

One of the most important side effects of Doxorubicin (DOX), a chemotherapeutic agent, is nephrotoxicity. The purpose of this study is to determine whether different doses of natural polyphenol Resveratrol (RSV) show antioxidative, anti-inflammatory or antiapoptotic effects in kidney tissue in DOX-induced nephrotoxicity and to detect how nephrin and OTULIN levels are affected in this process. A total of six equal groups made up of the 42 Sprague-Dawley rats utilized in the study (n = 7) were randomly assigned. Except for the control group (no treatment), all treatments were given intraperitoneally to the DOX (15 mg/kg), DOX + RSV I (15 mg/kg DOX+ 1 mg/kg/day RSV), DOX + RSV II (15 mg/kg DOX+ 5 mg/kg/day RSV), RSV I and RSV II groups. Kidney tissues taken from rats sacrificed on the fifteenth day were analyzed biochemically, histologically and immunohistochemically. Accordingly, it was determined that nephrin and OTULIN levels decreased in kidney tissue in DOX-induced nephrotoxicity. Furthermore, DOX caused oxidative stress, inflammation, and apoptosis, as well as histopathological changes in kidney tissue. However, it was observed that DOX-induced changes were regulated by RSV application. RSV was demonstrated to have antioxidant, anti-inflammatory and anti-apoptotic properties in dose-dependent DOX-induced nephrotoxicity. RSV may exert nephroprotective effects by modulating DOX-induced altered nephrin and OTULIN levels.

Synergistic combination of natural deep eutectic solvents and green extraction techniques for the valorization of date palm leaves: Optimization of the solvent-biomass interaction

This study was designed to explore date palm leaves as natural polyphenolics potential source using appropriate green Natural Deep Eutectic Solvent (NADES) and emerging green extraction technologies. Among the studied NADES, Glycerol-based NADES showed higher phenolics yield compared to saccharide and organic acid-based NADES. Experimental conditions for microwave (MAE)-NADES and ultrasonication (UAE)-NADES couplings were optimized using a 23-factorial design. Interestingly, it was found the UAE-NADES was not effective enough to enhance phenolics recovery, while MAE-NADES was significantly effective. Furthermore, MAE-NADES-based extracts portrayed higher bioactive properties compared to UAE-NADES-based extracts. Accordingly, MAE-NADES extraction parameters were further optimized using a Box-Behnken design of Response Surface Methodology (RSM). RSM predicted that MAE-NADES extraction can be maximized at a NADES concentration of 49 %, and power of 800 W for 0.84 min. The current study concludes that the application of MAE-NADES green extraction technology can be an effective approach for bioactive compounds recovery from date palm leaves.Industrial relevance:There are more than 120 million date palm trees in the world producing around 20–35 kg of leaves per palm tree annually. This is a huge burden on the environment and if explored as a potential source of polyphenols and other components may turn out to be a viable economic source for desert regions. During the last few decades, a special focus has been raised on ensuring that the extraction process is monitored in an economical and eco-friendly manner without downgrading the biological functionality of the resulting extracts. Recently, Natural Deep Eutectic Solvents (NADES) have been applied for the extraction of polyphenolic compounds. Moreover, the utilization of green extraction techniques, such as ultrasonication and microwave, have been extensively investigated for the extraction of bioactive compounds from plant-based matrices with promising future prospectus, in terms of the reduction in extraction time and higher recovery yields.

Thrombin-Induced COX-2 Expression and PGE2 Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation.

In this study, we confirmed that thrombin significantly increases the production of COX-2 and PGE2 in human tracheal smooth muscle cells (HTSMCs), leading to inflammation in the airways and lungs. These molecules are well-known contributors to various inflammatory diseases. Here, we investigated in detail the involved signaling pathways using specific inhibitors and small interfering RNAs (siRNAs). Our results demonstrated that inhibitors targeting proteins such as protein kinase C (PKC)δ, proline-rich tyrosine kinase 2 (Pyk2), c-Src, epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), or activator protein-1 (AP-1) effectively reduced thrombin-induced COX-2 and PGE2 production. Additionally, transfection with siRNAs against PKCδ, Pyk2, c-Src, EGFR, protein kinase B (Akt), or c-Jun mitigated these responses. Furthermore, our observations revealed that thrombin stimulated the phosphorylation of key components of the signaling cascade, including PKCδ, Pyk2, c-Src, EGFR, Akt, and c-Jun. Thrombin activated COX-2 promoter activity through AP-1 activation, a process that was disrupted by a point-mutated AP-1 site within the COX-2 promoter. Finally, resveratrol (one of the most researched natural polyphenols) was found to effectively inhibit thrombin-induced COX-2 expression and PGE2 release in HTSMCs through blocking the activation of Pyk2, c-Src, EGFR, Akt, and c-Jun. In summary, our findings demonstrate that thrombin-induced COX-2 and PGE2 generation involves a PKCδ/Pyk2/c-Src/EGFR/PI3K/Akt-dependent AP-1 activation pathway. This study also suggests the potential use of resveratrol as an intervention for managing airway inflammation.