Theoretical exploration of the phenolic compounds' inhibition mechanism of heterocyclic aromatic amines in roasted beef patties by density functional theory.

The ability of spices (bay leaf, star anise, and red pepper) and their characteristic phenolic compounds (quercetin, kaempferol, and capsaicin) to inhibit Heterocyclic aromatic amines (HAAs) in roasted beef patties were compared. Density functional theory (DFT) was used to reveal phenolic compounds interacting with HAAs-related intermediates and free radicals to explore possible inhibitory mechanisms for HAAs. 3 % red chili and 0.03 % capsaicin reduced the total HAAs content by 57.09 % and 68.79 %, respectively. DFT demonstrated that this was due to the stronger interaction between capsaicin and the ß-carboline HAAs intermediate (Ebind = -32.95 kcal/mol). The interaction between quercetin and phenylacetaldehyde was found to be the strongest (Ebind = -17.47 kcal/mol). Additionally, DFT indicated that capsaicin reduced the carbonyl content by transferring hydrogen atoms (HAT) to eliminate HO·, HOO·, and carbon-centered alkyl radicals. This study provided a reference for the development of DFT in the control of HAAs.

Protective effect of quercetin against macrophage-mediated hepatocyte injury via anti-inflammation, anti-apoptosis and inhibition of ferroptosis.

Yinchenhao Decoction (YCHD) is a classic prescription in traditional Chinese medicine (TCM). It appears to play an important role in anti-inflammation and autoimmunity protection. As one of the key active ingredients in YCHD, quercetin is a novel anti-inflammatory metabolite that exerts protective effects in many autoimmune diseases. However, its role in autoimmune hepatitis (AIH)-related hepatic injury has not been studied. The aim of this study was to reveal the hepatocyte protective mechanism of quercetin. In this study, we used Concanavalin A (Con A) to establish an in vitro hepatocyte injury-associated AIH model. Brl3a hepatocyte injury was induced by the supernatant of J774A.1 cells treated with Con A. We found that quercetin mitigated Con A-induced via macrophage-mediated Brl3a hepatocyte injury. Quercetin administration reduced the levels of alanine transaminase (ALT) and aspartate transaminase (AST) in the supernatant of Con A-treated Brl3a cells and attenuated the infiltration of J774A.1 macrophages induced by Con A. Moreover, quercetin effectively inhibited the expression of proinflammatory cytokines including interleukin-1ß (IL-1ß) by Con A. Furthermore, quercetin decreased hepatocyte apoptosis and ferroptosis levels in the macrophage-induced hepatocyte injury model. In conclusion, our study indicates that quercetin alleviates macrophage-induced hepatocyte damage by reducing the inflammatory response, apoptosis and ferroptosis. Our work suggests that quercetin might be a potential therapeutic strategy for AIH.

Fuzhengjiedu San inhibits porcine reproductive and respiratory syndrome virus by activating the PI3K/AKT pathway.

BACKGROUND: Traditional Chinese medicine (TCM) has been garnering ever-increasing worldwide attention as the herbal extracts and formulas prove to have potency against disease. Fuzhengjiedu San (FZJDS), has been extensively used to treat viral diseases in pigs, but its bioactive components and therapeutic mechanisms remain unclear. METHODS: In this study, we conducted an integrative approach of network pharmacology and experimental study to elucidate the mechanisms underlying FZJDS's action in treating porcine reproductive and respiratory syndrome virus (PRRSV). We constructed PPI network and screened the core targets according to their degree of value. GO and KEGG enrichment analyses were also carried out to identify relevant pathways. Lastly, qRT-PCR, flow cytometry and western blotting were used to determine the effects of FZJDS on core gene expression in PRRSV-infected monkey kidney (MARC-145) cells to further expand the results of network pharmacological analysis. RESULTS: Network pharmacology data revealed that quercetin, kaempferol, and luteolin were the main active compounds of FZJDS. The phosphatidylinositol-3-kinase (PI3K)/Akt pathway was deemed the cellular target as it has been shown to participate most in PRRSV replication and other PRRSV-related functions. Analysis by qRT-PCR and western blotting demonstrated that FZJDS significantly reduced the expression of P65, JNK, TLR4, N protein, Bax and IĸBa in MARC-145 cells, and increased the expression of Bcl-2, consistent with network pharmacology results. This study provides that FZJDS has significant antiviral activity through its effects on the PI3K/AKT signaling pathway. CONCLUSION: We conclude that FZJDS is a promising candidate herbal formulation for treating PRRSV and deserves further investigation.

Modulation of the microRNA-6089/E2F transcription factor2 axis by querceting: implications for osteoblast viability, proliferation, migration, and osteogenic differentiation in fracture healing.

Quercetin is widely distributed in plants as a flavonol compound with multiple biological activities. It has been found that quercetin can regulate bone homeostasis through multiple pathways and targets. This study investigated the role and specific molecular mechanisms of quercetin in regulating osteoblast viability, proliferation, migration and osteogenic differentiation. A mouse model of traumatic fracture was established and then 100 mg/kg quercetin corn oil suspension was gavaged at the same time every day for 28 days. miR-6089 and E2F transcription factor 2 (E2F2) expression levels in mice were measured. Fracture healing in mice was observed. MC3T3-E1 cells were transfected with plasmids targeting miR-6089 and E2F2, and cell viability, proliferation, migration, apoptosis, and osteogenic differentiation were determined. The targeting relationship between miR-6089 and E2F2 was verified. In vivo experiments showed that quercetin significantly increased osteocalcin (OCN) expression (P<0.05) and promoted fracture healing in traumatic fracture (TF) mice. miR-6089 expression was down-regulated (P<0.05) and E2F2 expression was up-regulated (P<0.05) in TF mice. Quercetin promoted miR-6089 expression and inhibited E2F2 expression (both P<0.05). In vitro results showed that quercetin promoted miR-6089 expression and inhibited E2F2 expression in a dose-dependent manner (both P<0.05). Quercetin dose-dependently promoted MC3T3-E1 cell viability, proliferation, migration, and osteogenic differentiation, and inhibited MC3T3-E1 cell apoptosis (all P<0.05). Up-regulating miR-6089 further promoted MC3T3-E1 cell viability, proliferation, migration and osteogenic differentiation, and inhibited MC3T3-E1 cell apoptosis (all P<0.05). miR-6089 targeted and regulated E2F2 expression. Up-regulating E2F2 attenuated the promoting effect of up-regulated miR-6089 on MC3T3-E1 cell viability, proliferation, migration, osteogenic differentiation, and inhibition of apoptosis (all P<0.05). We conclude that quercetin enhances osteoblast viability, proliferation, migration, and osteogenic differentiation by modulating the miR-6089/E2F2 axis, thereby promoting fracture healing.

Natural Compounds for Bone Remodeling: A Computational and Experimental Approach Targeting Bone Metabolism-Related Proteins.

Osteoporosis, characterized by reduced bone density and increased fracture risk, affects over 200 million people worldwide, predominantly older adults and postmenopausal women. The disruption of the balance between bone-forming osteoblasts and bone-resorbing osteoclasts underlies osteoporosis pathophysiology. Standard treatment includes lifestyle modifications, calcium and vitamin D supplementation and specific drugs that either inhibit osteoclasts or stimulate osteoblasts. However, these treatments have limitations, including side effects and compliance issues. Natural products have emerged as potential osteoporosis therapeutics, but their mechanisms of action remain poorly understood. In this study, we investigate the efficacy of natural compounds in modulating molecular targets relevant to osteoporosis, focusing on the Mitogen-Activated Protein Kinase (MAPK) pathway and the gut microbiome's influence on bone homeostasis. Using an in silico and in vitro methodology, we have identified quercetin as a promising candidate in modulating MAPK activity, offering a potential therapeutic perspective for osteoporosis treatment.

Quercetin Exhibits Preferential Binding Interaction by Selectively Targeting HRAS1 I-Motif DNA-Forming Promoter Sequences.

I-Motif (iM) DNA structures represent among the most significant noncanonical nucleic acid configurations. iM-forming DNA sequences are found in an array of vital genomic locations and are particularly frequent in the promoter islands of various oncogenes. Thus, iM DNA is a crucial candidate for anticancer medicines; therefore, binding interactions between iM DNA and small molecular ligands, such as flavonoids, are critically important. Extensive sets of spectroscopic strategies and thermodynamic analysis were utilized in the present investigation to find out the favorable interaction of quercetin (Que), a dietary flavonoid that has various health-promoting characteristics, including anticancer properties, with noncanonical iM DNA structure. Spectroscopic studies and thermal analysis revealed that Que interacts preferentially with HRAS1 iM DNA compared with VEGF, BCL2 iM, and duplex DNA. Que, therefore, emerged as a suitable natural-product-oriented antagonist for targeting HRAS1 iM DNA. The innovative spectroscopic as well as mechanical features of Que and its specific affinity for HRAS1 iM may be useful for therapeutic applications and provide crucial insights for the design of compounds with remarkable medicinal properties.

Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases.

Flavonoid aglycones are secondary plant metabolites that exhibit a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anticancer, and antiplatelet effects. However, the precise molecular mechanisms underlying their inhibitory effect on platelet activation remain poorly understood. In this study, we applied flow cytometry to analyze the effects of six flavonoid aglycones (luteolin, myricetin, quercetin, eriodictyol, kaempferol, and apigenin) on platelet activation, phosphatidylserine externalization, formation of reactive oxygen species, and intracellular esterase activity. We found that these compounds significantly inhibit thrombin-induced platelet activation and decrease formation of reactive oxygen species in activated platelets. The tested aglycones did not affect platelet viability, apoptosis induction, or procoagulant platelet formation. Notably, luteolin, myricetin, quercetin, and apigenin increased thrombin-induced thromboxane synthase activity, which was analyzed by a spectrofluorimetric method. Our results obtained from Western blot analysis and liquid chromatography-tandem mass spectrometry demonstrated that the antiplatelet properties of the studied phytochemicals are mediated by activation of cyclic nucleotide-dependent signaling pathways. Specifically, we established by using Förster resonance energy transfer that the molecular mechanisms are, at least partly, associated with the inhibition of phosphodiesterases 2 and/or 5. These findings underscore the therapeutic potential of flavonoid aglycones for clinical application as antiplatelet agents.

Quercetin attenuates inflammation in rosacea by directly targeting p65 and ICAM-1.

AIMS: Rosacea is an inflammatory skin disease with immune and vascular dysfunction. Although there are multiple treatment strategies for rosacea, the clinical outcomes are unsatisfactory. MAIN METHODS: Combining transcriptome data and the Connectivity Map database quercetin was identified as a novel candidate for rosacea. Next, the therapeutic efficacy of quercetin was substantiated through proteomic analyses, in vivo experiments, and in vitro assays. Additionally, the utilization of DARTS, molecular docking and experimental verification revealed the therapeutic mechanisms of quercetin. KEY FINDINGS: Treatment with quercetin resulted in the following effects: (i) it effectively ameliorated rosacea-like features by reducing immune infiltration and angiogenesis; (ii) it suppressed the expression of inflammatory mediators in HaCaT cells and HDMECs; (iii) it interacted with p65 and ICAM-1 directly, and this interaction resulted in the repression of NF-κB signal and ICAM-1 expression in rosacea. SIGNIFICANCE: We show for the first time that quercetin interacted with p65 and ICAM-1 directly to alleviated inflammatory and vascular dysfunction, suggesting quercetin is a novel, promising therapeutic candidate for rosacea.

Quercetin alleviates chronic unpredictable mild stress-induced depression-like behavior by inhibiting NMDAR1 with α2δ-1 in rats.

BACKGROUND: Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Chronic unpredictable mild stress (CUMS) can lead to a significant acceleration of depression development. Quercetin (Que) is a flavonoid compound with a wide range of pharmacological effects. Recent studies have shown that quercetin can improve CUMS-induced depression-like behavior, but the mechanism of its improvement is still unclear. α2δ-1 is a regulatory subunit of voltage-gated calcium channel, which can interact with N-methyl-D-aspartate receptor (NMDAR) to form a complex. OBJECTIVE: In this study, we found that Que could inhibit the increase of α2δ-1 and NMDAR expression in rat hypothalamus induced by CUMS. In pain, chronic hypertension and other studies have shown that α2δ-1 interacts with the NMDAR to form a complex, which subsequently affects the expression level of NMDAR. Consequently, the present study aimed to investigate the antidepressant effect of Que in vivo and in vitro and to explore its mechanism of action in terms of the interaction between α2δ-1 and NMDAR. METHODS: Rats were randomly exposed to two stressors every day for 4 weeks to establish a CUMS rat model, then sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST), and open field test (OFT) were performed to detect the behavior of CUMS rats, so as to evaluate whether the CUMS rat model was successfully established and the improvement effect of Que on CUMS-induced depression-like behavior in rats. Experimental techniques such as serum enzyme-linked immunosorbent assay (ELISA), immunofluorescence, Western blot, and co-immunoprecipitation, as well as in vitro experiments, were used to investigate the mechanisms by which Que exerts its antidepressant effects. RESULTS: Behavioral and ELISA test results showed that Que could produce a reduction in the excitability of the hypothalamic-pituitary-adrenal (HPA) axis in CUMS rats and lead to significant improvements in their depressive behavior. Western blot, immunofluorescence, and co-immunoprecipitation experiments showed that Que produced a decrease in NMDAR1 and α2δ-1 expression levels and interfered with α2δ-1 and NMDAR1 binding. In addition, the neural regulation mechanism of Que on antidepressant effect in PC12 cells knocked out α2δ-1 gene was further verified. Cellular experiments demonstrated that Que led to a reversal of up-regulation of NMDAR1 and α2δ-1 expression levels in corticosterone-injured PC12 cells, while Que had no effects on NMDAR1 expression in PC12 cells with the α2δ-1 gene knockout. CONCLUSIONS: Que has a good antidepressant effect and can significantly improve the depression-like behavior caused by CUMS. It exerts antidepressant effects by inhibiting the expression level of α2δ-1, interfering with the interaction between α2δ-1 and NMDAR, and then reducing the excitability of the HPA axis.

Can Compounds of Natural Origin Be Important in Chemoprevention? Anticancer Properties of Quercetin, Resveratrol, and Curcumin-A Comprehensive Review.

Malignant tumors are the second most common cause of death worldwide. More attention is being paid to the link between the body's impaired oxidoreductive balance and cancer incidence. Much attention is being paid to polyphenols derived from plants, as one of their properties is an antioxidant character: the ability to eliminate reactive oxygen and nitrogen species, chelate specific metal ions, modulate signaling pathways affecting inflammation, and raise the level and activity of antioxidant enzymes while lowering those with oxidative effects. The following three compounds, resveratrol, quercetin, and curcumin, are polyphenols modulating multiple molecular targets, or increasing pro-apoptotic protein expression levels and decreasing anti-apoptotic protein expression levels. Experiments conducted in vitro and in vivo on animals and humans suggest using them as chemopreventive agents based on antioxidant properties. The advantage of these natural polyphenols is low toxicity and weak adverse effects at higher doses. However, the compounds discussed are characterized by low bioavailability and solubility, which may make achieving the blood concentrations needed for the desired effect challenging. The solution may lie in derivatives of naturally occurring polyphenols subjected to structural modifications that enhance their beneficial effects or work on implementing new ways of delivering antioxidants that improve their solubility and bioavailability.

Exploring the potential of quercetin in Alzheimer's Disease: Pharmacodynamics, Pharmacokinetics, and Nanodelivery systems.

Alzheimer's disease (AD) is a primary cause of dementia that affects millions of people worldwide and its prevalence is likely to increase largely in the coming decades. Multiple complex pathways, such as oxidative stress, tau and amyloid-beta (Aß) pathology, and cholinergic dysfunction, are involved in the pathogenesis of Alzheimer's disease. The conventional treatments provide only symptomatic relief and not a complete cure for the disease. On the other hand, recent studies have looked into the possibility of flavonoids as an effective therapeutic strategy for treating AD. Quercetin, a well-known flavonol, has been extensively studied for AD treatment. Therefore, this review mainly focuses on the pharmacokinetics properties of quercetin and its modes of action, such as antioxidant, anti-inflammatory, anti-amyloidogenic, and neuroprotective properties, which are beneficial in treating AD. It also highlights the nano delivery systems of quercetin, including liposomes, nanostructures lipid carriers, solid lipid nanoparticles, nanoemulsions, microemulsions, self-emulsifying drug delivery systems, and nanoparticles reported for AD treatment. The remarkable potential of quercetin nanocarriers has been reflected in enhancing its bioavailability and therapeutic efficacy. Therefore, clinical studies must be conducted to explore it as a therapeutic strategy for Alzheimer's disease.

Quercetin-derived red emission carbon dots: A multifunctional theranostic nano-agent against Alzheimer's ß-amyloid fibrillogenesis.

Multifunctional agents with therapeutic and diagnostic capabilities are imperative to the prevention of Alzheimer's disease (AD), which is considered due to abnormal aggregation and deposition of ß-amyloid protein (Aß) as well as oxidative stress. Herein, quercetin (Que)- and p-phenylenediamine (p-PD)-derived red emission carbon dots (CDs) synthesized via a one-step hydrothermal method were designed as a novel theranostic nano-agent for the multi-target treatment of AD. R-CD-75 with an optimized composition exhibited significant inhibition of Aß aggregation and rapid depolymerization of mature Aß fibrils (<4 h) at micromolar concentrations (2 and 5 µg/mL, respectively). Moreover, R-CD-75 potently scavenged reactive oxygen species and showed turned-on red fluorescence imaging of Aß plaques both in vitro and in vivo. In vitro assays proved that R-CD-75 significantly mitigated the Aß-induced cytotoxicity and enhanced the cultured cell viability from 74.9 % to 98.0 %, while in vivo studies demonstrated that R-CD-75 prolonged the lifespan of AD nematodes by over 50 % (from 13 to 20 d). Compared to the precursors Que and p-PD, R-CD-75 inherited some of their structures and functional groups, such as aromatic structures, phenolic hydroxyl and amino groups, which were considered to interact with Aß species through hydrogen bonding, electrostatic interactions, hydrophobic interactions, and π-π stacking, thus contributing to its effectiveness in its theranostic functions. This research has opened a new avenue to the development of potent theranostic agents by designing novel carbon dots.

Curcumin and quercetin co-encapsulated in nanoemulsions for nasal administration: A promising therapeutic and prophylactic treatment for viral respiratory infections.

One of the most frequent causes of respiratory infections are viruses. Viruses reaching the airways can be absorbed by the human body through the respiratory mucosa and mainly infect lung cells. Several viral infections are not yet curable, such as coronavirus-2 (SARS-CoV-2). Furthermore, the side effect of synthetic antiviral drugs and reduced efficacy against resistant variants have reinforced the search for alternative and effective treatment options, such as plant-derived antiviral molecules. Curcumin (CUR) and quercetin (QUE) are two natural compounds that have been widely studied for their health benefits, such as antiviral and anti-inflammatory activity. However, poor oral bioavailability limits the clinical applications of these natural compounds. In this work, nanoemulsions (NE) co-encapsulating CUR and QUE designed for nasal administration were developed as promising prophylactic and therapeutic treatments for viral respiratory infections. The NEs were prepared by high-pressure homogenization combined with the phase inversion temperature technique and evaluated for their physical and chemical characteristics. In vitro assays were performed to evaluate the nanoemulsion retention into the porcine nasal mucosa. In addition, the CUR and QUE-loaded NE antiviral activity was tested against a murine ß-COV, namely MHV-3. The results evidenced that CUR and QUE loaded NE had a particle size of 400 nm and retention in the porcine nasal mucosa. The antiviral activity of the NEs showed a percentage of inhibition of around 99 %, indicating that the developed NEs has interesting properties as a therapeutic and prophylactic treatment against viral respiratory infections.

Layer-by-layer assembly of quercetin-loaded zein/γPGA/low-molecular-weight chitosan/fucoidan nanosystem for targeting inflamed blood vessels.

Chitosan acts as a versatile carrier in polymeric nanoparticle (NP) for diverse drug administration routes. Delivery of antioxidants, such as quercetin (Qu) showcases potent antioxidant and anti-inflammatory properties for reduction of various cardiovascular diseases, but low water solubility limits uptake. To address this, we developed a novel layer-by-layer zein/gamma-polyglutamic acid (γPGA)/low-molecular-weight chitosan (LC)/fucoidan NP for encapsulating Qu and targeting inflamed vessel endothelial cells. We used zein (Z) and γPGA (r) to encapsulate Qu (Qu-Zr NP) exhibited notably higher encapsulation efficiency compared to zein alone. Qu-Zr NP coated with LC (Qu-ZrLC2 NP) shows a lower particle size (193.2 ± 2.9 nm), and a higher zeta potential value (35.2 ± 0.4 mV) by zeta potential and transmission electron microscopy analysis. After coating Qu-ZrLC2 NP with fucoidan, Qu-ZrLC2Fa NP presented particle size (225.16 ± 0.92 nm), zeta potential (-25.66 ± 0.51 mV) and maintained antioxidant activity. Further analysis revealed that Qu-ZrLC2Fa NP were targeted and taken up by HUVEC cells and EA.hy926 endothelial cells. Notably, we observed Qu-ZrLC2Fa NP targeting zebrafish vessels and isoproterenol-induced inflamed vessels of rat. Our layer-by-layer formulated zein/γPGA/LC/fucoidan NP show promise as a targeted delivery system for water-insoluble drugs. Qu-ZrLC2Fa NP exhibit potential as an anti-inflammatory therapeutic for blood vessels.

Features of the Effect of Quercetin on Different Genotypes of Wheat under Hypoxia.

Hypoxia is one of the common abiotic stresses that negatively affects the development and productivity of agricultural crops. Quercetin is used to protect plants from oxidative stress when exposed to environmental stressors. O2 deficiency leads to impaired development and morphometric parameters in wheat varieties Orenburgskaya 22 (Triticum aestivum L.) and varieties Zolotaya (Triticum durum Desf.). Cytological analysis revealed various types of changes in the cytoplasm under conditions of hypoxia and treatment with quercetin. The most critical changes in the cytoplasm occur in the Zolotaya variety during pretreatment with quercetin followed by hypoxia, and in the Orenburgskaya 22 variety during hypoxia. Quercetin has a protective effect only on the Orenburgskaya 22 variety, and also promotes a more effective recovery after exposure to low O2 content. Hypoxia causes an increase in reactive oxygen species and activates the antioxidant system. It has been shown that the most active components of the antioxidant system in the Orenburgskaya 22 variety are MnSOD and Cu/ZnSOD, and in the Zolotaya variety GSH. We have shown that quercetin provides resistance only to the wheat genotype Orenburgskaya 22, as a protective agent against abiotic stress, which indicates the need for a comprehensive study of the effects of exogenous protectors before use in agriculture.

Inhibiting Pink1/Parkin-mediated mitophagy enhances the anticancer effects of quercetin in hepatocellular carcinomaf.

Quercetin, a naturally occurring flavonoid, has been investigated for its potential anti-cancer effects in various types of cancer, including hepatocellular carcinoma (HCC). However, its suppressing effect on reactive oxygen species (ROS) production might limited its anti-cancer effects. In this study, we aimed to explore the interplay among quercetin, mitochondrial dynamics and mitophagy and whether mitophagy-inhibition synergistically enhances the anti-tumor effects of quercetin. Huh7 and Hep3B cells were utilized for in vitro and in vivo studies. Results showed that quercetin treatment significantly increased the expression of mitochondrial fusion genes (MFN1 and MFN2) and decreased the expression of fission genes (DRP1 and FIS1) in Huh7 and Hep3B cells, leading to a more fused and elongated mitochondrial network. Quercetin upregulated the expression of key mitophagy regulators, PINK1 and PARK2, and enhanced the colocalization of mitochondria with lysosomes, indicating increased mitophagy. Knockdown of PINK1, PARK2, or SIRT1 attenuated quercetin-induced mitophagy and reduction of intracellular ROS levels. Quercetin treatment upregulates SIRT1 expression, which subsequently enhances PINK1 and PARK2 expression in Huh7 and Hep3B cells. In vivo experiments using Hep3B xenograft models revealed that the combination of quercetin with the mitophagy inhibitor hydroxychloroquine or SIRT1 knockdown significantly enhanced the anticancer effects of quercetin, as evidenced by reduced tumor size and weight, increased necrosis and apoptosis, and decreased proliferation in tumor tissues. These findings suggest that quercetin-induced mitochondrial fusion and Pink1/Parkin-dependent mitophagy may negatively influence its anti-cancer effects in HCC. Targeting mitophagy may enhance the therapeutic potential of quercetin in HCC treatment.

Protein disulfide isomerase uses thrombin-antithrombin complex as a template to bind its target protein and alter the blood coagulation rates.

During inflammation and situations of cellular stress protein disulfide isomerase (PDI) is released in the blood plasma from the platelet and endothelial cells to influence thrombosis. The addition of exogenous PDI makes the environment pro-thrombotic by inducing disulfide bond formation in specific plasma protein targets like vitronectin, factor V, and factor XI. However, the mechanistic details of PDI interaction with its target remain largely unknown. A decrease in the coagulation time was detected in activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) on addition of the purified recombinant PDI (175 nM). The coagulation time can be controlled using an activator (quercetin penta sulfate, QPS) or an inhibitor (quercetin 3-rutinoside, Q3R) of PDI activity. Likewise, the PDI variants that increase the PDI activity (H399R) decrease, and the variant with low activity (C53A) increases the blood coagulation time. An SDS-PAGE and Western blot analysis showed that the PDI does not form a stable complex with either thrombin or antithrombin (ATIII) but it uses the ATIII-thrombin complex as a template to bind and maintain its activity. A complete inhibition of thrombin activity on the formation of ATIII-thrombin-PDI complex, and the complex-bound PDI-catalyzed disulfide bond formation of the target proteins may control the pro- and anti-thrombotic role of PDI.

Development of nanoparticles incorporated with quercetin and ACE2-membrane as a novel therapy for COVID-19.

INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) and AXL tyrosine kinase receptor are known to be involved in the SARS-CoV-2 entry of the host cell. Therefore, targeting ACE2 and AXL should be an effective strategy to inhibit virus entry into cells. However, developing agents that can simultaneously target ACE2 and AXL remains a formidable task. The natural compound quercetin has been shown to inhibit AXL expression. MATERIALS AND METHODS: In this study, we employed PLGA nanoparticles to prepare nanoparticles encapsulated with quercetin, coated with ACE2-containing cell membranes, or encapsulated with quercetin and then coated with ACE-2-containing cell membranes. These nanoparticles were tested for their abilities to neutralize or inhibit viral infection. RESULTS: Our data showed that nanoparticles encapsulated with quercetin and then coated with ACE2-containing cell membrane inhibited the expression of AXL without causing cytotoxic activity. Nanoparticles incorporated with both quercetin and ACE2-containing cell membrane were found to be able to neutralize pseudo virus infection and were more effective than free quercetin and nanoparticles encapsulated with quercetin at inhibition of pseudo virus and SARS-CoV-2 infection. CONCLUSIONS: We have shown that the biomimetic nanoparticles incorporated with both ACE-2 membrane and quercetin showed the most antiviral activity and may be further explored for clinical application.

The Differential Effect of Senolytics on SASP Cytokine Secretion and Regulation of EMT by CAFs.

The tumor microenvironment (TME) plays an essential role in tumor progression and in modulating tumor response to anticancer therapy. Cellular senescence leads to a switch in the cell secretome, characterized by the senescence-associated secretory phenotype (SASP), which may regulate tumorigenesis. Senolytic therapy is considered a novel anticancer strategy that eliminates the deleterious effects of senescent cells in the TME. Here, we show that two different types of senolytic drugs, despite efficiently depleting senescent cells, have opposite effects on cancer-associated fibroblasts (CAFs) and their ability to regulate epithelial-mesenchymal transition (EMT). We found that senolytic drugs, navitoclax and the combination of dasatinib/quercetin, reduced the number of spontaneously senescent and TNF-induced senescent CAFs. Despite the depletion of senescent cells, the combination of dasatinib/quercetin versus navitoclax increased the secretion of the SASP pro-inflammatory cytokine IL-6. This differential effect correlated with the promotion of enhanced migration and EMT in MC38 colorectal cancer cells. Our results demonstrate that some senolytics may have side effects unrelated to their senolytic activity and may promote tumorigenesis. We argue for more careful and extensive studies of the effects of senolytics on various aspects of tumor progression and tumor resistance to therapy before the senolytic strategy is implemented in the clinic.

Effects of quercetin on polycystic ovary syndrome in animal models: a systematic review and meta-analysis.

BACKGROUND: Metformin is an insulin sensitizer that is widely used for the treatment of insulin resistance in polycystic ovary syndrome patients. However, metformin can cause gastrointestinal side effects. PURPOSE: This study showed that the effects of quercetin are comparable to those of metformin. Therefore, this study aimed to systematically evaluate the efficacy of quercetin in treating PCOS. METHODS: The present systematic search of the Chinese National Knowledge Infrastructure (CNKI), Wanfang Data Information Site, Chinese Scientific Journals Database (VIP), SinoMed, Web of Science, and PubMed databases was performed from inception until February 2024. The methodological quality was then assessed by SYRCLE's risk of bias tool, and the data were analyzed by RevMan 5.3 software. RESULTS: Ten studies were included in the meta-analysis. Compared with those in the model group, quercetin in the PCOS group had significant effects on reducing fasting insulin serum (FIS) levels (P = 0.0004), fasting blood glucose (FBG) levels (P = 0.01), HOMA-IR levels (P < 0.00001), cholesterol levels (P < 0.0001), triglyceride levels (P = 0.001), testosterone (T) levels (P < 0.00001), luteinizing hormone (LH) levels (P = 0.0003), the luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio (P = 0.01), vascular endothelial growth factor (VEGF) levels (P < 0.00001), malondialdehyde (MDA) levels (P = 0.03), superoxide dismutase (SOD) levels (P = 0.01) and GLUT4 mRNA expression (P < 0.00001). CONCLUSION: This meta-analysis suggested that quercetin has positive effects on PCOS treatment. Quercetin can systematically reduce insulin, blood glucose, cholesterol, and triglyceride levels in metabolic pathways. In the endocrine pathway, quercetin can regulate the function of the pituitary-ovarian axis, reduce testosterone and luteinizing hormone (LH) levels, and lower the ratio of LH to follicle-stimulating hormone (FSH). Quercetin can regulate the expression of the GLUT4 gene and has antioxidative effects at the molecular level.