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.

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.

Natural Product Quercetin-3-methyl ether Promotes Colorectal Cancer Cell Apoptosis by Downregulating Intracellular Polyamine Signaling.

Dysregulation of cellular metabolism is a key marker of cancer, and it is suggested that metabolism should be considered as a targeted weakness of colorectal cancer. Increased polyamine metabolism is a common metabolic change in tumors. Thus, targeting polyamine metabolism for anticancer therapy, particularly polyamine blockade therapy, has gradually become a hot topic. Quercetin-3-methyl ether is a natural compound existed in various plants with diverse biological activities like antioxidant and antiaging. Here, we reported that Quercetin-3-methyl ether inhibits colorectal cancer cell viability, and promotes apoptosis in a dose-dependent and time-dependent manner. Intriguingly, the polyamine levels, including spermidine and spermine, in colorectal cancer cells were reduced upon treatment of Quercetin-3-methyl ether. This is likely resulted from the downregulation of SMOX, a key enzyme in polyamine metabolism that catalyzes the oxidation of spermine to spermidine. These findings suggest Quercetin-3-methyl ether decreases cellular polyamine level by suppressing SMOX expression, thereby inducing colorectal cancer cell apoptosis. Our results also reveal a correlation between the anti-tumor activity of Quercetin-3-methyl ether and the polyamine metabolism modulation, which may provide new insights into a better understanding of the pharmacological activity of Quercetin-3-methyl ether and how it reprograms cellular polyamine metabolism.

Effect of ultrasonic power on delivery of quercetin in emulsions stabilized using octenyl succinic anhydride (OSA) modified broken japonica rice starch.

In this study, emulsions stabilized by octenyl succinic anhydride-modified broken japonica rice starch (OSA-BJRS) were prepared at different ultrasonic power intensities for the delivery, controlled release, and improved bioavailability of quercetin. The OSA-BJRS emulsions ultrasonicated at 400 W exhibited the highest encapsulation efficiency (89.37 %) and loading efficiency (58.34 %) of quercetin, the smallest volume-average droplet diameter (0.51 µm) and polydispersity index (0.19), the highest absolute value of the ζ-potential (26.73 mV), and the highest apparent viscosity and viscoelasticity. The oxidation stability, storage stability, thermal stability, and salt ion stability of the emulsions were also notably improved by the ultrasonication treatment. In addition, the results of the simulated in vitro digestion demonstrated that the ultrasonicated OSA-BJRS emulsions had an enhanced quercetin delivery performance and could stably transport quercetin to the small intestine for digestion. The OSA-BJRS emulsion ultrasonicated at 400 W exhibited the highest cumulative release rate (95.91 %) and the highest bioavailability (30.48 %) of quercetin. This suggests that OSA-BJRS emulsions prepared by ultrasonication can be considered effective delivery systems for hydrophobic functional components.

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.

Combinatorial metabolic engineering of Bacillus subtilis enables the efficient biosynthesis of isoquercitrin from quercetin.

BACKGROUND: Isoquercitrin (quercetin-3-O-ß-D-glucopyranoside) has exhibited promising therapeutic potentials as cardioprotective, anti-diabetic, anti-cancer, and anti-viral agents. However, its structural complexity and limited natural abundance make both bulk chemical synthesis and extraction from medical plants difficult. Microbial biotransformation through heterologous expression of glycosyltransferases offers a safe and sustainable route for its production. Despite several attempts reported in microbial hosts, the current production levels of isoquercitrin still lag behind industrial standards. RESULTS: Herein, the heterologous expression of glycosyltransferase UGT78D2 gene in Bacillus subtilis 168 and reconstruction of UDP-glucose (UDP-Glc) synthesis pathway led to the synthesis of isoquercitrin from quercetin with titers of 0.37 g/L and 0.42 g/L, respectively. Subsequently, the quercetin catabolism blocked by disruption of a quercetin dioxygenase, three ring-cleavage dioxygenases, and seven oxidoreductases increased the isoquercitrin titer to 1.64 g/L. And the hydrolysis of isoquercitrin was eliminated by three ß-glucosidase genes disruption, thereby affording 3.58 g/L isoquercitrin. Furthermore, UDP-Glc pool boosted by pgi (encoding glucose-6-phosphate isomerase) disruption increased the isoquercitrin titer to 10.6 g/L with the yield on quercetin of 72% and to 35.6 g/L with the yield on quercetin of 77.2% in a 1.3-L fermentor. CONCLUSION: The engineered B. subtilis strain developed here holds great potential for initiating the sustainable and large-scale industrial production of isoquercitrin. The strategies proposed in this study provides a reference to improve the production of other flavonoid glycosides by engineered B. subtilis cell factories.

Hydrogel loaded with thiolated chitosan modified taxifolin liposome promotes osteoblast proliferation and regulates Wnt signaling pathway to repair rat skull defects.

To alleviate skull defects and enhance the biological activity of taxifolin, this study utilized the thin-film dispersion method to prepare paclitaxel liposomes (TL). Thiolated chitosan (CSSH)-modified TL (CTL) was synthesized through charge interactions. Injectable hydrogels (BLG) were then prepared as hydrogel scaffolds loaded with TAX (TG), TL (TLG), and CTL (CTLG) using a Schiff base reaction involving oxidized dextran and carboxymethyl chitosan. The study investigated the bone reparative properties of CTLG through molecular docking, western blot techniques, and transcriptome analysis. The particle sizes of CTL were measured at 248.90 ± 14.03 nm, respectively, with zeta potentials of +36.68 ± 5.43 mV, respectively. CTLG showed excellent antioxidant capacity in vitro. It also has a good inhibitory effect on Escherichia coli and Staphylococcus aureus, with inhibition rates of 93.88 ± 1.59 % and 88.56 ± 2.83 % respectively. The results of 5-ethynyl-2 '-deoxyuridine staining, alkaline phosphatase staining and alizarin red staining showed that CTLG also had the potential to promote the proliferation and differentiation of mouse embryonic osteoblasts (MC3T3-E1). The study revealed that CTLG enhances the expression of osteogenic proteins by regulating the Wnt signaling pathway, shedding light on the potential application of TAX and bone regeneration mechanisms.

Isorhamnetin Alleviates Mitochondrial Injury in Severe Acute Pancreatitis via Modulation of KDM5B/HtrA2 Signaling Pathway.

Severe acute pancreatitis (SAP), a widespread inflammatory condition impacting the abdomen with a high mortality rate, poses challenges due to its unclear pathogenesis and the absence of effective treatment options. Isorhamnetin (ISO), a naturally occurring flavonoid, demonstrates robust antioxidant and anti-inflammatory properties intricately linked to the modulation of mitochondrial function. However, the specific protective impact of ISO on SAP remains to be fully elucidated. In this study, we demonstrated that ISO treatment significantly alleviated pancreatic damage and reduced serum lipase and amylase levels in the mouse model of SAP induced by sodium taurocholate (STC) or L-arginine. Utilizing an in vitro SAP cell model, we found that ISO co-administration markedly prevented STC-induced pancreatic acinar cell necrosis, primarily by inhibiting mitochondrial ROS generation, preserving ATP production, maintaining mitochondrial membrane potential, and preventing the oxidative damage and release of mitochondrial DNA. Mechanistically, our investigation identified that high-temperature requirement A2 (HtrA2) may play a central regulatory role in mediating the protective effect of ISO on mitochondrial dysfunction in STC-injured acinar cells. Furthermore, through an integrated approach involving bioinformatics analysis, molecular docking analysis, and experimental validation, we uncovered that ISO may directly impede the histone demethylation activity of KDM5B, leading to the restoration of pancreatic HtrA2 expression and thereby preserving mitochondrial function in pancreatic acinar cells following STC treatment. In conclusion, this study not only sheds new light on the intricate molecular complexities associated with mitochondrial dysfunction during the progression of SAP but also underscores the promising value of ISO as a natural therapeutic option for SAP.

Natural hyperoside extracted from hawthorn exhibits antiviral activity against porcine epidemic diarrhea virus in vitro and in vivo.

Porcine epidemic diarrhea virus (PEDV) causes severe diarrhea and death in piglets, resulting in significant economic losses for the pork industry. There is an urgent need for new treatment strategies. Here, we focused on optimizing the process of purifying natural hyperoside (nHYP) from hawthorn and evaluating its effectiveness against PEDV both in vitro and in vivo. Our findings demonstrated that nHYP with a purity >98% was successfully isolated from hawthorn with an extraction rate of 0.42 mg/g. Furthermore, nHYP exhibited strong inhibitory effects on PEDV replication in cells, with a selection index of 9.72. nHYP significantly reduced the viral load in the intestines of piglets and protected three of four piglets from death caused by PEDV infection. Mechanistically, nHYP could intervene in the interaction of PEDV N protein and p53. The findings implicate nHYP as having promising therapeutic potential for combating PEDV infections.

Exploring the role and mechanism of hyperoside against cardiomyocyte injury in mice with myocardial infarction based on JAK2/STAT3 signaling pathway.

BACKGROUND: Myocardial infarction (MI) is one of the most deadly diseases in the world. Hyperoside (Hyp) has been shown to have a protective effect on cardiovascular function through various signaling pathways, but whether it can protect myocardial infarction by regulating JAK2/STAT3 signaling pathway is unknown. AIM OF THE STUDY: To investigate whether Hyp could protect the heart against myocardial infarction injury in mice by modulating JAK2/STAT3 signaling pathway and its potential mechanism. METHODS: In vivo experiments, the myocardial infarction model was established by ligating the left anterior descending coronary artery (LAD) of male C57BL/6 mice permanently. The mice were divided into seven groups: sham group, MI group, MI+Hyp (9 mg/kg), MI+Hyp (18 mg/kg) group, MI+Hyp (36 mg/kg) group, MI+Captopril group (15 mg/kg) group and MI+Hyp (36 mg/kg)+AG490 (7.5 mg/kg) group. Each group of animals were given different concentrations of hyperoside, positive control drug or inhibitor of JAK2/STAT3 singaling. After 14 days of administration, the electrocardiogram (ECG), echocardiography and serum myocardial injury markers were examined; Slices of mouse myocardial tissue were assessed for histopathological changes by HE, Masson and Sirius Red staining. TTC and TUNEL staining were used to evaluate the myocardial infarction area and cardiomyocytes apoptosis respectively. The expression of JAK2/STAT3 signaling pathway, apoptosis and autophagy-related proteins were detected by western blot. In vitro experiments, rat H9c2 cardiomyocytes were deprived of oxygen and glucose (OGD) to stimulate myocardial ischemia. The experiment was divided into seven groups: Control group, OGD group, OGD+Hyp (20 µM) group, OGD+Hyp (40 µM) group, OGD+Hyp (80 µM), OGD+Captopril (10 µM) group and OGD+Hyp (80 µM)+AG490 (100 µM) group. Myocardial cell damage and redox index were measured 12 h after OGD treatment. ROS content in cardiomyocytes was detected by immunofluorescence. Cardiomyocytes apoptosis was detected by flow cytometry. The expressions of JAK2/STAT3 signaling pathway-related proteins, apoptosis and autophagy related proteins were detected by western blot. RESULTS: In vivo, hyperoside could ameolirate ECG abnormality, increase cardiac function, reduce myocardial infarction size and significantly reduce myocardial fibrosis level and oxidation level. The experimental results in vitro showed that Hyp could reduce the ROS content in cardiomyocytes, decrease the level of oxidative stress and counteract the apoptosis induced by OGD injury . Both in vivo and in vitro experiments showed that hyperoside could increase phosphorylated JAK2 and STAT3, indicating that hyperoside could play a cardioprotective role by activating JAK2/STAT3 signaling pathway. It was also shown that hyperoside could increase the autophagy level of cardiomyocytes in vivo and in vitro. However the cardiomyocyte-protective effect of Hyp was abolished in combination with JAK2/ STAT3 signaling pathway inhibitor AG490. These results indicated that the protective effect of Hyp on cardiomyocyte injury was at least partially achieved through the activation of the JAK2/STAT3 signaling pathway. CONCLUSION: Hyp can significantly improve cardiac function, ameliorate myocardial hypertrophy and myocardial remodeling in MI mice. The mechanism may be related to improving mitochondrial autophagy of cardiomyocytes to maintain the advantage of autophagy, and blocking apoptosis pathway through phagocytosis, thus suppressing apoptosis level of cardiomyocytes. These effects of Hyp are achieved, at least in part, by activating the JAK2/STAT3 signaling pathway.

Determination of In Vitro and In Vivo Effects of Taxifolin and Epirubicin on Epithelial-Mesenchymal Transition in Mouse Breast Cancer Cells.

Background: One of the most significant characteristics of cancer is epithelial-mesenchymal transition and research on the relationship between phenolic compounds and anticancer medications and epithelial-mesenchymal transition is widespread. Methods: In order to investigate the potential effects of Taxifolin on enhancing the effectiveness of Epirubicin in treating breast cancer, specifically in 4T1 cells and an allograft BALB/c model, the effects of Taxifolin and Epirubicin, both individually and in combination, were examined. Cell viability assays and cytotoxicity assays in 4T1 cells were performed. In addition, 4T1 cells were implanted into female BALB/c mice to conduct in vivo studies and evaluate the therapeutic efficacy of Taxifolin and Epirubicin alone or in combination. Tumor volumes and histological analysis were also assessed in mice. To further understand the mechanisms involved, we examined the messenger RNA and protein levels of epithelial-mesenchymal transition-related genes, as well as active Caspase-3/7 levels, using quantitative real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assays, respectively. Results: In vitro results demonstrated that the coadministration of Taxifolin and Epirubicin reduced cell viability and cytotoxicity in 4T1 cell lines. In vivo, coadministration of Taxifolin and Epirubicin suppressed tumor growth in BALB/c mice with 4T1 breast cancer cells. Additionally, this combination treatment significantly increased the levels of active caspase-3/7 and downregulated the messenger RNA and protein levels of N-cadherin, ß-catenin, vimentin, snail, and slug, but upregulated the E-cadherin gene. It significantly decreased the messenger RNA levels of the Zeb1 and Zeb2 genes. Conclusion: The in vitro and in vivo results of our study indicate that the concurrent use of Epirubicin with Taxifolin has supportive effects on breast cancer treatment.

In vitro and in vivo protective potential of quercetin-3-glucuronide against lipopolysaccharide-induced pulmonary injury through dual activation of nuclear factor-erythroid 2 related factor 2 and autophagy.

In vitro and in vivo models of lipopolysaccharide (LPS)-induced pulmonary injury, quercetin-3-glucuronide (Q3G) has been previously revealed the lung-protective potential via downregulation of inflammation, pyroptotic, and apoptotic cell death. However, the upstream signals mediating anti-pulmonary injury of Q3G have not yet been clarified. It has been reported that concerted dual activation of nuclear factor-erythroid 2 related factor 2 (Nrf2) and autophagy may prove to be a better treatment strategy in pulmonary injury. In this study, the effect of Q3G on antioxidant and autophagy were further investigated. Noncytotoxic doses of Q3G abolished the LPS-caused cell injury, and reactive oxygen species (ROS) generation with inductions in Nrf2-antioxidant signaling. Moreover, Q3G treatment repressed Nrf2 ubiquitination, and enhanced the association of Keap1 and p62 in the LPS-treated cells. Q3G also showed potential in inducing autophagy, as demonstrated by formation of acidic vesicular organelles (AVOs) and upregulation of autophagy factors. Next, the autolysosomes formation and cell survival were decreased by Q3G under pre-treatment with a lysosome inhibitor, chloroquine (CQ). Furthermore, mechanistic assays indicated that anti-pulmonary injury effects of Q3G might be mediated via Nrf2 signaling, as confirmed by the transfection of Nrf2 siRNA. Finally, Q3G significantly alleviated the development of pulmonary injury in vivo, which may result from inhibiting the LPS-induced lung dysfunction and edema. These findings emphasize a toxicological perspective, providing new insights into the mechanisms of Q3G's protective effects on LPS-induced pulmonary injury and highlighting its role in dual activating Nrf2 and autophagy pathways.

Hyperoside inhibits EHV-8 infection via alleviating oxidative stress and IFN production through activating JNK/Keap1/Nrf2/HO-1 signaling pathways.

Equine herpesvirus type 8 (EHV-8) causes abortion and respiratory disease in horses and donkeys, leading to serious economic losses in the global equine industry. Currently, there is no effective vaccine or drug against EHV-8 infection, underscoring the need for a novel antiviral drug to prevent EHV-8-induced latent infection and decrease the pathogenicity of this virus. The present study demonstrated that hyperoside can exert antiviral effects against EHV-8 infection in RK-13 (rabbit kidney cells), MDBK (Madin-Darby bovine kidney), and NBL-6 cells (E. Derm cells). Mechanistic investigations revealed that hyperoside induces heme oxygenase-1 expression by activating the c-Jun N-terminal kinase/nuclear factor erythroid-2-related factor 2/Kelch-like ECH-associated protein 1 axis, alleviating oxidative stress and triggering a downstream antiviral interferon response. Accordingly, hyperoside inhibits EHV-8 infection. Meanwhile, hyperoside can also mitigate EHV-8-induced injury in the lungs of infected mice. These results indicate that hyperoside may serve as a novel antiviral agent against EHV-8 infection.IMPORTANCEHyperoside has been reported to suppress viral infections, including herpesvirus, hepatitis B virus, infectious bronchitis virus, and severe acute respiratory syndrome coronavirus 2 infection. However, its mechanism of action against equine herpesvirus type 8 (EHV-8) is currently unknown. Here, we demonstrated that hyperoside significantly inhibits EHV-8 adsorption and internalization in susceptible cells. This process induces HO-1 expression via c-Jun N-terminal kinase/nuclear factor erythroid-2-related factor 2/Kelch-like ECH-associated protein 1 axis activation, alleviating oxidative stress and triggering an antiviral interferon response. These findings indicate that hyperoside could be very effective as a drug against EHV-8.

Antidepressant-like effects of hyperoside on chronic stress-induced depressive-like behaviors in mice: Gut microbiota and short-chain fatty acids.

BACKGROUND: The antidepressant effect of hyperoside (HYP), which is the main component of Hypericum perforatum, is not established. This study aimed to determine the effects of HYP on depression. METHODS: The antidepressant-like effect of HYP was studied in mice induced by chronic restraint stress (CRS). The effects of HYP on behavior, inflammation, neurotransmitters, gut microbiota, and short-chain fatty acids (SCFAs) were studied in CRS mice. RESULTS: HYP improved depressive-like behavior in mice induced by CRS. Nissl staining analysis showed that HYP improved neuronal damage in CRS mice. Western blot (WB) analysis showed that HYP increased the expression levels of BDNF and PSD95 in the hippocampus of CRS mice. The results of ELISA showed that HYP down-regulated the expression levels of IL-6, IL-1ß, TNF-α, and CORT in the hippocampus, blood, and intestinal tissues of mice and up-regulated the expression levels of 5-HT and BDNF. Hematoxylin and eosin (HE) staining results indicate that HYP can improve the intestinal histopathological injury of CRS mice. The results of 16S rRNA demonstrated that HYP attenuated the dysbiosis of the gut microbiota of depressed mice, along with altering the concentration of SCFAs. LIMITATIONS: In the present study, direct evidence that HYP improves depressive behaviors via gut microbiota and SCFAs is lacking, and only female mice were evaluated, which limits the understanding of the effects of HYP on both sexes. CONCLUSIONS: HYP can improve CRS-induced depressive-like behaviors in mice, which is associated with regulating the gut microbiota and SCFAs concentration.

Effects of isorhamnetin on liver injury in heat stroke-affected rats under dry-heat environments via oxidative stress and inflammatory response.

Isorhamnetin is a natural flavonoid compound, rich in brass, alkaloids, and sterols with a high medicinal value. This study investigated the effects of isorhamnetin on liver injury and oxidative and inflammatory responses in heat-stroke-affected rats in a dry-heat environment. Fifty Sprague Dawley rats were randomly divided into five groups: normal temperature control (NC, saline), dry-heat control (DHC, saline), low-dose isorhamnetin-pretreated (L-AS, 25 mg/Kg), medium-dose isorhamnetin-pretreated (M-AS, 50 mg/Kg), and high-dose isorhamnetin-pretreated (H-AS, 100 mg/Kg) group. Saline was administered to the NC and DHC groups and corresponding concentrations of isorhamnetin were administered to the remaining three groups for 1 week. Blood and liver tissue were analyzed for oxidative stress and inflammation. The liver histopathological injury score, serum liver enzyme (alanine transaminase, aspartate transaminase, and lactate dehydrogenase), liver oxidative stress index (superoxide dismutase [SOD], catalase [CAT], and malondialdehyde), and inflammation index (tumor necrosis factor α [TNF-α], interleukin [IL]-1ß, IL-6, and lipopolysaccharides) were significantly higher in the DHC group than in the NC group (P < 0.05). These index values in the L-AS, M-AS, and H-AS groups were significantly lower than those in the DHC group (P < 0.05). The index values decreased significantly with an increase in the concentration of isorhamnetin (P < 0.05), while the index values of CAT and SOD showed the opposite tendency (P < 0.05). The expression of liver tissue nuclear factor kappa B (NF-κB), caspase-3, and heat shock protein (HSP-70) was higher in the DHC group than in the NC group (P < 0.05). Comparison between the isorhamnetin and DHC groups revealed that the expression of NF-кB and caspase-3 was decreased, while that of HSP-70 continued to increase (P < 0.05). The difference was significant for HSP-70 among all the isorhamnetin groups (P < 0.05); however, the NF-кB and caspase-3 values in the L-AS and H-AS groups did not differ. In summary, isorhamnetin has protective effects against liver injury in heat-stroke-affected rats. This protective effect may be related to its activities concerning antioxidative stress, anti-inflammatory response, inhibition of NF-кB and caspase-3 expression, and enhancement of HSP-70 expression.

Comparison of the fecal bacterial microbiota in mice, rats, and pigs after oral administration of alpha-glycosyl isoquercitrin.

Alpha-glycosyl isoquercitrin (AGIQ) is composed of isoquercitrin and its glucosylated derivatives and has many biological activities, including anti-inflammatory, antioxidant, and anti-cancer properties. However, the effect of AGIQ administered orally on gut microbiota composition remains unclear. The objective of this study was to evaluate the effect of AGIQ on the gut microbiota of animals in different dose groups. Male rats and mice received different doses of AGIQ (1.5%, 3%, or 5% w/v) in diet for carcinogenic or chronic toxicity studies (rasH2 mice: 6 months; Sprague-Dawley rats: 12 months). Male minipigs received 100, 300, or 1000 mg/kg/day for 28 days. Fecal samples were collected from the different animal species and analyzed using 16S-rRNA gene sequencing. No significant changes were observed in alpha and beta diversity of the gut microbiota. Characteristic bacteria that responded to AGIQ were identified in each animal species, and, interestingly, Kineothrix alysoides, a butyrate-producing bacterium, was commonly detected in all three species, suggesting that it may be related to the biological activities of AGIQ. AGIQ selectively modulated the number of beneficial butyrate-producing commensal bacterium beneficial bacteria without changing the diversity of gut microbiota, which further supports the safe use of AGIQ in food products.

Alpha-glycosyl isoquercitrin alleviates subchronic social defeat stress-induced depression symptoms by modulating the microbiota-gut-brain axis in mice.

AIMS: Increasing evidence suggests a link between gut microbial dysbiosis and the pathogenesis of depression. Alpha-glycosyl isoquercitrin (AGIQ), consisting of isoquercitrin and its glycosylated quercetin, has beneficial effects on the gut microbiome and brain function. Here, we detected the potential antidepressant impact of a four-week administration of AGIQ and its underlying mechanisms using a mouse model of depression. MAIN METHODS: Male C57BL/6 mice were orally administered AGIQ (0.05 % or 0.5 % in drinking water) for 28 days; subchronic social defeat stress was performed in the last 10 days. Behavior tests were conducted to assess anxiety and depressive-like behaviors. Additionally, evaluations encompassed 5-hydroxytryptamine (5-HT) levels, the gut microbiota composition, lipopolysaccharide (LPS) concentrations, short-chain fatty acids levels, and intestinal barrier integrity changes. KEY FINDINGS: AGIQ significantly alleviated depression-like behaviors and increased hippocampal 5-HT levels. Further, AGIQ mitigated stress-induced gut microbial abnormalities and reduced the levels of LPS in the serum, which affected the relative gene expression levels of 5-HT biosynthesis enzymes in vitro. Furthermore, AGIQ reversed the reduced butyrate levels in cecal contents and improved the impaired intestinal barrier by increasing the expression of colonic zonula occluden-1 (ZO-1) and occludin, thereby decreasing LPS leakage. SIGNIFICANCE: Our results suggest that AGIQ could improve stress-induced depression by regulating the gut microbiome, which inhibits LPS production and maintains the gut barrier. This is the first report on the potential effect of AGIQ on depression via the gut microbiota-brain axis, shedding new light on treatment options.

Quercitrin improves cardiac remodeling following myocardial infarction by regulating macrophage polarization and metabolic reprogramming.

The death and disability caused by myocardial infarction is a health problem that needs to be addressed worldwide, and poor cardiac repair and fibrosis after myocardial infarction seriously affect patient recovery. Postmyocardial infarction repair by M2 macrophages is of great significance for ventricular remodeling. Quercitrin (Que) is a common flavonoid in fruits and vegetables that has antioxidant, anti-inflammatory, antitumor and other effects, but whether it has a role in the treatment of myocardial infarction is unclear. In this study, we constructed a mouse myocardial infarction model and administered Que. We found through cardiac ultrasound that Que administration improved cardiac ejection fraction and reduced ventricular remodeling. Staining of heart sections and detection of fibrosis marker protein levels revealed that Que administration slowed fibrosis after myocardial infarction. Flow cytometry showed that the proportion of M2 macrophages in the mouse heart was increased and that the expression levels of M2 macrophage markers were increased in the Que-treated group. Finally, we identified by metabolomics that Que reduces glycolysis, increases aerobic phosphorylation, and alters arginine metabolic pathways, polarizing macrophages toward the M2 phenotype. Our research lays the foundation for the future application of Que in myocardial infarction and other cardiovascular diseases.

Synthesis of Taxifolin-Loaded Polydopamine for Chemo-Photothermal-Synergistic Therapy of Ovarian Cancer.

Chemotherapy is a well-established method for treating cancer, but it has limited effectiveness due to its high dosage and harmful side effects. To address this issue, researchers have explored the use of photothermal agent nanoparticles as carriers for precise drug release in vivo. In this study, three different sizes of polydopamine nanoparticles (PDA-1, PDA-2, and PDA-3) were synthesized and evaluated. PDA-2 was selected for its optimal size, encapsulation rate, and drug loading rate. The release of the drug from PDA-2@TAX was tested at different pH and NIR laser irradiation levels. The results showed that PDA-2@TAX released more readily in an acidic environment and exhibited a high photothermal conversion efficiency when exposed to an 808 nm laser. In vitro experiments on ovarian cancer cells demonstrated that PDA-2@TAX effectively inhibited cell proliferation, highlighting its potential for synergistic chemotherapy-photothermal treatment.

Hyperoside induces cell cycle arrest and suppresses tumorigenesis in bladder cancer through the interaction of EGFR-Ras and Fas signaling pathways.

Hyperoside is a natural flavonol glycoside widely found in plants and has been reported to have a variety of pharmacological effects, including anticancer abilities. In this study, we demonstrated for the first time that hyperoside inhibited the proliferation of bladder cancer cells in vitro and in vivo. Moreover, hyperoside could not only induce cell cycle arrest, but also induce apoptosis of a few bladder cancer cells. Quantitative proteomics, bioinformatics analysis and Western blotting confirmed that hyperoside induced the overexpression of EGFR, Ras and Fas proteins, which affects a variety of synergistic and antagonistic downstream signaling pathways, including MAPKs and Akt, ultimately contributing to its anticancer effects in bladder cancer cells. This study reveals that hyperoside could be a promising therapeutic strategy for the prevention of bladder cancer.