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The host stimulator of interferon genes (STING) signaling pathway is a major innate immune sensing pathway, and the stimulation of this pathway within antigen-presenting cells shows ...promise in targeting immune-suppressed tumors. Macrophages resident in tumors exhibit anti-inflammatory properties and enhance tumor growth and development. Polarizing such macrophages towards a pro-inflammatory phenotype is an effective strategy for tumor suppression. In the present study, we observed that the STING pathway was inactivated in breast and lung carcinomas, and a positive correlation existed between STING and macrophage markers in these tumors. We found that vanillic acid (VA) could stimulate the STING/TBK1/IRF3 pathway. VA mediated the production of type I IFN and promoted macrophage polarization into the M1 phenotype; this activity was dependent on STING activation. A direct-contact co-culture model and a transwell co-culture model revealed that macrophages with VA-induced STING activation exhibited anti-proliferative effects on SKBR3 and H1299 cells, although a STING antagonist and M2 macrophage-related cytokines alleviated this anti-proliferative effect. Further investigation indicated that phagocytosis and apoptosis-inducing effects were the major mediators of the anti-tumor effect of VA-treated macrophages. Mechanistically, VA promoted the polarization of macrophages to a M1 phenotype via IL-6R/JAK signaling, resulting in enhanced phagocytosis and apoptosis-induction effects. Additionally, STING activation-induced IFNβ production also participated in the apoptosis mediated by VA-treated macrophage in SKBR3 and H1299 cells. Mouse models with 4 T1 tumors confirmed the anti-tumor properties of VA in vivo and revealed the infiltration of VA-induced cytotoxic T cells into the tumors. These data suggest that VA is an effective agonist of STING and provides a new perspective for cancer immunotherapy.
Diabetes is the most prevalent disorder in the world characterized by uncontrolled high blood glucose levels and nephropathy is one of the chief complications allied with hyperglycemia. Vanillic ...acid; the main bioactive compound derived from natural sources such as vegetables, fruits and plants possesses various pharmacological activities such as antioxidant, anti‐inflammatory and anti‐proliferative. The current study was designed to investigate the antidiabetic and renoprotective effects of vanillic acid by its various pharmacological activities. Streptozotocin (50 mg/kg)/nicotinamide (110 mg/kg) was used to induce diabetes in rats. Oral administration of vanillic acid once daily for 6 weeks (25, 50 and 100 mg/kg) significantly reduced the hyperglycemia, increased liver enzymes and normalized lipid profile that was altered in diabetic rats. Moreover, vanillic acid attenuated the impaired renal function as evidenced by a reduction in serum creatinine, urea, uric acid and urinary microproteinuria levels with a concomitant increase in urinary creatinine clearance in the nephropathic rats. Diabetic rats showed a marked increase in thiobarbituric acid reactive substances (TBARS) and superoxide anion generation (SAG) along with decreased reduced glutathione (GSH) in the renal tissue which was ameliorated in the vanillic acid‐treated rats. Histopathologically, vanillic acid treatment was associated with reduced damage with normalized structural changes in renal tissue. Furthermore, treatment groups showed the suppression of upregulation of nuclear factor (NF)‐κB, tumor necrosis factor (TNF)‐α, cyclo‐oxygenase (COX)‐2 and up‐regulation of Nuclear factor‐erythroid 2‐related factor 2 (Nrf‐2) in the renal tissue. In conclusion, vanillic acid's ameliorative impact on diabetic nephropathic rats may be attributed to its powerful free radical scavenging property, down‐regulation of NF‐κB, TNF‐α, COX‐2 and up‐regulation of Nrf‐2 proteins in renal tissue.
This study aimed to evaluate the cancer chemopreventive activity of vanillic acid (VA) in diethylnitrosamine- and 1,2-dimethylhydrazine-induced liver and colon carcinogenesis in rats. VA did not ...induce the formation of hepatic glutathione
-transferase placental form (GST-P) positive foci and colonic aberrant crypt foci, demonstrating no carcinogenic activity. VA (75 mg kg
body weight) could significantly reduce the number and areas of hepatic GST-P positive foci when administered before carcinogen injections, but no such effect was seen when it was administered after carcinogen injection. No protection was seen in the colon when VA was treated before or after carcinogen injection. Immunohistochemical studies demonstrated the decreased expression of proliferating cell nuclear antigen and the induction of apoptosis. Mechanistic studies showed that VA significantly induced the expression of
and
genes, which are associated with the detoxification system. Likewise, the antiproliferative effect was noticed by the reduction of
expression. The apoptotic activity may be due to the upregulation of
and
levels and downregulation of the
level. These data suggest that VA exhibited significant protection against diethylnitrosamine- and 1,2-dimethylhydrazine-induced hepatocarcinogenesis, which might be related to the induction of the detoxifying enzyme, the reduction of proliferation and the induction of apoptosis.
Microbial tolerance to lignocellulose-derived inhibitors, such as aromatic acids, is critical for the economical production of biofuels and biochemicals. Here, adaptive laboratory evolution was ...applied to improve the tolerance of Yarrowia lipolytica to a representative aromatic acid inhibitor vanillic acid. The transcriptome profiling of evolved strain suggested that the tolerance could be related to the up-regulation of RNA processing and multidrug transporting pathways. Further analysis by reverse engineering confirmed that the amplification of YALI0_F13475g coding for transcriptional coactivator and YALI0_E25201g coding for multidrug transporter conferred tolerance not only to vanillic acid but also towards ferulic acid, p-coumaric acid, p-hydroxybenzoic acid and syringic acid. These findings suggested that regulation of RNA processing and multidrug transporting pathways may be important for enhanced aromatic acid tolerance in Y. lipolytica. This study provides valuable genetic information for robust strain construction for lignocellulosic biorefinery.
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•A vanillic acid tolerant Yarrowia lipolytica was obtained by adaptive evolution.•Transcriptome profile offered potential targets for robust strain construction.•Two genes contribute to increased tolerance to multiple aromatic acids.•Aromatic acid tolerance is tightly linked to transcriptional and transport processes.
Three chemicals, veratric acid, maltol, and (−)-loliolide, were isolated from crabgrass and their structures were identified by spectroscopic analysis. The chemicals were detected in crabgrass root ...exudates and rhizosphere soils, and their concentrations ranged from 0.16 to 8.10 μg/g. At an approximate concentration determined in crabgrass root exudates, all chemicals significantly inhibited the growth of wheat, maize, and soybean and reduced soil microbial biomass carbon. Phospholipid fatty acid profiling showed that veratric acid, maltol, and (−)-loliolide affected the signature lipid biomarkers of soil bacteria, actinobacteria, and fungi, resulting in changes in soil microbial community structures. There were significant relationships between crop growth and soil microbes under the chemicals’ application. Chemical-specific changes in the soil microbial community generated negative feedback on crop growth. The results suggest that veratric acid, maltol, and (−)-loliolide released from crabgrass may act as allelochemicals interfering with crop growth and the soil microbial community.
Hydroxytyrosol is an antioxidant free radical scavenger that is biosynthesized from tyrosine. In metabolic engineering efforts, the use of the mouse tyrosine hydroxylase limits its production. Here, ...we design an efficient whole-cell catalyst of hydroxytyrosol in Escherichia coli by de-bottlenecking two rate-limiting enzymatic steps. First, we replace the mouse tyrosine hydroxylase by an engineered two-component flavin-dependent monooxygenase HpaBC of E. coli through structure-guided modeling and directed evolution. Next, we elucidate the structure of the Corynebacterium glutamicum VanR regulatory protein complexed with its inducer vanillic acid. By switching its induction specificity from vanillic acid to hydroxytyrosol, VanR is engineered into a hydroxytyrosol biosensor. Then, with this biosensor, we use in vivo-directed evolution to optimize the activity of tyramine oxidase (TYO), the second rate-limiting enzyme in hydroxytyrosol biosynthesis. The final strain reaches a 95% conversion rate of tyrosine. This study demonstrates the effectiveness of sequentially de-bottlenecking rate-limiting steps for whole-cell catalyst development.
Osteoarthritis (OA) is a frequently seen arthropathy that features cartilage loss and destruction. Vanillic acid (VA), is a well-known flavonoid, which possesses various pharmacological activities. ...However, the effects of Vanillic acid on articular cartilage destruction and the pathogenesis of OA remain unknown. The present study observed that VA attenuated OA progression in vivo and vitro. VA inhibited the expression of inflammation responses, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs) and aggrecanase −2(ADAMTS5). Moreover, the major markers of hypertrophic chondrocytes such as Collagen X, Runt related transcription factor 2 (Runx2) and Vascular endothelial growth factor (VEGFA) were also reduced by VA. In addition, the interleukin-1β (IL-1β) -stimulated collagen 2 and aggrecan destruction were suppressed by VA. Moreover, VA concentration -dependently inhibited IL-1β induced production of High-mobility group box 1 (HMGB1), a classic damage-associated molecular pattern (DAMP) molecule with strong pro-inflammatory effects in OA. Meanwhile, we revealed that VA suppressed the IL-1β induced activation of MAPK and PI3K/AKT/NF-κB pathways. In vivo, VA alleviated osteoarthritis progression in a rat OA model. Collectively, our results demonstrate that VA could potentially be a new candidate for OA therapy.
Schematic illustration of the potential protective effects of VA in osteoarthritis development. Our findings demonstrate that Vanillic acid inhibits the IL-1β induced inflammation responses such as iNOS, COX2, MMP1, MMP3, MMP13 and ADMATS5, and hypertrophic change like Collagen X, VEGFA, RUNX2 and HMGB1 in vitro. Cartilage matrix (mainly collagen and aggrecan) degradation induced by IL-1β can also be suppressed by Vanillic acid. The mechanism of the protective effect of Vanillic acid in osteoarthritis may be through the inhibition of MAPK and PI3K/AKT/NF-κB pathways. Display omitted
•Epicatechin vanillate has been firstly identified in grape seeds and red wines.•A new strategy was developed to purify epicatechin vanillate from grape seed.•The structure of the purified compound ...was characterized by NMR and HRMS.•Epicatechin vanillate was quantified in grape seed and red wine.
Flavan-3-ols are units incorporating condensed tannin, which are widely present in grape and wine. They play a considerable role in wine sensory perception such as astringency, bitterness and mouth-feel. In grape and wine, the flavan-3-ols reported to date are (epi)catechin, (epi)gallocatechin, (epi)gallocatechin gallate and (epi)catechin glycoside. This study now shows the presence of a new flavan-3-ol epicatechin vanillate in grape seed and red wine. A putative unknown flavan-3-ol derived from grape seed was targeted by LC-HRMS/MS. Fractionation and purification by centrifugal partition chromatography and Prep HPLC allowed us to obtain the pure new flavan-3-ol. NMR and HRMS data revealed this compound to be epicatechin-3-O-vanillate. Quantification analysis results showed that epicatechin vanillate present in grape seed and red wine in the μg/g dry seed and the μg/L concentration range, respectively.
Vanillic acid, a phenolic compound isolated from Angelica sinensis and green tea, exhibits excellent antioxidant and anti‐inflammatory activities. In this study, a rapid and sensitive ...ultra‐high‐performance liquid chromatography tandem mass spectrometry method was established and validated for the determination of vanillic acid in rat plasma. Plasma samples were prepared by protein precipitation with acetonitrile. Chromatographic separation was performed on a Zorbax RRHD Eclipse Plus C18 column (2.1 × 100 mm, 1.8 μm) with gradient elution at a flow rate of 0.3 ml/min, using mobile phase consisting of 0.1% formic acid (A) and acetonitrile (B). Vanillic acid and caffeic acid (internal standard, IS) were quantified by multiple reaction monitoring in negative ion mode. The method was fully validated according to the US Food and Drug Administration guidelines. The calibration curve was linear over the range of 2–1,000 ng/ml with a correlation coefficient of >0.99. The carryover, matrix effect, extraction recovery, dilution effect, intra‐ and interday precision and accuracy were within acceptable limits. The method was then applied to a pharmacokinetic study of vanillic acid in rats. After oral administration at doses of 2, 5 and 10 mg/kg, the plasma concentration reached peaks of 0.42 ± 0.09, 0.73 ± 0.21 and 0.92 ± 0.28 μg/ml at the time of 0.55–0.64 h, respectively. The oral bioavailability was calculated as 25.3–36.2% in rat plasma. The result provided pre‐clinical information for further application of vanillic acid.
•Vanillic acid alleviated the anxiety-like behaviors, depression-like behaviors, and memory in rats exposed to early life maternal separation stress.•Vanillic acid decreased the expression of ...inflammatory genes of IL-1β, TNF-α, NLRP3, and TLR4 in the hippocampal samples.•Vanillic acid alleviated impairment in long term potentiation in hippocampus in rats exposed to early life maternal separation stress.
Compounds derived from herbs exhibit a range of biological properties, including anti-inflammatory, antioxidant, and neuroprotective properties. However, the exact mechanism of action of these compounds in various neurological disorders is not fully discovered yet. Herein, the present work detected the effect of Vanillic acid (VA), a widely-used flavoring agent derived from vanillin, on autistic-like behaviors to assess the probable underlying mechanisms that mediate behavioral, electrophysiological, molecular, and histopathological alterations in the rat model of maternal separation (MS) stress. Maternal separated rats were treated with VA (25, 50, and 100 mg/kg interperitoneally for 14 days). In addition, anxiety-like, autistic-like behaviors, and learning and memory impairment were evaluated using various behavioral tests. Hippocampus samples were assessed histopathologically by H&E staining. Levels of malondialdehyde (MDA) and antioxidant capacity (by the FRAP method), as well as nitrite levels, were measured in brain tissue. Moreover, gene expression of inflammatory markers (IL-1β, TLR-4, TNF-α, and NLRP3) was evaluated in the hippocampus. Electrophysiological alterations were also estimated in the hippocampus by long-term potentiation (LTP) assessments. Results showed that VA reversed the negative effects of MS on behavior. VA increased the diameter and decreased the percentage of dark neurons in the CA3 area. Accordingly, VA decreased MDA and nitrite levels and increased the antioxidant capacity in brain samples and decreased the expression of all inflammatory genes. VA treated rats showed significant improvements in all LTP parameters. This study provided evidence suggesting a possible role for VA in preventing autism spectrum disorder (ASD) by regulating immune signaling.
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