PMID: 

Cell Physiol Biochem. 2018 ;46(6):2517-2531. Epub 2018 May 5. PMID: 29742507

Abstract Title: 

Cyanidin Curtails Renal Cell Carcinoma Tumorigenesis.

Abstract: 

BACKGROUND/AIMS: Cyanidin is an anthocyanin found in many foods. Although its variable antioxidant levels are well-documented, little is known about its effects on renal cell carcinoma (RCC) tumorigenesis. This study, therefore, investigated the effects of cyanidin on the proliferation, migration, and invasion of renal cell carcinoma lines and demonstrated, for the first time, significant inhibitory effects of cyanidin on RCC tumorigenesis.METHODS: RCC cells were treated with different doses of cyanidin and the effects were tested by Cell Counting Kit-8 reagent, clone formation assay, transwell assay, and flow cytometry. Moreover, the cyanidin-mediated mechanism that curtailed tumorigenesis was analyzed by RNA sequencing (RNA-seq). Sequencing data from The Cancer Genome Atlas (TCGA) were used to compare the expression of both early growth response protein 1 (EGR1) and selenoprotein W (SEPW1) in RCC and tumor-free adjacent normal tissue samples. Real-time PCR (RT-PCR) and/or western blot were used to assess the expression of E-cadherin, cleaved-caspase3, Bcl2, p62, and ATG4.RESULTS: We found significantly greater induction of cell-cycle arrest, apoptosis, and suppression of RCC cell invasion and migration at concentrations of 25µM and 100 µM than at a concentration of 50 µM. It was also discovered, first through RNA-seq then confirmed by RT-PCR, that cyanidin (100 µM) inhibited RCC carcinogenesis through EGR1 and SEPW1. TCGA data indicated that the expression level of EGR1 was lower and that of SEPW1 was higher in RCCtumor tissue than in normal tissues. Moreover, western blot and/or RT-PCR indicated that cleaved-caspase3 was enhanced and E-cadherin was inhibited by cyanidin treatment. Furthermore, western blot and RT-PCR also showed regulation of p62 and ATG4, which are associated with autophagy. Cyanidin in vivo significantly inhibited the growth of xenografts in nude mice.CONCLUSIONS: The results of this study showed the therapeutic potential of cyanidin for the treatment of RCC and the prevention of recurrence and metastasis.

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PMID: 

Nutrients. 2019 May 9 ;11(5). Epub 2019 May 9. PMID: 31075971

Abstract Title: 

Liquiritigenin Reduces Blood Glucose Level and Bone Adverse Effects in Hyperglycemic Adult Zebrafish.

Abstract: 

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia that induces other pathologies including diabetic retinopathy and bone disease. Adult(zebrafish) represents a powerful model to study both glucose and bone metabolism. Then, the aim of this study was to evaluate the effects of liquiritigenin (LTG) on blood glucose level and diabetes complications in hyperglycemic adult zebrafish. LTG is a flavonoid extracted fromroots which possess important antioxidant, anti-inflammatory, and anti-diabetic properties. During four weeks of glucose treatment, LTG significantly prevented the onset of the hyperglycemia in adult zebrafish. Moreover, hyperglycemic fish showed increased advanced glycation end-products (AGEs) and parathormone levels whereas LTG completely prevented both of these metabolic alterations. Large bone-loss areas were found in the scales of glucose-treated fish whereas only small resorption lacunae were detected after glucose/LTG treatment. Biochemical and histological tartrate resistant acid phosphatase (TRAP) assays performed on explanted scales confirmed that LTG prevented the increase of osteoclastic activity in hyperglycemic fish. The osteoblastic alkaline phosphatase (ALP) activity was clearly lost in scales of glucose-treated fish whereas the co-treatment with LTG completely prevented such alteration. Gene expression analysis showed that LTG prevents the alteration in crucial bone regulatory genes. Our study confirmed that LTG is a very promising natural therapeutic approach for blood glucose lowering and to contrast the development of bone complications correlated to chronic hyperglycemia.

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PMID: 

Phytomedicine. 2018 Dec 10 ;62:152780. Epub 2018 Dec 10. PMID: 31121384

Abstract Title: 

Liquiritigenin inhibits hepatic fibrogenesis and TGF-β1/Smad with Hippo/YAP signal.

Abstract: 

BACKGROUND: Recent reports highlighted the possibility that Yes-associated protein (YAP) and transforming growth factor-β1 (TGF-β1) can act as critical regulators of hepatic stellate cells (HSCs) activation; therefore, it is natural for compounds targeting Hippo/YAP and TGF-β1/Smad signaling pathways to be identified as potential anti-fibrotic candidates.PURPOSE: Liquiritigenin (LQ) is an aglycone of liquiritin and has been reported to protect the liver from injury. However, its effects on the Hippo/YAP and TGF-β1/Smad pathways have not been identified to date.METHODS: We conducted a series of experiments using CCl-induced fibrotic mice and cultured LX-2 cells.RESULT: LQ significantly inhibited liver fibrosis, as indicated by decreases in regions of hepatic degeneration, inflammatory cell infiltration, and the intensity ofα-smooth muscle actin (α-SMA) staining in mice. Moreover, LQ blocked the TGF-β1-induced phosphorylation of Smad 3, and the transcript levels of plasminogen activator inhibitor-1 (PAI-1) and matrix metalloproteinase-2 (MMP-2) in LX-2 cells, which is similar with resveratrol and oxyresveratrol (positive controls). Furthermore, LQ increased activation of large tumor suppressor kinase 1 (LATS1) with the induction of YAP phosphorylation, thereby preventing YAP transcriptional activity and suppressing the expression of exacerbated TGF-β1/Smad signaling molecules.CONCLUSION: These results clearly show that LQ ameliorated experimental liver fibrosis by acting on the TGF-β1/Smad and Hippo/YAP pathways, indicating that LQ has the potential for effective treatment of liver fibrosis.

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PMID: 

Eur J Pharmacol. 2019 Aug 5 ;856:172421. Epub 2019 May 25. PMID: 31136760

Abstract Title: 

The involvement of DAMPs-mediated inflammation in cyclophosphamide-induced liver injury and the protection of liquiritigenin and liquiritin.

Abstract: 

Cyclophosphamide (CPA) is a chemotherapeutic drug widely used in the treatment of breast cancer or leukemia in clinic. However, CPA was reported to have hepatotoxicity. This study aims to observe the engaged mechanism of CPA-induced liver injury in mice and the protection of liquiritin (LQ) and liquiritigenin (LG). Liver sinusoidal endothelial injury induced by CPA (20, 40 mg/kg) in mice was evidenced by the elevated hepatic metalloproteinase-9 (MMP-9) expression, and the results from liver histological evaluation and scanning electron microscope observation. CPA increased hepatic infiltration of neutrophils, liver myeloperoxidase (MPO) activity, serum interleukin-6 (IL-6) content, hepatic IL-6 mRNA expression, toll-like receptor-4 (TLR4) expression and nuclear factor κB (NFκB) activation in mice. Elevated serum contents of damage associated molecular patterns (DAMPs) including high mobility group box 1 (HMGB1), heat shock protein 60 (HSP60) and glucose-regulated protein 94 (Grp94) were found in mice treated with CPA. Liver sinusoidal endothelial injury and inflammation induced by CPA were diminished in TLR4 knock-out mice. LG and LQ (40, 80 mg/kg) both ameliorated liver sinusoidal endothelial injury, and reduced the increased hepatic infiltration of neutrophils, MPO activity, hepatic IL-6 mRNA expression and NFκB activation induced by CPA. In summary, these results indicate that TLR4-NFκB-mediated inflammatory injury initiated by DAMPs was critically involved in CPA-induced hepatotoxicity. LG and LQ alleviated CPA-induced liver sinusoidal endothelial injury and inflammatory injury in mice.

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PMID: 

Eur J Pharmacol. 2019 Sep 5 ;858:172445. Epub 2019 Jun 15. PMID: 31211985

Abstract Title: 

Liquiritigenin inhibits IL-1β-induced inflammation and cartilage matrix degradation in rat chondrocytes.

Abstract: 

Osteoarthritis (OA) is an age-related arthropathy which has been considered to be associated with inflammatory damage and cartilage degradation. Liquiritigenin (LG), the main bioactive component of the rhizomes of Glycyrrhiza uralensis, has exhibited promising anti-inflammatory and anti-oxidative potential in numerous inflammatory diseases. However, the effects of LG on OA remain unclear. In this study, the therapeutic effects as well as the underlying mechanisms of LG on interleukin-1β (IL-1β)-treated rat chondrocytes had been investigated. Our results showed that LG could inhibit the IL-1β-induced expression of nitic oxide (NO) and prostaglandin E(PGE). In consist with these findings, the IL-1β-induced production of inducible nitic oxide synthase (iNOS) and cyclooxygenase-2 (COX2) could also be decreased by LG. Meanwhile, LG could suppress the IL-1β-induced upregulation of cartilage matrix catabolic enzymes including aggrecanase-2 (ADAMTS5) and matrix metalloproteinases (MMPs). Besides, the IL-1β-induced degradation of collagen II and aggrecan could be alleviated by LG. Moreover, LG prevented cartilage damage in IL-1β-treated rat cartilage explants. Mechanistically, LG functioned by inhibiting mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathwaysactivation. In general, this study reveals the anti-inflammatory properties of LG on IL-1β-treated rat chondrocytes and the possible mechanisms behind it, which may provide new ideas for OA therapy.

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PMID: 

Nutrients. 2019 Mar 29 ;11(4). Epub 2019 Mar 29. PMID: 30934945

Abstract Title: 

Exploring Common Culinary Herbs and Spices as Potential Anti-Quorum Sensing Agents.

Abstract: 

Quorum sensing controls bacterial pathogenesis and virulence; hence, interrupting this system renders pathogenic bacteria non-virulent, and presents a novel treatment for various bacterial infections. In the search for novel anti-quorum sensing (AQS) compounds, 14 common culinary herbs and spices were screened for potential antipathogenicity activity againstATCC 12472. Extracts of(liquorice),(celery),(cayenne pepper) and(aniseed) demonstrated good AQS potential, yielding opaque halo zones ranging from 12⁻19 mm diameter at sub-minimum inhibitory concentrations (0.350⁻4.00 mg/mL). For the same species, the percentage reduction in violacein production ranged from 56.4 to 97.3%. Zones with violacein inhibitory effects were evident in a celery extract analysed using high performance thin layer chromatography-bio-autography. The major active compound was isolated from celery using preparative-high performance liquid chromatography-mass spectrometry and identified using gas chromatography-mass spectrometry (GC-MS) as 3–butyl-4,5-dihydrophthalide (sedanenolide). Potent opaque zones of inhibition observed on the HPTLC-bio-autography plate seeded withconfirmed that sedanenolide was probably largely responsible for the AQS activity of celery. The bacteriocidal properties of many herbs and spices are reported. This study, however, was focussed on AQS activity, and may serve as initial scientific validation for the anti-infective properties ascribed to several culinary herbs and spices.

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PMID: 

J Food Biochem. 2019 Sep ;43(9):e12970. Epub 2019 Jul 18. PMID: 31489653

Abstract Title: 

Anti-inflammatory effect of hydrolyzed celery leaves extract in murine primary splenocyte.

Abstract: 

Apium graveolens (celery) has been used in traditional medicine for the treatment of various ailments. However, its molecular mechanism of action in inflammatory response is unclear. In this study, we sought to investigate the anti-inflammatory properties of celery leaves. We prepared an acid-hydrolyzed extract of celery leaves (HCE) and studied its effects on concanavalin A (ConA)-stimulated primary splenocytes. HCE at noncytotoxic concentrations, inhibited ConA-induced proliferation of splenocytes. HCE treatment reduced CD4T cell population and decreased expressions and production of cytokines in stimulated splenocytes. In addition, HCE significantly inhibited NO production and reduced the expression of COX-2 mRNA in the stimulated splenocytes. The effects seen were probably due to HCE's downregulation of NF-κB/p65 activation in splenocytes. By providing the anti-inflammatory mechanism of action of HCE, these findings are potentially important for future studies that may, ultimately result in the potential use of celery for the treatment/prevention of inflammatory diseases. PRACTICAL APPLICATIONS: Apium graveolens is a well-known edible plant with high concentrations of bioactive compounds such as apigenin, luteolin, and kaempferol. The research investigated the effects of A. graveolens leaves in splenocyte proliferation, and production of inflammatory mediators and cytokines. The data obtained from this study shed light on the use of plant extracts and plant-based bioactives in nutraceutical industries as potential functional food materials for preventing inflammatory diseases.

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PMID: 

Animals (Basel). 2019 Aug 20 ;9(8). Epub 2019 Aug 20. PMID: 31434330

Abstract Title: 

Clinical Effects of the Extract of the Seeds of the Indian Celery–In Horses Affected by Chronic Osteoarthritis.

Abstract: 

The extract of the seeds from Indian celery,(CSE), tested in experimental animals (rodents), and in humans affected by chronic osteoarthritic diseases, exhibits anti-inflammatory effects that can be compared, to some degree, to those of non-steroid anti-inflammatory drugs (NSAID). In view of a potential use of CSE in the equine species, it was tested on horses affected by chronic articular pathologies. The trial was performed on 20 horses divided into three different groups, orally treated with 0 (controls), 7.0 or 30 g of CSE BID. Basic orthopedic examinations were conducted, vital signs were observed, and blood samples collected. Improvement was observed at the highest dosage tested (30 g of CSE BID), as reflected in the score values of three clinical parameters, (i) amplitude and (ii) sensitivity to passive flexion and (iii) flexion test. Since the improvement of these parameters can be correlated with a lower perception of the pain, the present data suggest that the CSE treatment can have an analgesic effect in horses affected by chronic osteoarthritic diseases.

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PMID: 

Planta Med. 1995 Feb ;61(1):18-21. PMID: 7700983

Abstract Title: 

Effects of aqueous celery (Apium graveolens) extract on lipid parameters of rats fed a high fat diet.

Abstract: 

The antihyperlipidemic property of aqueous celery extract was studied in rats. Two groups of Wistar rats were fed a high fat diet for eight weeks to induce hyperlipidemia. One group was supplemented with aqueous celery extract in the diet while the other group served as control. At the end of the experiment, a significant reduction was found in the serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglyceride (TG) concentrations in the celery-treated rats. However, the concentration of hepatic TG was significantly higher in the celery-treated group than in the control group. Hepatic triacylglycerol lipase (HL) activity was found to be significantly lower in the celery-treated rats while the reverse was observed for the hepatic microsomal P450 content. Analysis of an ethereal extract of the aqueous extract of celery by thin layer chromatography (TLC) with two different solvent systems showed that the extract did not contain 3-n-butylphthalide (BuPh), a unique compound in celery that has previously been reported to have lipid-lowering action. Our study indicates that other active principle(s) could be responsible for the observed effects of aqueous celery extract on serum and hepatic lipid levels.

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PMID: 

J Pharm Pharmacol. 2007 Jun ;59(6):891-7. PMID: 17637182

Abstract Title: 

An extract of Apium graveolens var. dulce leaves: structure of the major constituent, apiin, and its anti-inflammatory properties.

Abstract: 

Flavonoids, natural compounds widely distributed in the plant kingdom, are reported to affect the inflammatory process and to possess anti-inflammatory as well as immunomodulatory activity in-vitro and in-vivo. Since nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) is one of the inflammatory mediators, the effects of the ethanol/water (1:1) extract of the leaves of Apium graveolens var. dulce (celery) on iNOS expression and NO production in the J774.A1 macrophage cell line stimulated for 24 h with Escherichia coli lipopolysaccharide (LPS) were evaluated. The extract of A. graveolens var. dulce contained apiin as the major constituent (1.12%, w/w, of the extract). The extract and apiin showed significant inhibitory activity on nitrite (NO) production in-vitro (IC50 0.073 and 0.08 mg mL(-1) for the extract and apiin, respectively) and iNOS expression (IC50 0.095 and 0.049 mg mL(-1) for the extract and apiin, respectively) in LPS-activated J774.A1 cells. The croton-oil ear test on mice showed that the extract exerted anti-inflammatory activity in-vivo (ID50 730 microg cm(-2)), with a potency seven-times lower than that of indometacin (ID50 93 microg cm(-2)), the non-steroidal anti-inflammatory drug used as reference. Our results clearly indicated the inhibitory activity of the extract and apiin in-vitro on iNOS expression and nitrite production when added before LPS stimulation in the medium of J774.A1 cells. The anti-inflammatory properties of the extract demonstrated in-vivo might have been due to reduction of iNOS enzyme expression.

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