PMID: 

Biochimie. 2020 Jan ;168:10-16. Epub 2019 Oct 25. PMID: 31669604

Abstract Title: 

Pelargonidin ameliorates acetaminophen-induced hepatotoxicity in mice by inhibiting the ROS-induced inflammatory apoptotic response.

Abstract: 

The common analgesic acetaminophen (N-acetyl-p-aminophenol, APAP) is non-toxic to the liver at therapeutic doses. However, an overdose of APAP can lead to APAP-induced liver failure, which has emerged as a serious issue in the US and Europe. Pelargonidin is an anthocyanidin found in pomegranates, plums, and various berries. Pelargonidin has strong antioxidant effects, directly scavenging superoxide radicals and inhibiting H₂O₂-induced lipid peroxidation. Focusing on these effects, we studied the preventative effect of pelargonidin on APAP-induced hepatotoxicity and its underlying mechanisms in vivo. We observed that pelargonidin mitigates serum alanine aminotransferase and aspartate aminotransferase activity, which are strongly associated with APAP-induced hepatotoxicity. We also found that pelargonidin reduced APAP-induced hepatic necrosis by removing excessive ROS. Hepatic necrosis stimulates the release of molecular pathogens that induce inflammation, which increases cell stress and can lead to apoptosis. Therefore, pelargonidin was able to reduce levels of necrosis, inflammation, and hepatocyte apoptosis. These results indicate that the administration of pelargonidin protects against APAP-induced hepatotoxicity and that it could be a novel protective strategy against APAP-induced liver failure.

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PMID: 

Eur J Nutr. 2019 Nov 7. Epub 2019 Nov 7. PMID: 31696323

Abstract Title: 

Pelargonidin 3-glucoside-enriched strawberry attenuates symptoms of DSS-induced inflammatory bowel disease and diet-induced metabolic syndrome in rats.

Abstract: 

PURPOSE: To determine whether the anthocyanin, pelargonidin 3-glucoside (P3G), attenuates symptoms of inflammatory bowel disease (IBD) and metabolic syndrome in rats.METHODS: We tested P3G-enriched strawberry in two models of chronic inflammation in rats, chronic IBD induced by 0.5% dextran sodium sulphate in the drinking water for 12 weeks (D) and metabolic syndrome induced by a high-carbohydrate, high-fat diet (H) for 16 weeks. P3G-enriched strawberry was added to the diet for the final 6 weeks in IBD rats (DP) or 8 weeks in H rats (HP) to provide a dose of 8 mg P3G/kg/day.RESULTS: D rats had marked diarrhoea, bloody stools, erosion of mucosal epithelium, crypt atrophy, loss of villi and goblet cells, and inflammatory cell infiltration. These symptoms were reversed by P3G with healthy stools and mucosal lining of ileum and colon including increased villi, crypts and goblet cells and reduced inflammation. H rats developed hypertension, dyslipidaemia, central obesity, increased ventricular stiffness, cardiac and liver inflammation, and steatosis. P3G treatment in H rats improved systolic blood pressure, ventricular stiffness, and cardiac and liver structure, and reduced abdominal fat, abdominal circumference and body weight gain.CONCLUSIONS: Our study indicates that dietary P3G decreased inflammation to decrease the symptoms of IBD, and to improve cardiovascular, liver and metabolic functions in metabolic syndrome.

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PMID: 

Biol Pharm Bull. 2007 Sep ;30(9):1805-7. PMID: 17827745

Abstract Title: 

Galbanic acid from Ferula szowitsiana enhanced the antibacterial activity of penicillin G and cephalexin against Staphylococcus aureus.

Abstract: 

In this study the enhancement effect of Ferula szowitsiana roots' acetone extract on the antibacterial activity of penicillin G and cephalexin was evaluated against Staphylococcus aureus. Disk diffusion and broth dilution methods were used to determine the antibacterial activity of these antibiotics in the absence and presence of plant extract and its various fractions separated by TLC plate. The active component of plant extract involved in enhancement of penicillin G's and cephalexin's activities had Rf=0.336 on a TLC plate. The spectral data ((1)H-, (13)C-NMR) of this compound revealed that this compound was 7-[6-(beta-carboxyethyl)-5-isopropylidene-1,2-dimethylcyclo-hexylmethoxy]coumarin (galbanic acid), previously isolated from Ferula assa-foetida. In the presence of sub-inhibitory concentration of galbanic acid (100 microg/ml) the MIC of penicillin G for S. aureus decreased from 64 to 1 (a sixteen four-fold decrease) and for cephalexin from 128 to 1 microg/ml (a one hundred twenty eight-fold decrease). The highest fold decrease in MIC was observed for cephalexin in combination of galbanic acid against test strain. These results signify that the low concentration of galbanic acid (100 microg/ml) potentiates the antimicrobial action of penicillin G and cephalexin suggesting a possible utilization of these compounds in combination therapy against S. aureus.

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PMID: 

Braz J Microbiol. 2010 Jul ;41(3):574-80. Epub 2010 Sep 1. PMID: 24031531

Abstract Title: 

Effect of galbanic Acid, a sesquiterpene coumarin from ferula szowitsiana, as an inhibitor of efflux mechanism in resistant clinical isolates of Staphylococcus aureus.

Abstract: 

Galbanic acid, a sesquiterpene coumarin from Ferula szowitsiana roots, was investigated for its potentiating effect on the antimicrobial activity of antibiotics as well as ethidium bromide, in 6 multidrug resistance (MDR) clinical isolates of Staphylococcus aureus. Galbanic acid had inhibitory effect on none of the isolated bacteria tested (up to 800μg /ml). The MIC range of ciprofloxacin, tetracycline and ethidium bromide, against all tested S. aureus were 10-80, 10-80 and 4-16 μg/ml, respectively. These were reduced to ≤2.5-5, 2.5-5 and 0.5-2 μg/ml in the presence of galbanic acid (300 μg /ml) or verapamil (100 μg /ml). The rate of ethidium bromide (2 μg /ml) accumulation in clinical isolates was enhanced with galbanic acid (300 μg /ml). There is also a decrease in loss of ethidium bromide from bacteria in the presence of galbanic acid. Similar results were obtained when verapamil (100 μg /ml) was used as an efflux pump inhibitor. Galbanic acid, like verapamil, a typical inhibitor of efflux pump, reduced the MIC of ethidium bromide and tested antibiotics. Since efflux is the only known reported mechanism for ethidium bromide resistance, the reduction in ethidium bromide MIC and enhanced accumulation as well as decreasedefflux of ethidium bromide in the presence of galbanic acid, can be attributed to this efflux inhibitory properties.

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PMID: 

Pharm Res. 2011 Mar ;28(3):597-609. Epub 2010 Nov 10. PMID: 21063754

Abstract Title: 

Galbanic acid isolated from Ferula assafoetida exerts in vivo anti-tumor activity in association with anti-angiogenesis and anti-proliferation.

Abstract: 

PURPOSE: To investigate whether galbanic acid (GBA) exerts anti-angiogenic and anti-cancer activities.METHODS: Using human umbilical vein endothelial cell (HUVEC) model, we analyzed effects of GBA on cellular and molecular events related to angiogenesis. We tested its direct anti-proliferative action on mouse Lewis lung cancer (LLC) cells and established its in vivo anti-angiogenic and anti-tumor efficacy using LLC model.RESULTS: GBA significantly decreased vascular endothelial growth factor (VEGF)-induced proliferation and inhibited VEGF-induced migration and tube formation of HUVECs. These effects were accompanied by decreased phosphorylation of p38-mitogen-activated protein kinase (MAPK), c-jun N-terminal kinase (JNK), and AKT, and decreased expression of VEGFR targets endothelial nitric oxide synthase (eNOS) and cyclin D1 in VEGF-treated HUVECs. GBA also decreased LLC proliferation with an apparent G2/M arrest, but did not induce apoptosis. In vivo, inclusion of GBA in Matrigel plugs reduced VEGF-induced angiogenesis in mice. Galbanic acid given by daily i.p. injection (1 mg/kg) inhibited LLC-induced angiogenesis in an intradermal inoculation model and inhibited the growth of s.c. inoculated LLC allograft in syngenic mice. Immunohistochemistry revealed decreased CD34 microvessel density index and Ki-67 proliferative index in GBA-treated tumors.CONCLUSIONS: GBA exerts anti-cancer activity in association with anti-angiogenic and anti-proliferative actions.

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PMID: 

Int J Cancer. 2012 Jan 1 ;130(1):200-12. Epub 2011 May 9. PMID: 21328348

Abstract Title: 

Galbanic acid decreases androgen receptor abundance and signaling and induces G1 arrest in prostate cancer cells.

Abstract: 

Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(-) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(-) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA downregulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide (Bic), LNCaP cell culture assays did not detect agonist activity of GBA. GBA and Bic exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G(1) arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D(1) without the causal involvement of cyclin-dependent kinase (CDK) inhibitory proteins P21(Cip1) and P27(Kip1) . In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and Bic with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multitargeting drug candidate for the prevention and therapy of PCa.

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PMID: 

Fitoterapia. 2015 Mar ;101:1-11. Epub 2014 Dec 13. PMID: 25510323

Abstract Title: 

Galbanic acid inhibits HIF-1α expression via EGFR/HIF-1α pathway in cancer cells.

Abstract: 

Hypoxia Inducible Factor-1 plays a key transcriptional role in the adaptation of hypoxic solid tumors to low oxygen environment. Here, we aimed to investigate galbanic acid (GBA) inhibitory effects on HIF-1 activation during hypoxia and normoxia. MTT survival and Annexin V assays were used to evaluate GBA cytotoxicity and apoptosis in treated cells. Quantitative real time PCR and western blotting were used to estimate mRNA expression and translated protein, respectively. Results showed that GBA dose- and time-dependently decreased the in vitro growth of OVCAR-3 human epithelial carcinoma cells with an IC50 of approximately 37, 12.1 and 10μM GBA at 24, 48 and 72h, respectively. Following phosphatidylserine of outer leaflet of the plasma membrane revealed occurrence of early/late apoptosis in GBA treated cells. In addition, we found that GBA down-regulates HIF-1α and HIF-1β mRNA expression in both hypoxia and normoxia. To determinethe mechanism of action, we showed that GBA did not inhibit Akt and EGFR mRNA expression, yet protein degradation investigation showed that GBA shortened the half-life of EGFR through decreasing its stability with a decrease of nearly 2 and 3h in A549 and OVCAR-3 cell lines, respectively. We also found that downstream genes contributed in glycolysis, including Eno 1 and GluT-1, are underexpressed in GBA treated cells in hypoxia. Conclusively, GBA may inhibit HIF-1 activation through down-regulation of its subunit expression in hypoxia, and increasing of EGFR degradation in normoxia.

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PMID: 

Phytother Res. 2015 Jun ;29(6):844-9. Epub 2015 Mar 6. PMID: 25753585

Abstract Title: 

Apoptotic Effect of Galbanic Acid via Activation of Caspases and Inhibition of Mcl-1 in H460 Non-Small Lung Carcinoma Cells.

Abstract: 

Galbanic acid (GBA), a major compound of Ferula assafoetida, was known to have cytotoxic, anti-angiogenic and apoptotic effects in prostate cancer and murine Lewis lung cancer cells; the underling apoptotic mechanism of GBA still remains unclear so far. Thus, in the present study, the apoptotic mechanism of GBA was investigated mainly in H460 non-small cell lung carcinoma (NSCLC) cells because H460 cells were most susceptible to GBA than A549, PC-9 and HCC827 NSCLC cells. Galbanic acid showed cytotoxicity in wild EGFR type H460 and A549 cells better than other mutant type PC-9 and HCC827 NSCLC cells. Also, GBA significantly increased the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells and sub G1 population in H460 cells. Western blotting revealed that GBA cleaved poly (ADP-ribose) polymerase (PARP), activated Bax and caspase 9, attenuated the expression of Bcl-2, Bcl-x(L), and Myeloid cell leukemia 1 (Mcl-1) in H460 cells. However, interestingly, overexpression of Mcl-1 blocked the ability of GBA to exert cytotoxicity, activate caspase9 and Bax, cleave PARP, and increase sub G1 accumulation in H460 cells. Overall, these findings suggest that GBA induces apoptosis in H460 cells via caspase activation and Mcl-1 inhibition in H460 cells as a potent anticancer agent for NSCLC treatment.

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PMID: 

Eur J Pharmacol. 2019 Mar 15 ;847:91-96. Epub 2019 Jan 25. PMID: 30689998

Abstract Title: 

Galbanic acid potentiates TRAIL induced apoptosis in resistant non-small cell lung cancer cells via inhibition of MDR1 and activation of caspases and DR5.

Abstract: 

Galbanic acid (GBA) is known a sesquiterpene coumarin to have apoptotic, anti-hypoxic, anti-proliferative, anti-hepatitis, anti-angiogenic, anti-bacteria and anti-thrombotic effects. Also, antitumor effect of GBA was reported in prostate, ovary, breast and lung cancers. Nevertheless, the underlying molecular mechanism of GBA was not fully understood to overcome chemoresistance in resistant lung cancer so far. Thus, synergistic antitumor mechanism of GBA and TNF-related apoptosis-inducing ligand (TRAIL) was elucidated in H460 and resistant H460/R non-small cell lung cancer cells (NSCLCs). Combination of GBA and TRAIL significantly exerted cytotoxicity in a dose dependent manner compared to GBA or TRAIL alone in H460/R cells. Also, GBA and TRAIL significantly increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells and sub-G1 population in a dose dependent manner in H460/R cells. Consistently, GBA and TRAIL induced cleavages of poly (ADP-ribose) polymerase (PARP), caspase-9 and caspase-8 along with upregulation of death receptor 5 (DR5) and also attenuated the expression of B-cell lymphoma-extra-large (Bcl-x), B-cell lymphoma 2 (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP) in H460/R cells. Furthermore, combination of GBA and TRAIL remarkably inhibited the expression of decoy receptor 1 (DcR1) and multidrug resistance 1(MDR1) in H460/R cells. Consistently, GBA and TRAIL effectively maintained Rhodamine 123 accumulation in H460/R cells compared to GBA or TRAIL alone by blocking multidrug efflux pump from the cells. Overall, our findings suggest that galbanic acid enhances TRAIL induced apoptosis via inhibition of MDR1 and activation of caspases and DR5 in H460/R cells as a potent TRAIL sensitizer.

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PMID: 

Avicenna J Phytomed. 2019 May-Jun;9(3):237-247. PMID: 31143691

Abstract Title: 

Interactive anticancer effect of nanomicellar curcumin and galbanic acid combination therapy with some common chemotherapeutics in colon carcinoma cells.

Abstract: 

Objective: In the current investigation, we aimed to study the combined cytotoxicity of curcumin, as a nanomicellar formulation, and galbanic acid (Gal), dissolved in DMSO against the murine C26 and human Caco-2 colon carcinoma cells. Further, curcumin potential for cisplatin and doxorubicin (Dox) co-therapy was studied.Materials and Methods: The combined cytotoxic effect of these phytochemicals at varying dose ratios were examined using the MTT colorimetric assay. Moreover, the time-dependent toxicity of curcumin, cisplatin, Dox, and pegylated liposomal Dox (Doxil) was determined. The interactive anti-proliferative behavior of these compounds was examined using the CompuSyn software.Results: Nanomicellar curcumin showed considerable cytotoxicity in C26 cells 24 hr post-treatment. Co-treatment of cells with curcumin nanomicelles: Gal had a synergistic effect in C26 (at 10:1 molar ratio), and Caco-2 (at 1:5 molar ratio) cell lines in cell cultures. Nanomicellar curcumin showed strong and mild synergistic inhibitory effects in C26 cells when co-administered with Doxil and cisplatin, respectively.Conclusion: Curcumin nanomicelles and Gal had a synergistic effect in C26 and Caco-2 cell lines. It is speculated that nanomicellar curcumin shows synergistic cancer cell killing if administered 24-hr post-injection of Doxil and cisplatin.

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