PMID: 

Iran J Med Sci. 2020 Jan ;45(1):59-66. PMID: 32038060

Abstract Title: 

The Hydroalcoholic Extract of Saffron Protects PC12 Cells against Aluminum-Induced Cell Death and Oxidative Stress.

Abstract: 

Background: Aluminum (Al) exposure is among the environmental risk factors that may involve in the pathogenesis of neurodegenerative diseases. Oxidative stress has a critical role in the Al-induced toxicity. Saffron is a plant with potent radical scavenging and anti-oxidative properties. This investigation was designed to evaluate the possible protective effects of saffron extract (SE) on aluminum maltolate (Almal)-induced oxidative stress and apoptosis in PC12 cell line.Methods: In thisstudy, PC12 cells were divided into four groups including control, Almal (500µM), Almal+SE (50 μg/ml), and Almal+SE (100 μg/ml). After 48 hours of treatment with Almal in the absence and presence of SE, cell viability and apoptosis were determined using MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay and Annexin V flow cytometry, respectively. Catalase activity was determined as an index of oxidative stress. Statistical analyses were performed using one-way ANOVA (SPSS version 16.0). P

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PMID: 

Infect Disord Drug Targets. 2019 Jun 25. Epub 2019 Jun 25. PMID: 31241021

Abstract Title: 

Monoterpenoid Geraniol improves anti-TB drug efficiency by interfering with lipidome and virulence of mycobacteria.

Abstract: 

BACKGROUND: Tuberculosis (TB) remains a global infectious disorder for which efficient therapeutics are elusive. Nature is a source of novel pharmacologically active compounds with many potential drugs being derived directly or indirectly from plants, microorganisms and marine organisms.OBJECTIVE: The present study aimed to elucidate the antimycobacterial potential of Geraniol (Ger), a monoterpene alcohol, against Mycobacterium tuberculosis (MTB), which is the causative agent of TB.METHODS: Drug susceptibilities were performed by broth microdilution and REMA method. Disrupted membrane integrity was studied by membrane permeability assay and PI uptake. Cell surface phenotypes were studied by colony morphology, sliding motility and cell sedimentation rate. Lipidome profile was demonstrated by thin layer chromatography and liquid chromatography electrospray ionization mass spectrometry. Amendment in iron homeostasis was assessed by using iron chelator ferrozine and ferroxidase assay while genotoxicity was estimated with EtBr and DAPI staining. Biofilm formation was measured by staining, dry mass and metabolic activity using MTT. Cell adherence was examined microscopically and spectrophotometrically.RESULTS: We found the antimycobacterial activity of Ger to be 250µg/ml against MTB and explored that Ger leads to enhanced drug susceptibilities of most common anti-TB drugs. Underlying mechanisms revealed impaired cell surface phenotypes. Lipidomics analysis exposed profound decrement of mycolic acids, phosphatidylinositol mannosides and triacylglycerides whichare crucial for MTB pathogenicity. We further explored that Ger impairs iron homeostasis and leads to genotoxic stress. Moreover, Ger inhibited the potential virulence attributes such as biofilm formation and cell adherence to both polystyrene surface and human oral epithelial cells. Finally, we have validated all the disrupted phenotypes by RT-PCR which showed good correlation with the biochemical assays.CONCLUSION: Taken together, the current study demonstrates the antimycobacterial mechanisms of Ger, which may be exploited as an effective candidate of pharmacological interest.

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PMID: 

Pharmaceutics. 2020 Jan 17 ;12(1). Epub 2020 Jan 17. PMID: 31963479

Abstract Title: 

Novel Intranasal Drug Delivery: Geraniol Charged Polymeric Mixed Micelles for Targeting Cerebral Insult as a Result of Ischaemia/Reperfusion.

Abstract: 

Brain damage caused by cerebral ischaemia/reperfusion (I/R) can lead to handicapping. So, the present study aims to evaluate the prophylactic and therapeutic effects of geraniol in the form of intranasal polymeric mixed micelle (PMM) on the central nervous system in cerebral ischaemia/reperfusion (I/R) injury. A 3factorial design was used to prepare and optimize geraniol PMM to investigate polymer and stabilizer different concentrations on particle size (PS) and percent entrapment efficiency (%EE). F3 possessing the highest desirability value (0.96), with a PS value of 32.46  ±  0.64 nm, EE of 97.85  ±  1.90%, and release efficiency of 59.66  ±  0.64%, was selected for further pharmacological and histopathological studies. In the prophylactic study, animals were classified into a sham-operated group, a positive control group for which I/R was done without treatment, and treated groups that received vehicle (plain micelles), geraniol oil, and geraniol micelles intranasally before and after I/R. In the therapeutic study, treated rats received geraniol oil and micelles after I/R. Evaluation of the effect of geraniol on behavior was done by activity cage and rotarod and the analgesic effect tested by hot plate. Anti-inflammatory activity was assessed by measuring interleukin β6, cyclooxygenase-2, hydrogen peroxide, and inducible nitric oxide synthase. Histopathogical examination of cerebral cortices was also done to confirm the results of a biochemical assay. Geraniol nanostructured polymeric mixed micelles showed an enhanced neuro-protective effect compared to geraniol oil, confirming that PMM via intranasal route could be an efficient approach for delivering geraniol directly to the brain through crossing the blood-brain barrier.

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PMID: 

Fitoterapia. 2019 Nov ;139:104394. Epub 2019 Oct 25. PMID: 31669719

Abstract Title: 

Geraniol targets K1.3 ion channel and exhibits anti-inflammatory activity in vitro and in vivo.

Abstract: 

Naturally occurring monoterpenes are known for their various pharmacological activities including anti-inflammation. K1.3 ion channel is a voltage-gated potassium channel and has been validated as a drug target for autoimmune and chronic inflammatory diseases like psoriasis. Here we experimentally test the direct interaction between monoterpenes and K1.3 ion channel. Our electrophysiological analysis determined that monoterpenes (geraniol, nerol,β-citronellol, citral and linalool) have inhibitory effects on K1.3 ion channel. Representatively, geraniol reversibly blocked K1.3 currents in a voltage-dependent manner with an ICof 490.50 ± 1.04 μM at +40 mV in HEK293T cells. At the effective concentrations, geraniol also inhibited cytokine secretion of activated human T cells, including IL-2, TNF-α and IFN-γ. In an imiquimod-induced psoriasis-like animal model, geraniol administration significantly reduced psoriasis area and severity index scores, ameliorated the deteriorating histopathology and decreased the degree of splenomegaly. Together, our findings not only suggest that monoterpenes may serve as lead molecules for the development of K1.3 inhibitors, but also indicate that geraniol could be considered as a promising therapeutic candidate to treat autoimmune diseases.

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PMID: 

Hum Exp Toxicol. 2019 Dec 26:960327119896614. Epub 2019 Dec 26. PMID: 31876192

Abstract Title: 

The cytotoxic concentration of rosmarinic acid increases MG132-induced cytotoxicity, proteasome inhibition, autophagy, cellular stresses, and apoptosis in HepG2 cells.

Abstract: 

Rosmarinic acid (RA) is a natural polyphenolic compound derived from many common herbal plants. Although it is known that RA has many important biological activities, its effect on proteasome inhibitor-induced changes in cancer treatment or its effects on any experimental proteasome inhibition model is unknown. The aim of the study was to investigate the effect of RA on MG132-induced cytotoxicity, proteasome inhibition, autophagy, cellular stresses, and apoptosis in HepG2 cells. HepG2 cells were treated with 10, 100, and 1000µM RA in the presence of MG132 for 24 h; 10 and 100 µM RA did not affect but 1000 µM RA decreased cell viability in HepG2 cells. MG132 caused a significant decrease in cell viability and phosphorylation of mammalian target of rapamycin and a significant increase in levels of polyubiquitinated protein, microtubule-associated proteins 1A/1B light chain 3B-II (LC3B-II), heat shock protein 70 (HSP70), binding immunoglobulin protein (BiP), activating transcription factor 4 (ATF4), protein carbonyl, and cleaved poly(adenosine diphosphate-ribose) polymerase 1 (PARP1); 10 and 100 µM RA did not significantly change these effects of MG132 in HepG2 cells; 1000 µM RA caused a significant decrease in cell viability and a significant increase in polyubiquitinated protein, LC3B-II, HSP70, BiP, ATF4, protein carbonyl, and cleaved PARP1 levels in MG132-treated cells. Our study showed that only 1000µM RA increased MG132-induced cytotoxicity, proteasome inhibition, autophagy, cellular stresses, and apoptosis in HepG2 cells. According to our results, cytotoxic concentration of RA can potentiate the effects of MG132 in hepatocellular carcinoma treatment.

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PMID: 

Phytother Res. 2020 Jan 27. Epub 2020 Jan 27. PMID: 31985119

Abstract Title: 

Rosmarinic acid reverses non-small cell lung cancer cisplatin resistance by activating the MAPK signaling pathway.

Abstract: 

Cisplatin (DDP) is one of the first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC). However, repeated use of cisplatin in clinical practice often induces chemoresistance. The aims of this study were to investigate whether rosmarinic acid (RA) could reverse multidrug resistance (MDR) in NSCLC and to explore the underlying mechanisms. Our data demonstrated that RA significantly inhibited NSCLC cell proliferation and cell colony formation in a dose-dependent manner, induced G1 phase cell cycle arrest and apoptosis, and increased the sensitivity of cell lines resistant to DDP. Mechanistically, RA inhibited NSCLC cell growth, arrested cell cycle, and induced apoptosis by activating MAPK and inhibiting the expression of P-gp and MDR1, which correspondingly enhanced p21 and p53 expression. We observed that the growth of xenograft tumors derived from NSCLC cell lines in nude mice was significantly inhibited by combination therapy. We demonstrate that RA is a potentially effective MDR reversal agent for NSCLC, based on downregulation of MDR1 mRNA expression and P-gp. Together, these results emphasize the putative role of RA as a resistance reversal agent in NSCLC.

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PMID: 

Anticancer Res. 2020 Feb ;40(2):751-758. PMID: 32014917

Abstract Title: 

Rosmarinic Acid/ Blue Light Combination Treatment Inhibits Head and Neck Squamous Cell Carcinoma.

Abstract: 

BACKGROUND/AIM: This study investigated a novel combined therapy of rosmarinic acid (RA)/blue light on head and neck squamous cell carcinoma (HNSCC) cell proliferation in vitro.MATERIALS AND METHODS: HNSCC cells were exposed to BL (500 mW/cm) for 90 s, and incubated with 80μg/ml RA for 1 hour. Cell viability was determined after 24 h using WST-1 assay. Western blot was used to detect treatment-induced changes in epidermal growth factor receptor (EGFR) activation. Hydrogen peroxide (HO) and nitric oxide levels were quantified using CM-HDCFH-DA assays. Apoptosis was assessed using Annexin V/PI staining and flow cytometry.RESULTS: RA/blue light treatment resulted in a significant reduction in cell viability, EGFR activation and HOlevels in all HNSCC cell lines. However, no significant changes in NO production or apoptosis induction were found.CONCLUSION: RA/blue light effectively decreased HNSCC cell proliferation through reduction in EGFR activation and HOproduction, and not via induction of apoptosis.

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PMID: 

Life Sci. 2020 Feb 15 ;243:117245. Epub 2020 Jan 8. PMID: 31926253

Abstract Title: 

Anti-metastatic properties of a potent herbal combination in cell and mice models of triple negative breast cancer.

Abstract: 

AIM: To determine the anti-metastatic potential of combinations of two bioactive carotenoids of saffron, crocin and crocetin, on 4T1 breast cancer and on a mice model of TNBC, and assess the effect of the most potent combination on the Wnt/β-catenin pathway.MAIN METHODS: The effects of the carotenoid combinations on the viability of 4T1 cells were determined by MTT assay. The effects of the nontoxic doses on migration, mobility, invasion and adhesion to ECM were examined by scratch assay, Transwell/Matrigel-coated Transwell chamber and adhesion assay respectively. Tumors were inoculated by injecting mice with 4T1 cells. The weights and survival rates of the mice and tumor sizes were monitored. Histological analysis of the tissues was conducted. The expression levels of Wnt/β-catenin pathway genes were measured by Real-time PCR and western blotting.KEY FINDINGS: Treatment of 4T1 cells with combination doses inhibited viability in a dose-dependent manner. The nontoxic combinations significantly inhibited migration, cell mobility and invasion, also attenuating adhesion to ECM. The combination therapy mice possessed more weight, higher survival rates and smaller tumors. Histological examination detected remarkably fewer metastatic foci in their livers and lungs. It was also demonstrated that the combinations exerted anti-metastatic effects by disturbing the Wnt/β-catenin target genes in the liver and tumors.SIGNIFICANCE: Our findings propose a carotenoid combination as an alternative potent herbal treatment for TNBC, which lacks the adverse effects associated with either chemotherapeutic agents or herb-chemotherapeutic drugs.

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PMID: 

Pharmacol Rep. 2019 Nov ;71(6):1228-1234. Epub 2019 Jul 30. PMID: 32002862

Abstract Title: 

Crocin protects cardiomyocytes against LPS-Induced inflammation.

Abstract: 

BACKGROUND: Sepsis causes organ dysfunctions via elevation of oxidative stress and inflammation. Lipopolysaccharide (LPS) is the major surface molecule of most gram-negative bacteria and routinely used as a sepsis model in investigation studies. Crocin is an active compound of saffron which has different pharmacological properties such as anti-oxidant and anti-inflammatory. In this research, the protective effect of crocin was evaluated against LPS-induced toxicity in the embryonic cardiomyocyte cell line (H9c2).METHODS: The cells were pre-treated with different concentration of crocin ( 10,20 and 40μM) for 24 h, and then LPS was added (10μg/ml) for another 24 h. Afterward, the percentage of cell viability and the levels of inflammatory cytokines (TNF-α, PGE, IL-1β, and IL-6), gene expression levels (TNF-α, COX-2, IL-1β, IL-6, and iNOS), and the level of nitric oxide (NO) and thiol were measured.RESULTS: Our results showed that LPS reduced cell viability, increased the levels of cytokines, gene- expression, nitric oxide, and thiol. Crocin attenuated the LPS-induced toxicity in H9c2 cells via reducing the levels of inflammatory factors (TNF-α, PGE, IL-1β, and IL-6, p

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PMID: 

Arch Physiol Biochem. 2020 Feb 4:1-13. Epub 2020 Feb 4. PMID: 32013614

Abstract Title: 

Metabolic impact of saffron and crocin: an updated systematic and meta-analysis of randomised clinical trials.

Abstract: 

The present systematic and meta-analysis study was designed to show the protective impact of saffron and crocin supplementation on hyperlipidaemia and hyperglycaemia in randomised and clinical trials (RCTs). A pooled analysis using a model for random-effects showed that HDL-C levels were 0.21 fold higher in the saffron and 0.01 fold higher in the crocin group than placebo. LDL-C levels in the saffron group reduced by 0.51 and 0.04 fold in the crocin group versus the placebo. Moreover, TC levels in the saffron group were 0.19 lower and 0.11 fold lower in crocin group than in the placebo group. TG level in saffron group was 0.04 lower and 0.02 fold lower in crocin than the control group. The blood glucose levels did not significantly differ from the control group. This study suggests that saffron and crocin may modulate the serum lipid profile in patient with metabolic disorders.

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