PMID: 

Biomed Pharmacother. 2017 Dec ;96:313-319. Epub 2017 Oct 7. PMID: 29017143

Abstract Title: 

Protective effect of carvacrol on acetic acid-induced colitis.

Abstract: 

The pharmacological therapy for inflammatory bowel diseases continues to be problematic, and requires new alternative options. In this study, we tested the hypothesis that carvacrol (CAR), a phenolic monoterpene with anti-inflammatory and antioxidant activities, can treat experimental colitis in mice. C57BL/6 mice (n=8/group) were subjected to intrarectal administration of acetic acid (5%) to induce colitis. Mice were pretreated with CAR (25, 50 or 100mg/kg, p.o.) every 12h for three days prior to the induction. Abdominal hyperalgesia, macroscopic and microscopic colon damage, myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels, oxidative stress markers, and antioxidant enzyme activities were evaluated. Pretreatment with all doses of CAR significantly decreased abdominal hyperalgesia and colon MPO activity and TNF-α and IL-1β levels. A reduction in macroscopic and microscopic damage (p

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PMID: 

Phytother Res. 2018 Jan ;32(1):151-159. Epub 2017 Nov 28. PMID: 29193478

Abstract Title: 

Possible therapeutic effect of carvacrol on asthmatic patients: A randomized, double blind, placebo-controlled, Phase II clinical trial.

Abstract: 

The relaxant effects of carvacrol, a phenolic monoterpene, on tracheal smooth muscle and its preventive effect on asthmatic animals were reported. The effect of carvacrol in asthmatic patients was examined in the placebo group (Group P, n = 11) receiving placebo and treatment group (Group C, n = 12), which received carvacrol capsule (1.2 mg/kg/day) for 2 months in a double-blind manner. Pulmonary function tests, respiratory symptoms, hematological indices, and high-sensitivity C-reactive protein (hs-CRP) were measured before,1 and 2 months after starting treatment. At the end of treatment period, Pulmonary function tests values in Group C were significantly increased (p 

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PMID: 

Mol Med Rep. 2018 Mar ;17(3):3987-3992. Epub 2017 Dec 19. PMID: 29257341

Abstract Title: 

Carvacrol ameliorates inflammatory response in interleukin 1β-stimulated human chondrocytes.

Abstract: 

Carvacrol, a monoterpenic phenol present in Origanum vulgare (oregano) and Thymus vulgaris (thyme), possesses anti‑inflammatory effects; however, little is known about the effects and underlying mechanism of carvacrol on chondrocytes in osteoarthritis (OA). The present study aimed to investigate the protective effects of carvacrol against inflammation in interleukin 1β (IL‑1β)‑stimulated human chondrocytes. The results indicated that carvacrol inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production, and decreased the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX‑2). Carvacrol also suppressed the protein expression levels of matrix metalloproteinase (MMP)‑3 and MMP‑13 in IL‑1β‑stimulated human OA chondrocytes. Furthermore, carvacrol suppressed the activation of nuclear factor (NF)‑κB signaling pathway in IL‑1β‑induced human chondrocytes. In conclusion, the present results demonstrated that carvacrol was able to inhibit IL‑1β‑induced NO and PGE2 production, as well as iNOS, COX‑2 and MMPs expression in human chondrocytes by suppressing the activation of NF‑κB signaling pathway. Thus, carvacrol may have potential therapeutic functions for the treatment of OA.

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PMID: 

Anticancer Res. 2018 01 ;38(1):279-286. PMID: 29277784

Abstract Title: 

Carvacrol Targets AXL to Inhibit Cell Proliferation and Migration in Non-small Cell Lung Cancer Cells.

Abstract: 

BACKGROUND/AIM: AXL has been reported to be overexpressed and highly activated in various cancer types. In this study, we demonstrated the effect of carvacrol on cell proliferation and migration in non-small cell lung cancer (NSCLC) cells by impeding the expression and activation of AXL.MATERIALS AND METHODS: The levels of AXL protein, mRNA and promoter activity were evaluated by western blot, reverse transcription polymerase chain reaction (RT-PCR) and luciferase assay, respectively. AXL-overexpressing cells were established by ectopic expression of AXL cDNA. Cell viability, clonogenicity, and migration were measured in carvacrol-treated NSCLC cells.RESULTS: Carvacrol treatment of NSCLC cells caused down-regulation of AXL expression at the transcriptional level and also inhibited phosphorylation of AXL upon ligand stimulation. Carvacrol suppressed cell proliferation and migration and its inhibitory effect was attenuated in AXL-overexpressing NSCLC cells.CONCLUSION: Our data demonstrate that AXL is a crucial therapeutic target of carvacrol-induced inhibition of NSCLC cell proliferation and migration.

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PMID: 

Nutrients. 2018 Sep 14 ;10(9). Epub 2018 Sep 14. PMID: 30223488

Abstract Title: 

Bergamot Polyphenol Fraction Exerts Effects on Bone Biology by Activating ERK 1/2 and Wnt/β-Catenin Pathway and Regulating Bone Biomarkers in Bone Cell Cultures.

Abstract: 

Epidemiological studies show that fruit consumption may modulate bone mineral density. However, data regarding the effect of theRisso (Bergamot orange), a citrus fruit containing a high concentration of flavonoids, on bone health are still lacking. In this study, we investigated the effects of Bergamot polyphenols on the Wnt/β-catenin pathway in two distinct bone cell types (Saos-2 and MG63). Findings showed that exposure to 0.01 and 0.1 mg/mL doses upregulate β-catenin expression (= 0.001), osteoblast differentiation markers (e.g.,and), and downregulate RANKL (= 0.028), as compared to the control. Our results highlight, for the first time, that Bergamot polyphenols act on bone cells through theβ-catenin pathway. In vivo studies are necessary to fully understand Bergamot's role against bone resorption.

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PMID: 

J Biol Regul Homeost Agents. 2017 Oct-Dec;31(4):1087-1093. PMID: 29254319

Abstract Title: 

Lipid-lowering effect of bergamot polyphenolic fraction: role of pancreatic cholesterol ester hydrolase.

Abstract: 

Bergamot polyphenolic fraction (BPF) has been shown to positively modulate several mechanisms involved in metabolic syndrome, suggesting its use in therapy. In particular, it is able to induce a significant amelioration of serum lipid profile in hyperlipemic patients at different levels. The purpose of our study was to investigate the effect of BPF on cholesterol absorption physiologically mediated by pancreatic cholesterol ester hydrolase (pCEH). An in vitro activity assay was performed to study the effect of BPF on pCEH, whereas the rate of cholesterol absorption was evaluated through in vivo studies. In particular, male, Sprague-Dawley rats (200–225 g) were fed either normal chow or chow supplemented with 0.5% cholic acid, 5.5% peanut oil, and varying amounts of cholesterol (0 to 1.5%). BPF (10 mg/Kg) was daily administrated by means of a gastric gavage to animals fed with lipid supplemented diet for 4 weeks and, at the end of the study,plasma lipids and liver cholesteryl esters were measured in all experimental groups. Our results show that BPF was able to inhibit pCEH activity and this effect was confirmed, in vivo, via detection of lymphatic cholesteryl ester in rats fed with a cholesterol-rich diet. This evidence clarifies a further mechanism responsible for the hypolipemic properties of BPF previously observed in humans, confirming its beneficial effect in the therapy of hypercholesterolemia and in the treatment of metabolic syndrome.

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PMID: 

Endocr Metab Immune Disord Drug Targets. 2019 ;19(2):136-143. PMID: 30501605

Abstract Title: 

Hypoglycemic and Hypolipemic Effects of a New Lecithin Formulation of Bergamot Polyphenolic Fraction: A Double Blind, Randomized, Placebo- Controlled Study.

Abstract: 

OBJECTIVE: Hyperlipemia represents an independent risk factor in the development of atherosclerosis in patients undergoing type 2 diabetes mellitus (DM). Moreover, the pharmacological treatment of dyslipemia in patients undergoing type 2 DM (e.g. by means of statins), is accompanied by relevant side effects and oral supplementation with natural antioxidants, such as Citrus polyphenols, has recently been suggested to improve cardioprotection in such patients. However, due to the poor gastrointestinal absorption of polyphenols, novel formulations have recently been developed for getting a better bioavailability of polyphenolic rich fractions of citrus species extract rich in polyphenols.METHODS: Here, we investigated the effect of standard bergamot polyphenolic fraction (BPF®) as well as of its phytosomal formulation (BPF Phyto), in patients with type 2 DM and hyperlipemia. A randomized, double blind, placebo-controlled study was carried out in 60 patients suffering from type 2 DM and mixed hyperlipemia. Patients were divided into three groups: one receiving placebo,the second receiving standard BPF and the third BPF Phyto.RESULTS: In the groups receiving BPF and BPF Phyto, a significant reduction of fasting plasma glucose, serum LDL cholesterol and triglycerides accompanied by increased HDL cholesterol was observed. This effect was associated with significant reduction of small dense atherogenic LDL particles, as detected by means of proton NMR Spectroscopy, thus confirming the hypolipemic and hypoglycemic effect of bergamot extract both when using standard formulation as well as BPF Phyto. No differences were seen in the therapeutic response among groups receiving BPF and BPF Phyto, thus suggesting a substantial bioequivalence in their hypoglycemic and hypolipemic profile. However, when comparing the pharmacokinetic profile of naringin (the major component of BPF) and its metabolites, in patients treated with BPF Phyto, an at least 2,5 fold increase in its absorption was found, confirming in human studies the better profile of BPF Phyto compared to standard BPF.CONCLUSION: These data suggest that better absorption and tissue distribution of BPF Phyto formulation represents an innovative approach in supplementation treatments of cardiometabolic disorders.

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PMID: 

Front Pharmacol. 2018 ;9:1563. Epub 2019 Jan 17. PMID: 30705631

Abstract Title: 

Treatment With a Flavonoid-Rich Fraction of Bergamot Juice Improved Lipopolysaccharide-Induced Periodontitis in Rats.

Abstract: 

In this study, we investigated the effects of a flavonoid-rich fraction of Bergamot juice (BJe) in rats subjected to experimental periodontitis induced by a single intragingival injection of lipopolysaccharides (LPS).Periodontitis was induced by a single intragingival injection of 1μl LPS (10 μg/μl) derived fromin sterile saline solution. The injection was made in the mesolateral side at the interdental papilla between the first and the second molar. Fourteen days after LPS injection, we performed radiographic analyses and then we surgically removed the gingivomucosal tissue surrounding the mandibular first molar for histological, immunohistochemical and molecular analysis.LPS significantly induced oedema, tissue damage and increased neutrophil infiltration. At molecular level, we found increased NF-κB translocation as well as raised both TNF-α and IL-1β expression, other than modulation of apoptosis-associated proteins. Moreover, the increased myeloperoxidase activity was associated with up-regulation of adhesion molecules. Immunohistochemical analysis for nitrotyrosine and poly ADP-ribosedisplayed an intense staining in the gingivomucosal tissue. Oral administration of BJe for 14 consecutive days reduced tissue injury and several markers of gingival inflammation including nuclear NF-κB translocation, cytokines expression, myeloperoxidase activity and the expression of some adhesionmolecules such as ICAM and-selectin. BJe also decreased both nitrosative stress and PARP positive staining. Moreover, it caused down-regulation of Bax and up-regulation of Bcl-2 expression.Our findings demonstrate that BJe improves LPS-induced periodontitis in rats by reducing the typical markers of inflammation, thus suggesting its potential in the treatment of periodontal diseases.

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PMID: 

Antioxidants (Basel). 2019 Mar 16 ;8(3). Epub 2019 Mar 16. PMID: 30884780

Abstract Title: 

Oxidative Imbalance and Kidney Damage in Cafeteria Diet-Induced Rat Model of Metabolic Syndrome: Effect of Bergamot Polyphenolic Fraction.

Abstract: 

Obesity is a potent risk factor for kidney disease as it increases the possibility of developing diabetes and hypertension, and it has a direct impact on the development of chronic kidney disease and end-stage renal disease. In this study, we tested the effect of bergamot polyphenolic fraction in a cafeteria with diet-fed rats, an excellent experimental model for studying human metabolic syndrome, as it is able to induce severe obesity with insulin resistance and high plasma triglyceride levels more efficiently than a traditional lard-based high-fat diet used in rodent models. We analyzed the plasmatic oxidative balance by photometric tests, and the expression of cytoplasmic antioxidant enzymes (superoxide dismutase 1 and glutatione S-tranferasi P1) and apoptotic markers (Caspase 8 and 9) in kidney tissues by Western blot analysis. Our results clearly showed that the cafeteria diet induces a marked pro-oxidant effect: significant reduction of plasmatic antioxidant capacity; downregulation of cytoplasmic antioxidant enzymes expression; and activation of apoptotic pathways. All these hallmarks of redox disequilibrium were mitigated by treatment with polyphenolic fraction of bergamot, highlighting its antioxidant effect in the metabolic syndrome. Our data show that the link between obesity and renal damage could be represented by oxidative stress.

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PMID: 

Integr Food Nutr Metab. 2019 Mar ;6(2). Epub 2019 Feb 28. PMID: 31057945

Abstract Title: 

Clinical application of bergamot () for reducing high cholesterol and cardiovascular disease markers.

Abstract: 

The bergamot is a citrus fruit native to southern Italy with traditional uses that include improving immune response and cardiovascular function. There are a variety of phytochemicals that have been found in the bergamot including brutieridin and melitidin as well as other flavonoids, flavones O-glucosides and C-glucosides. Multiple clinical trials have provided evidence that different forms of orally administered bergamot can reduce total cholesterol and low-density lipoprotein cholesterol. In vitro mechanistic studies have provided evidence that polyphenols from the bergamot can alter the function of AMPK and pancreatic cholesterol ester hydrolase (pCEH). The use of bergamot in multiple clinical trials has consistently shown that it is well tolerated in studies ranging from 30 days to 12 weeks. This mini-review reports on the clinical studies performed with different forms of bergamot along with their effectiveness in reducing total cholesterol and LDL cholesterol in patients with hypercholesterolemia.

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