PMID: 

Life Sci. 2019 Feb 15 ;219:257-263. Epub 2018 Nov 23. PMID: 30472298

Abstract Title: 

Carvacrol ameliorates experimental autoimmune encephalomyelitis through modulating pro- and anti-inflammatory cytokines.

Abstract: 

AIM: The inflammatory process is a key step in multiple sclerosis (MS) development. Carvacrol exhibits various anti-inflammatory properties. We aimed to assess the Carvacrol effects on clinical manifestations and production of pro-inflammatory (IFN-γ, IL-6 and IL-17) and anti-inflammatory (TGF-β, IL-4, and IL-10) cytokines in experimental autoimmune encephalomyelitis (EAE) as MS animal model.MAIN METHODS: EAE mice were treated with 5, 10 mg/kg dose of Carvacrol or vehicle, as the control EAE group, every other day until day-21 post EAE induction. On day22, the leukocyte infiltration within the CNS was estimated using hematoxylin-eosin staining. The cytokine production by splenocytes was determined after in vitro stimulating withmyelin oligodendrocyte protein (MOG).KEY FINDINGS: The EAE clinical scores in 5 and 10 mg/kg Carvacrol-treated mice were lower than untreated group (P 

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PMID: 

J Cell Biochem. 2018 Nov 28. Epub 2018 Nov 28. PMID: 30485517

Abstract Title: 

Carvacrol suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes.

Abstract: 

BACKGROUND: Fibroblast-like synoviocytes (FLSs) play an essential role in the chronic inflammatory process of rheumatoid arthritis (RA). Carvacrol is a natural monoterpenic phenol that retains significant anti-inflammatory activity. However, the effect of carvacrol on inflammatory response in RA-FLSs has not yet been reported. The present study aimed to investigate the role of carvacrol in lipopolysaccharides (LPS)-induced inflammatory response in human RA-FLSs.METHODS: Cell viability and proliferation were measured by MTT and Cell Counting Kit-8 assays, respectively. The migration was detected by transwell assay. The production of inflammatory cytokines and matrix metalloproteinases (MMPs) were analyzed by enzyme-linked immunosorbent assay. The expressions of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), NF-κB, p38, p-p38, ERK1/2, p-ERK1/2, c-Jun N-terminal kinase (JNK), and p-JNK were detected by Western blot analysis.RESULTS: Carvacrol-inhibited LPS-induced cell proliferation and migration of RA-FLSs. The production of inflammatory cytokines, including tumor necrosis factor alpha, interleukin (IL)- 6, and IL-8, was reduced by carvacrol in LPS-induced RA-FLSs. Meanwhile, the induction of MMPs, including MMP-1, MMP-3, and MMP-13, caused by LPS stimulation was inhibited by carvacrol in RA-FLSs. Furthermore, carvacrol prevented LPS-induced activation of the TLR4/MyD88/NF-κB, p38, and ERK1/2 pathways in RA-FLSs.CONCLUSIONS: Carvacrol-mitigated LPS-induced cell proliferation, migration, and inflammation in RA-FLSs. The TLR4/MyD88/NF-κB, p38 and ERK1/2 pathways might be involved in the protective effect of carvacrol.

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PMID: 

Cells. 2018 Nov 26 ;7(12). Epub 2018 Nov 26. PMID: 30486272

Abstract Title: 

Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7.

Abstract: 

Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague⁻Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation.

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PMID: 

Biomed Pharmacother. 2019 Mar ;111:568-578. Epub 2018 Dec 29. PMID: 30597310

Abstract Title: 

The ameliorative effect of carvacrol on oxidative stress and germ cell apoptosis in testicular tissue of adult diabetic rats.

Abstract: 

BACKGROUND: Diabetes is one of the most chronic and widespread diseases causing the damages to the male reproductive system. Nowadays, several studies have been performed to show the role of phenolic compounds in reducing the complications of diabetes. Carvacrol is a phenolic monoterpene which has been shown to have much therapeutic efficacy in various diseases.METHODS: Thirty-two adult male Wistar rats (n = 8 in each group) were used in this experimental study. The induction of diabetes was performed using a single intraperitoneal (IP) injection of STZ (50 mg/kg). Rats were assigned into the following groups: control group, diabetic group, diabetic group daily fed with carvacrol at a dose of 75 mg/kg for 8 weeks, and the control group daily fed with carvacrol at a dose of 75 mg/kg for 8 weeks.RESULTS: Treatment with carvacrol significantly improved the histological morphology of the testis, reduced the tissue activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymes, and diminished the elevated levels of tissue malondialdehyde (MDA) (p

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PMID: 

Immunopharmacol Immunotoxicol. 2019 Feb ;41(1):163-171. Epub 2019 Feb 1. PMID: 30706740

Abstract Title: 

Carvacrol ameliorates the progression of liver fibrosis through targeting of Hippo and TGF-β signaling pathways in carbon tetrachloride (CCl)-induced liver fibrosis in rats.

Abstract: 

Little is known about the exact underlying molecular mechanisms of the hepatoprotective effect of carvacrol against liver fibrosis. In the current study, we aimed to investigate the effect of carvacrol on the suppression of liver fibrosis progression via regulation of yes-associated protein (YAP) and transcriptional coactivators with a PDZ-binding motif (TAZ) and transforming growth factor beta (TGF-β) pathway.To fulfill our target, rats received carbon tetrachloride (CCl) and carvacrol intraperitoneally, and orally, respectively for 10 weeks. Body weight, liver weight, serum biochemical parameters, hepatic hydroxyproline content, and histological changes were determined. Furthermore, gene expression of collagen and key elements of Hippo and TGF-β pathways were analyzed and then the protein levels of YAP, TAZ, and TGF-β were detected in liver tissue.Carvacrol administration normalized liver and body weight, serum biochemical parameters and hepatic hydroxyproline in CCltreated rats. Also, carvacrol downregulated TAZ and TGF-β signaling pathway at transcriptional levels. Furthermore, carvacrol decreased hepatic protein levels of TGF-β, TAZ, and YAP. Low expression of TAZ and YAP were accompanied with inhibition of TGF-β signaling pathway.Our data clearly revealed that carvacrol suppresses the progression of liver fibrosis via targeting of TAZ, YAP, and TGF-β signaling pathway.

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PMID: 

J Infect Dis. 2017 11 15 ;216(8):977-980. PMID: 28968738

Abstract Title: 

Measles Virus Neutralizing Antibodies in Intravenous Immunoglobulins: Is an Increase by Revaccination of Plasma Donors Possible?

Abstract: 

We report a screen of plasma donors confirming that widespread use of childhood measles vaccination since 1963 resulted in a decrease in average measles virus antibody titers among plasma donors, which is reflected in intravenous immunoglobulins (IVIGs). The measles virus antibody titer, however, is a potency requirement for IVIGs, as defined in a Food and Drug Administration regulation. To mitigate the decline in measles virus antibody titers in IVIGs and to ensure consistent product release, revaccination of plasma donors was investigated as a means to boost titers. However, revaccination-induced titer increases were only about 2-fold and short-lived.

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PMID: 

Int Immunopharmacol. 2019 Jul 26 ;75:105743. Epub 2019 Jul 26. PMID: 31357087

Abstract Title: 

Carvacrol suppresses LPS-induced pro-inflammatory activation in RAW 264.7 macrophages through ERK1/2 and NF-kB pathway.

Abstract: 

Macrophages are immune system cells that respond to various pathogenic insults. The recognition of antigens is performed through receptors such as TLR4 and RAGE, which recognize pathogen-associated patterns (PAMPs), including lipopolysaccharide (LPS) from Gram-negative bacteria. Carvacrol (CAR) is a phenolic compound found in some essential oils commonly used in folk medicine for treatment of inflammation-related diseases. Previous works observed strong antioxidant actions and some anti-inflammatory effects by CAR in in vivo and in vitro assays. However, the potential pharmacological application of CAR remains limited as details on its mechanisms of action are still missing. Here we investigated the molecular pathways by which CAR acts on LPS-mediated pro-inflammatory activation of RAW 264.7 macrophages. CAR 100 μM protected cells against loss of cell viability induced by LPS (1 μg/mL). Pre-incubation with CAR prevented LPS-induced ERK1/2 phosphorylation, but it had no effect on p38 and JNK activation. The effect of LPS on NF-kB (p65) translocation from cytoplasm to nucleus was inhibited by CAR, as well as NF-kB transcriptional activation. Moreover, LPS-elicited release of TNF-α and IL-1β were inhibited by CAR, as well as activation of phagocytic activity. Such effects may be related to the antioxidant effect of CAR, as the LPS-induced increase in reactive species (RS) production (assessed byDCFH oxidation) and nitric oxide (NO) production (assessed by nitrite quantification) were inhibited by CAR. Altogether, these results demonstrate that CAR exerts relevant anti-inflammatory actions through a cellular mechanism involving ERK1/2 and NF-kB inhibition and possibly related to the antioxidant properties of this phenolic compound.

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PMID: 

Neurotox Res. 2019 Jul 30. Epub 2019 Jul 30. PMID: 31364033

Abstract Title: 

Carvacrol Protects Against 6-Hydroxydopamine-Induced Neurotoxicity in In Vivo and In Vitro Models of Parkinson's Disease.

Abstract: 

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons that project from the substantia nigra pars compacta to the striatum. Evidence from human and animal studies has suggested that oxidative damage critically contributes to neuronal loss in PD. Carvacrol (CAR), a monoterpenic phenol, is the main constituents in the essential oil of many aromatic plants and possesses some properties including anti-inflammatory and anti-oxidant effects. In this study, in vitro and in vivo experiments were performed with the CAR in order to investigate its potential neuroprotective effects in models of PD. Post-treatment with CAR in vitro was found to protect rat adrenal pheochromocytoma PC12 cells from toxicity induced by 6-hydroxydopamine (6-OHDA) administration in a dose-dependent manner by (1) increasing cell viability and (2) reduction in intracellular reactive oxygen species, intracellular lipid peroxidation, and annexin-positive cells. In vivo, post-treatment with CAR (15 and 20 mg/kg) was protective against neurodegenerative phenotypes associated with systemic administration of 6-OHDA. Results indicated that CAR improved the locomotor activity, catalepsy, akinesia, bradykinesia, and motor coordination and reduced the apomorphine-caused rotation in 6-OHDA-stimulated rats.Increased level of reduced glutathione content and a decreased level of MDA (malondialdehyde) were observed in the 6-OHDA rats post-treated with CAR. These findings suggest that CAR exerts protective effects, possibly related to an anti-oxidation mechanism, in these in vitro and in vivo models of Parkinson's disease.

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PMID: 

Anticancer Agents Med Chem. 2019 Jul 31. Epub 2019 Jul 31. PMID: 31364516

Abstract Title: 

Carvacrol Induced Program Cell Death and Cell Cycle Arrest in Androgen-Independent Human Prostate Cancer Cells via Inhibition of Notch Signaling.

Abstract: 

BACKGROUND: Several studies have revealed that abnormal activation of Notch signaling is closely related with the development and progression of prostate cancer. Although there are numerous therapeutic strategies, a more effective modality with least side effects is urgently required for the treatment of prostate cancer. Carvacrol is a monoterpenoid phenol and majorly present in the essential oils of Lamiaceae family plants. Many previous reports have shown various biological activities of carvacrol like antioxidant, anti-inflammatory and anticancer properties. Recently, we have shown potent anticancer property of carvacrol against prostate cancer cell line DU145. In the current study, we report the chemopreventive and therapeutic potential of carvacrol against another prostate cancer cell line PC-3 with its detailed mechanism of action.METHODS: To determine the effect of the carvacrol on prostate cancer cells, the cell viability was estimated by MTT assay and cell death was estimated by LDH release assay. The apoptotic assay was performed by DAPI staining and FITC-Annexin V assay. Reactive Oxygen Species (ROS) was estimated by DCFDA method. Cell cycle analysis was performed by flow cytometry. Gene expression analysis was performed quantitative real time PCR.RESULTS: Our results suggested that the carvacrol treatment significantly reduced the cell viability of PC-3 cells in a dose- and time-dependent manner. The antiproliferative action of carvacrol was correlated with apoptosis which was confirmed by nuclear condensation, FITC-Annexin V assay, modulation in expression of Bax, Bcl-2 and caspase activation. The mechanistic insight into carvacrol-induced apoptosis leads to finding of elevated level of Reactive Oxygen Species (ROS) and mitochondrial membrane potential disruption. Cell cycle analysis revealed that carvacrol prevented cell cycle in G0/G1 that was associated with decline in expression of cyclin D1 and Cyclin-Dependent Kinase 4 (CDK4) and augmented expression of CDK inhibitor p21. Having been said the role of hyperactivation of Notch signaling in prostate cancer, we also deciphered that carvacrol could inhibit Notch signaling in PC-3 cells via downregulation of Notch-1, and Jagged-1.CONCLUSION: Thus, our previous and current findings have established the strong potential of carvacrol as a chemopreventive agent against androgen-independent human prostate cancer cells.

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PMID: 

Arq Neuropsiquiatr. 2019 Jul 29 ;77(7):493-500. Epub 2019 Jul 29. PMID: 31365641

Abstract Title: 

Effects of carvacrol and physical exercise on motor and memory impairments associated with Parkinson's disease.

Abstract: 

The present study was undertaken to investigate the effects of carvacrol and treadmill exercise on memory deficit, rotational behavior and oxidative stress biomarkers in a 6-OHDA-lesioned rat model of Parkinson's disease. Wistar rats were treated with carvacrol at a dose of 25 mg/kg and/or ran on a treadmill for a week. Then, 6-OHDA was microinjected into the medial forebrain bundle and treatments continued for six more weeks. Aversive memory, rotational behavior and oxidative stress biomarkers were assessed at the end of week six. The 6-OHDA-lesioned group showed a significant increase in rotational behavior and a decrease in step-through latency in the passive avoidance test compared with the sham group. These behaviors were accompanied by increased lipid peroxidation levels and decreased total thiol concentration in the striatum and/or hippocampus of the hemiparkinsonian rats. Moreover, treatment with carvacrol and exercise reduced rotational behavior and improved aversive memory deficit, which was accompanied by decreased lipid peroxidation levels and increased total thiol concentration in the striatum and/or hippocampus. In conclusion, treatment with carvacrol and treadmill exercise ameliorated motor and memory deficits by modulating oxidative stress in the striatum and hippocampus of hemiparkinsonian rats. Therefore, the combination of carvacrol and treadmill exercise could be an effective therapeutic tool for treatment of neurobehavioral deficits in Parkinson's disease patients.

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