PMID: 

Am J Reprod Immunol. 2019 Sep 4:e13186. Epub 2019 Sep 4. PMID: 31483910

Abstract Title: 

Resveratrol Treatment in Patients with Polycystic Ovary Syndrome Decreased Pro-inflammatory and Endoplasmic Reticulum Stress Markers.

Abstract: 

PROBLEM: Polycystic ovary syndrome (PCOS) is associated with endoplasmic reticulum (ER) stress and pro-inflammatory condition. The aim of the present study was to evaluate the effect of resveratrol treatment on pro-inflammatory and ER stress markers in PCOS patients.METHOD OF STUDY: Cumulus cells were obtained from 40 PCOS patients who were divided into two groups: placebo and resveratrol treatment (receiving 800 mg/day for 40 days) groups. Blood samples were obtained from all patients before and after the procedure to evaluate interleukin (IL)- 6, IL-1β, IL-18, TNF-α, NF-κB, and C-reactive protein (CRP). Total RNA was extracted from cumulus cells and cDNA was synthesized by reverse transcription. Expressions of five genes in ER stress response pathway (ATF4, ATF6, CHOP, GRP78, and XBP1s) were assessed with quantitative real-time PCR. Statistical analysis was performed with Student's t-test.RESULTS: After treatment with resveratrol, it was found that serum levels of IL-6, IL-1β, TNF-α, IL-18, NF-κB, and CRP decreased in treatment group. In addition, gene expression results showed that the expression levels of ATF4 (p

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PMID: 

Food Funct. 2019 Sep 5. Epub 2019 Sep 5. PMID: 31486447

Abstract Title: 

The effects of resveratrol on metabolic status in patients with type 2 diabetes mellitus and coronary heart disease.

Abstract: 

This study was performed to investigate the effects of resveratrol on metabolic status in patients with type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD). This randomized, double-blind, placebo-controlled trial was performed with 56 patients having T2DM and CHD. The patients were randomly divided into two groups to receive either 500 mg resveratrol per day (n = 28) or placebo (n = 28) for 4 weeks. Resveratrol reduced fasting glucose (β -10.04 mg dL-1; 95% CI, -18.23, -1.86; P = 0.01), insulin (β -1.09 μIU mL-1; 95% CI, -1.93, -0.24; P = 0.01) and insulin resistance (β -0.48; 95% CI, -0.76, -0.21; P = 0.001) and significantly increased insulin sensitivity (β 0.006; 95% CI, 0.001, 0.01; P = 0.02) when compared with the placebo. Resveratrol also significantly increased HDL-cholesterol levels (β 3.38 mg dL-1; 95% CI, 1.72, 5.05; P

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PMID: 

J Periodontol. 2017 07 ;88(7):e120-e128. Epub 2017 Apr 7. PMID: 28387609

Abstract Title: 

Carvacrol Ameliorates Ligation-Induced Periodontitis in Rats.

Abstract: 

BACKGROUND: This study aims to evaluate the ameliorative effect of carvacrol, an anti-inflammatory monoterpenoid phenol and a major component of Plectranthus amboinicus, on periodontal damage in an experimental rat model of periodontitis.METHODS: Forty Sprague-Dawley rats were divided into ligation (Lig), non-ligation (n-Lig), and two ligation plus carvacrol (Lig+C) groups. Carvacrol (17.5 or 35.0 mg/kg body weight/day) was administered intragastrically from 1 day before ligation. On day 8, dental alveolar bone loss and gingival inflammation in periodontal specimens were examined by dental radiography, microcomputed tomography, and histology. Expressions of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and inducible nitric oxide synthase messenger (m)RNAs, and levels of matrix metalloproteinase (MMP)-2 and MMP-9 in gingiva were examined by reverse transcription-polymerase chain reaction and zymography.RESULTS: Dental radiography revealed periodontal bone-supporting ratios in Lig and Lig+C groups were lower than the n-Lig group, with Lig group ratios being lowest. Compared with the n-Lig group, the cemento-enamel junction-bone distance was significantly longer in Lig and Lig+C groups, with Lig+C groups showing shorter distances regardless of radiographic methods used. Histology and histometry showed less inflammatory area and stronger connective tissue attachment in Lig+C groups than in the Lig group. Cytokine/mediator mRNA expression and MMP-9 levels were reduced in the Lig+C groups.CONCLUSIONS: Carvacrol reduced tissue damage and bone loss caused by ligation-induced periodontitis. The present results indicate that carvacrol might reduce tissue destruction by downregulating expression of proinflammatory mediators and MMP-9.

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PMID: 

Front Microbiol. 2017 ;8:625. Epub 2017 Apr 21. PMID: 28484429

Abstract Title: 

Protective Effect of Carvacrol against Gut Dysbiosis andAssociated Disease in a Mouse Model.

Abstract: 

This study investigated the effect of carvacrol (CR), a phytophenolic compound on antibiotic-associated gut dysbiosis andinfection in a mouse model. Five to six-week-old C57BL/6 mice were randomly divided into seven treatment groups (challenge and control) of eight mice each. Mice were fed with irradiated feed supplemented with CR (0, 0.05, and 0.1%); the challenge groups were made susceptible toby orally administering an antibiotic cocktail in water and an intra-peritoneal injection of clindamycin. Both challenge and control groups were infected with 10CFU/ml of hypervirulent(ATCC 1870) spores or PBS, and observed for clinical signs for 10 days. Respective control groups for CR, antibiotics, and their combination were included for investigating their effect on mouse enteric microflora. Mouse body weight and clinical and diarrhea scores were recorded daily post infection. Fecal samples were collected for microbiome analysis using rRNA sequencing in MiSeq platform. Carvacrol supplementation significantly reduced the incidence of diarrhea and improved the clinical and diarrhea scores in mice (

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PMID: 

Neuroscience. 2017 07 25 ;356:176-181. Epub 2017 May 17. PMID: 28526576

Abstract Title: 

Carvacrol promotes neuroprotection in the mouse hemiparkinsonian model.

Abstract: 

Carvacrol is a monoterpene that has been linked to neuroprotection in several animal models of neurodegeneration, including ischemia, epilepsy and traumatic neuronal injury. In this study, we investigated the effects of carvacrol (i.p.) upon the neurodegeneration induced by 6-hydroxy-dopamine unilateral intrastriatal injections in mice. We have also used the cylinder test to assess the behavioral effects of carvacrol in that model of Parkinson's disease, and immunoblots to evaluate the levels of caspase-3 and TRPM7, one of major targets of carvacrol. Behavioral testing revealed that carvacrol largely reduced the asymmetrical use of the forelimbs induced by unilateral 6-hydroxy-dopamine. Carvacrol dramatically reduced the loss of tyrosine hydroxylase immunostaining both in the substantia nigra and in the striatum that are typical of the model. Immunoblots for tyrosine hydroxylase confirmed this effect. Caspase-3 levels were very high after toxin injections, but carvacrol appeared to reduce them to control levels. Finally, TRPM7, observed by immunoblots, increased after 6-hydroxy-dopamine, suggesting the involvement of this cation channel in the ensuing neurodegenerative process. The present data suggest that carvacrol promotes a marked neuroprotection in the 6-hydroxy-dopamine model of Parkinson's disease, possibly by its non-specific blocking effect upon TRPM7 channels.

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PMID: 

Inflammation. 2017 Oct ;40(5):1654-1663. PMID: 28646428

Abstract Title: 

Effects of Carvacrol on Survival, Mesenteric Blood Flow, Aortic Function and Multiple Organ Injury in a Murine Model of Polymicrobial Sepsis.

Abstract: 

Carvacrol (CRV) has strong cytoprotective, antioxidant, and anti-inflammatory properties. We aimed to demonstrate the possible protective effects of CRV on survival, mesenteric artery blood flow (MBF), vascular reactivity, and oxidative and inflammatory injuries in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Wistar rats were allocated into the following four groups: Sham, CLP, Sham + CRV, and CLP + CRV. The animals were orally administered with CRV (80 mg/kg/day) or vehicle (corn oil; 1 mL/kg/day) for 7 days. At the eighth day, Sham or CLP procedure was applied. Twenty hours after the operations, MBF and contractile responses of isolated aortic preparations to phenylephrine were measured. Tissue samples were obtained for biochemical and histopathological assessments. Additionally, survival rates were recorded throughout 96 h. CRV administration improved the mesenteric perfusion, contractile function of aorta, and survival after CLP. CRV substantially prevented the elevations in the levels of LDH, BUN, Cr, and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) but could not prevent the elevations of AST and ALT after CLP. The decreased liver, kidney, and spleen glutathione levels and increased liver, kidney, lung, andspleen malondialdehyde levels induced by CLP were substantially restored by CRV. Also, histopathological protective effects of CRV on multiple organ damage due to CLP were observed. CRV possesses strong ameliorative effects on sepsis due to its protective effects on mesenteric perfusion and aorticfunction and its antioxidative and anti-inflammatory effects.

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PMID: 

Nutr Cancer. 2017 Oct ;69(7):1075-1087. Epub 2017 Sep 5. PMID: 28872904

Abstract Title: 

Carvacrol Induces Reactive Oxygen Species (ROS)-mediated Apoptosis Along with Cell Cycle Arrest at G/Gin Human Prostate Cancer Cells.

Abstract: 

Carvacrol, a major monoterpenoid phenol from Origanum and Thymus species, has been shown to exhibit antiproliferative and anticancer properties in a few recent studies. Nevertheless, detailed mechanism of the action of this compound in prostate cancer has not been elucidated yet. Therefore, in the current study, we examined the anticancer activity and mechanism of the action of carvacrol against human prostate cancer cells. It was found that the treatment of DU145 cells with carvacrol decreased cell viability in a concentration and time-dependent manner. The antiproliferative action of carvacrol leads to induction of apoptosis as confirmed by nuclear condensation, Annexin V-FITC/PI positive cells, and caspase-3 activation. In addition, carvacrol augmented reactive oxygen species generation and disruption in the mitochondrial membrane potential which has not been reported in the previous studies of carvacrol with prostate cancer. Moreover, carvacrol-induced apoptosis of prostate cancer cells was also accompanied by significant amount of growth arrest at the G/Gphase of the cell cycle which has also not been documented previously. To sum up, this study has established that carvacrol could be a promising chemotherapeutic agent and could have a direct practical implication and translational relevance to prostate cancer patients as Origanum consumption may retard prostate cancer progression.

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PMID: 

Oncol Lett. 2019 Aug ;18(2):1467-1474. Epub 2019 May 27. PMID: 31423212

Abstract Title: 

Ursolic acid isolated frominduces apoptosis and inhibits invasion of GBC-SD gallbladder carcinoma cells.

Abstract: 

Gallbladder carcinoma (GBC) is a relatively rare but terminal malignancy, and drug/chemical development is an important aspect of prevention and treatment of GBC. Ursolic acid (UA), a pentacyclic triterpenoid, has been reported to exhibit various pharmaceutical effects. In the present study, the antiproliferative and anti-invasive effects of UA and the associated mechanisms in GBC were examined. UA was isolated from. The GBC cells (GBC-SD and NOZ) were treated with UA and subjected to a Cell Counting Kit-8 assay. The GBC-SD cells were subsequently selected for an Annexin V-FITC/propidium iodide assay, Transwell chamber assay, RTprofiler polymerase chain reaction (PCR) array and western blot analysis. The results indicated that UA inhibited the proliferation and invasion and induced the apoptosis of GBC-SD cells in a dose-dependent manner. Furthermore, the PCR arrays demonstrated that there were 24 differentially expressed genes between the UA-treated and untreated groups. These differentially expressed genes suggested that UA induced the apoptosis of GBC-SD cells through activation of the cell extrinsic pathway. According to Kyoto Encyclopedia of Genes and Genomes pathway analysis of these differentially expressed genes, the suppression of nuclear factor (NF)-κB and protein kinase B (Akt) signaling pathways was further validated. In summary, UA induces the apoptosis and inhibits the invasion of GBC-SD cells, which may be associated with the suppression of NF-κB and Akt signaling pathways. These results may offer a potential therapeutic strategy for thechemoprevention or chemotherapy of GBC in humans.

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PMID: 

Chin J Physiol. 2017 Oct 31 ;60(5):275-283. PMID: 28950692

Abstract Title: 

Effect of Carvacrol on Ca²⁺ Movement and Viability in PC3 Human Prostate Cancer Cells.

Abstract: 

Carvacrol, a monoterpenic phenol compound, has been shown to possess various biological
effects in different models. However, the effect of carvacrol on intracellular Ca²⁺ and its related
physiology in human prostate cancer is unknown. This study explored the effect of carvacrol on
cytosolic free Ca²⁺ levels ([Ca²⁺]i) and viability in PC3 human prostate cancer cells. Fura-2, a Ca²⁺-
sensitive fluorescent dye, was used to assess [Ca²⁺]i. Cell viability was measured by the detecting
reagent WST-1. Carvacrol at concentrations of 200-800 μM caused [Ca²⁺]i rises in a concentration-dependent
manner. Removal of extracellular Ca²⁺ reduced carvacrol’s effect by approximately 60%.
Carvacrol-induced Ca²⁺ entry was confirmed by Mn²⁺ entry-induced quench of fura-2 fluorescence,
and was inhibited by approximately 30% by nifedipine, econazole, SKF96365, and the protein kinase
C (PKC) inhibitor GF109203X. In Ca²⁺-free medium, treatment with the endoplasmic reticulum Ca²⁺
pump inhibitor thapsigargin (TG) abolished carvacrol-induced [Ca²⁺]i rises. Treatment with
carvacrol also abolished TG-induced [Ca²⁺]i rises. Carvacrol-induced Ca²⁺ release from the
endoplasmic reticulum was abolished by inhibition of phospholipase C (PLC). Carvacrol killed cells
at concentrations of 200-600 μM in a concentration-dependent fashion. Chelating cytosolic Ca²⁺ with
BAPTA/AM did not prevent carvacrol’s cytotoxicity. Together, in PC3 cells, carvacrol induced [Ca²⁺]i
rises by inducing PLC-dependent Ca²⁺ release from the endoplasmic reticulum and Ca²⁺ entry via
PKC-sensitive store-operated Ca²⁺ channels and other unknown channels. Carvacrol also induced
Ca²⁺-dissociated cell death.

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PMID: 

J Biomol Struct Dyn. 2018 Oct ;36(13):3434-3443. Epub 2017 Oct 20. PMID: 28984500

Abstract Title: 

Ursolic acid and carvacrol may be potential inhibitors of dormancy protein small heat shock protein16.3 of Mycobacterium tuberculosis.

Abstract: 

Small heat shock protein16.3 (sHSP16.3) is a crucial protein for survival of Mycobacterium tuberculosis (MTB) in its host. Besides, this protein acts as a molecular chaperone during stress and is indispensable for MTB's growth, virulence and cell-wall thickening. sHSP16.3 is also a promising candidate for vaccine, serodiagnosis and drug design as well. In the present study, we have targeted sHSP16.3 with two phytochemicals, namely ursolic acid and carvacrol using in silico approach. Molecular docking analysis showed that both phytochemicals (ursolic acid and carvacrol) have docked with sHSP16.3 and shown tendency to inhibit the function of this vital protein of MTB. In addition, both compounds have exhibited strong compatibility with sHSP16.3 during whole 60 ns duration of molecular dynamics simulation. Further, the molecular mechanic/generalized Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energies were calculated which showed that both phytocompounds have stable and favourable binding energies causing strong binding with binding site of sHSP16.3. Taking together, the data of present study suggest that both phytocompounds may be potential inhibitor of sHSP16.3 of MTB and a best alternative to standard anti-tuberculosis drugs.

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