Linalool Treatment Research Articles

Linalool Prevents Cisplatin Induced Muscle Atrophy by Regulating IGF-1/Akt/FoxO Pathway.

Skeletal muscle atrophy is an important feature of cancer cachexia, which can be induced by chemotherapy, and affects the survival and quality of life of cancer patients seriously. No specific drugs for cancer cachexia have been applied in clinical practice. This study explored the therapeutic effect of linalool (LIN) on cisplatin (DDP) induced skeletal muscle atrophy. In vivo, LIN can improve skeletal muscle weight loss, anorexia, muscle strength decline and other cachexia symptoms caused by cisplatin treatment in a Lewis lung cancer tumor bearing mouse model, and cause no adverse effects on the anti-tumour effect. LIN treatment decreased the expression of muscle RING-finger protein-1 (MuRF1) and Atrogin1(MAFbx) in muscle, and the activation of insulin-like growth factor-1 (IGF-1)/protein kinase B (Akt)/forkhead box O (FoxO) pathway was observed. In vitro, LIN alleviated DDP induced C2C12 myotube atrophy, and IGF-1 receptor inhibitor Picropodophyllin (PIC), which had no adverse effect on C2C12 myotube cells, could reverse the protective effect of LIN. These results indicate that LIN down-regulates the expression of Atrogin1 and MuRF1 through the IGF-1/Akt/FoxO pathway, alleviating DDP-induced muscle atrophy and improving cachexia symptoms. LIN has the potential to be developed as a drug against cancer cachexia.

Anti-listeria Activities of Linalool and Its Mechanism Revealed by Comparative Transcriptome Analysis.

Listeria monocytogenes, which causes serious foodborne infections and public health problems worldwide, is one of the most important foodborne pathogens. Linalool has been identified as an antimicrobial agent against some microorganism, but its mechanism of action is currently unclear. Here, we investigated the efficacy of linalool against L. monocytogenes while planktonic and as a biofilm and explored potential mechanisms of action. Linalool exhibited strong anti-listeria activity in the planktonic stage. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations revealed seven stages were classified of cells at microscopic level. Mesosome-like structures were observed for the first time in L. monocytogenes after linalool treatment. Linalool also showed significant anti-biofilm activity through both dispersal and killing of cells in the biofilm based on confocal scanning laser microscopy (CLSM) and SEM imaging, crystal violet staining, XTT and COMSTAT assays. Moreover, comparative transcriptome analysis demonstrated many potential mechanisms of action for linalool and some important pathways were screened out through the analysis of GO enrichment and KEGG. Our study provides evidence that linalool exhibits a strong antimicrobial activity against both the planktonic and biofilm forms of L. monocytogenes and gives insight into its mechanism of action.

Unveiling the Mechanisms for the Plant Volatile Organic Compound Linalool To Control Gray Mold on Strawberry Fruits.

Fungal infections significantly alter the emissions of volatile organic compounds (VOCs) by plants, but the mechanisms for VOCs affecting fungal infections of plants remain largely unknown. Here, we found that infection by Botrytis cinerea upregulated linalool production by strawberries and fumigation with linalool was able to inhibit the infection of fruits by the fungus. Linalool treatment downregulated the expression of rate-limiting enzymes in the ergosterol biosynthesis pathway, and this reduced the ergosterol content in the fungi cell membrane and impaired membrane integrity. Linalool treatment also caused damage to mitochondrial membranes by collapsing mitochondrial membrane potential and also downregulated genes involved in adenosine triphosphate (ATP) production, resulting in a significant decrease in the ATP content. Linalool treatment increased the levels of reactive oxygen species (ROS), in response to which the treated fungal cells produced more of the ROS scavenger pyruvate. RNA-Seq and proteomic analysis data showed that linalool treatment slowed the rates of transcription and translation.

Anti-inflammatory effects of linalool on ovalbumin-induced pulmonary inflammation

Linalool is a natural product present in fruits and aromatic plants with biological activities. Researchers have reported that the inhalation of linalool exerts anti-inflammatory activities. In this study, we examined the therapeutic effects of linalool on airway inflammation and mucus overproduction in mice with allergic asthma. Oral administration of linalool significantly inhibited the levels of eosinophil numbers, Th2 cytokines and immunoglobulin E (IgE) caused by ovalbumin (OVA) exposure. Linalool exerted preventive effects against the influx of inflammatory cells and mucus hypersecretion in the lung tissues. Linalool also dose-dependently decreased the levels of inducible nitric oxide synthase (iNOS) expression and protein kinase B (AKT) activation in the lung tissues. Linalool effectively downregulated the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) caused by OVA exposure. Furthermore, linalool exerted inhibitory effect on OVA-induced airway hyperresponsiveness (AHR). In the in vitro study, the increased secretion of MCP-1 was attenuated with linalool treatment in lipopolysaccharide (LPS)-stimulated H292 airway epithelial cells. In conclusion, linalool effectively exerts a protective role in OVA-induced airway inflammation and mucus hypersecretion, and its protective effects are closely related to the downregulation of inflammatory mediators and MAPKs/NF-κB signaling.

Virulence targeted inhibitory effect of linalool against the exclusive uropathogen Proteus mirabilis

Proteus mirabilis is one of the leading causes of catheter-associated UTIs (CAUTI) in individuals with prolonged urinary catheterization. Since, biofilm assisted antibiotic resistance is reported to complicate the treatment strategies of P. mirabilis infections, the present study was aimed to attenuate biofilm and virulence factor production in P. mirabilis. Linalool is a naturally occurring monoterpene alcohol found in a wide range of flowers and spice plants and has many biological applications. In this study, linalool exhibited concentration dependent anti-biofilm activity against crystalline biofilm of P. mirabilis through reduced production of the virulence enzyme urease that raises the urinary pH and drives the formation of crystals (struvite) in the biofilm. The results of q-PCR analysis unveiled the down regulation of biofilm/virulence associated genes upon linalool treatment, which was in correspondence with the in vitro bioassays. Thus, this study reports the feasibility of linalool acting as a promising anti-biofilm agent against P. mirabilis mediated CAUTI.

Linalool odor stimulation improves heat stress tolerance and decreases fat accumulation in nematodes.

Aromatherapy uses plant essential oils and fragrant ingredients for relaxation, sleep assistance, and improvement of restlessness related to dementia. Certain aromatic substances increase the life span and stress tolerance of nematodes. We investigated effects of exposure to linalool, a linear chain monoterpenic alcohol that is present in the essential oils of many plants, and its optical isomer, l-linalool, in Caenorhabditis elegans. Nematodes were repelled by the odor of both linalool and l-linalool; however, linalool odor stimulation decreased fat accumulation and increased motility after thermal stress. Analysis of a gene-deficient mutant revealed that the DAF-16 insulin-signaling pathway, which is involved in heat stress tolerance, was enhanced by linalool treatment. Linalool stimulation increased the expression of downstream genes such as sod-3 and hsp-12.6 via DAF-16. We conclude that linalool odor induces a repelling behavior in nematodes, improves heat stress tolerance through the DAF-16 signaling pathway, and affects fat accumulation.

Linalool- and α-terpineol-induced programmed cell death in Chlamydomonas reinhardtii

Plant allelochemicals effectively inhibit and/ or control algal growth, and have potential to use as algaecide. To uncover the lethal mechanism of 2 anti-algal compounds linalool and α-terpineol identified from Cinnamomum camphora extracts, and promote their development as algaecide, the H2O2 production, photosynthetic abilities, caspase-like activities, nuclear changes and DNA degradation were investigated in Chlamydomonas reinhardtii treated with the 2 compounds. H2O2 content burst in linalool treatment at 0.5 h and in α-terpineol treatment at 1 h, with increases of 2.7 folds and 1.3 folds, respectively, compared to that at 0 h. The photosynthetic pigments gradually degraded, and Fv/Fm gradually declined to zero, indicating that the cell death was not a necrosis due to the gradual disappearance of physiological process. In C. reinhardtii cells, the caspase-9-like and caspase-3-like were activated in the treatments with the 2 compounds for 1 h. With prolonging the treatment time, the fluorescent intensity of the cell nucleuses stained by DAPI gradually enhanced and then faded, and the genomic DNA isolated from the cells gradually degraded. These hallmarks indicated that the death of C. reinhardtii cells in linalool and α-terpineol treatments was a programmed cell death (PCD) triggered by the increased reactive oxygen species (ROS). Compared to α-terpineol treatment, linalool treatment showed stronger promoting effects on PCD at the same time point, which may be caused by the higher ROS content inducing higher caspase-9-like and caspase-3-like activities in a short time.

SIRT3-SOD2-ROS pathway is involved in linalool-induced glioma cell apoptotic death.

Glioma is the most prevalent type of adult primary brain tumor and chemotherapy of glioma was limited by drug-resistance. Linalool is an acyclic monoterpene alcohol possessing various pharmacological activities. The present study was conducted to evaluate the effect of linalool on glioma cell growth. The effect of linalool on cell viability in U87-MG cells was investigated and the results showed that linalool significantly reduced cell viability in a concentration- and time-dependent manner. In addition, exposure of the cells to linalool resulted in a concentration-dependent increase of TUNEL-stained cells, indicating the occurrence of apoptotic cell death. Linalool decreased mitochondrial oxygen consumption rate, increased the expression of Bax and Bak, reduced the expression of Bcl-2 and Bcl-xl, and increased the activities of caspase 3 and caspase 9, leading to increase of apoptosis. Linalool resulted in a concentration-dependent decrease of SOD activity but had no significant effect on mRNA and protein expression of SOD2. Moreover, linalool resulted in a significant increase of the expression of acetylated SOD2. The mRNA and protein expression of SIRT3 was significantly inhibited by linalool. Immunoblot analysis showed that there was an evident protein/protein interaction between SOD2 and SIRT3 under normal condition. Linalool treatment significantly decreased the interaction between SOD2 and SIRT3. Overexpression of SIRT3 significantly inhibited linalool-induced increase of mitochondrial ROS production and apoptotic cell death, and decrease of cell viability. In summary, the data demonstrated that linalool exhibited inhibitory effect on glioma cells through regulation of SIRT3-SOD2-ROS signaling.

Linalool prevents oxidative stress activated protein kinases in single UVB-exposed human skin cells.

Ultraviolet-B radiation (285–320 nm) elicits a number of cellular signaling elements. We investigated the preventive effect of linalool, a natural monoterpene, against UVB-induced oxidative imbalance, activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling in HDFa cells. We observed that linalool treatment (30 μM) prevented acute UVB-irradiation (20 mJ/cm2) mediated loss of activities of antioxidant enzymes in HDFa cells. The comet assay results illustrate that linalool significantly prevents UVB-mediated 8-deoxy guanosine formation (oxidative DNA damage) rather than UVB-induced cyclobutane pyrimidine (CPD) formation. This might be due to its ability to prevent UVB-induced ROS formation and to restore the oxidative imbalance of cells. This has been reflected in UVB-induced overexpression of MAPK and NF-κB signaling. We observed that linalool inhibited UVB-induced phosphorylation of ERK1, JNK and p38 proteins of MAPK family. Linalool inhibited UVB-induced activation of NF-κB/p65 by activating IκBa. We further observed that UVB-induced expression of TNF-α, IL6, IL-10, MMP-2 and MMP-9 was modulated by linalool treatment in HDFa cells. Thus, linalool protects the human skin cells from the oxidative damages of UVB radiation and modulates MAPK and NF-κB signaling in HDFa cells. The present findings substantiate that linalool may act as a photoprotective agent against UVB-induced skin damages.

Protective effects of linalool against amyloid beta-induced cognitive deficits and damages in mice

AimAmyloid-beta (Aβ)-mediated neurotoxicity plays a pivotal role in the pathogenesis of Alzheimer's disease (AD), which induces oxidative stress and apoptosis. Linalool (LI) is a volatile monoterpene showing positive effect in AD treatment. This study was designed to research the protective effect of LI against neurotoxicity and cognitive deficits induced by Aβ1–40 in mice. Main methodsAβ1–40 (4μg) solution was injected in the bilateral hippocampus to induce cognitive deficits of mice. The protective effects of LI were evaluated by behavioral tests and the related mechanism was further explored by observing the apoptosis and oxidative stress changes in the hippocampus of mice. Key findingsLI (100mg/kg, i.p.) administration significantly improved the cognitive performance of model mice in Morris water maze test and step-through test. Meanwhile, LI effectively reversed the Aβ1–40 induced hippocampal cell injury in histological examination, apoptosis in TUNEL assay, changes of oxidative stress indicators (SOD, GPX, AChE). Besides, the activated cleaved caspase (caspase-3, caspase-9) was suppressed and Nrf2, HO-1 expression was elevated by LI treatment. SignificanceLI could attenuate cognitive deficits induced by Aβ, and the neuroprotective effect of LI might be mediated by alleviation of apoptosis, oxidative stress depending on activation of Nrf2/HO-1 signaling. We could assume that LI has the potential to be a neuroprotective substance for AD therapy.

Anticancer effect of linalool via cancer-specific hydroxyl radical generation in human colon cancer.

AIMTo investigate the anticancer mechanisms of the monoterpenoid alcohol linalool in human colon cancer cells.METHODSThe cytotoxic effect of linalool on the human colon cancer cell lines and a human fibroblast cell line was examined using the WST-8 assay. The apoptosis-inducing effect of linalool was measured using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and flow cytometry with Annexin V. Oxidative stress was investigated by staining for diphenyl-1-pyrenylphosphine, which is a cellular lipid peroxidation marker, and electron spin resonance spectroscopy. Sixteen SCID mice xenografted with human cancer cells were randomized into 3 groups for in vivo analysis: control and low-dose and high-dose linalool groups. The control group was administered tap water orally every 3 d. The linalool treatment groups were administered 100 or 200 μg/kg linalool solution orally for the same period. All mice were sacrificed under anesthesia 21 d after tumor inoculation, and tumors and organs were collected for immunohistochemistry using an anti-4-hydroxynonenal antibody. Tumor weights were measured and compared between groups.RESULTSLinalool induced apoptosis of cancer cells in vitro, following the cancer-specific induction of oxidative stress, which was measured based on spontaneous hydroxyl radical production and delayed lipid peroxidation. Mice in the high-dose linalool group exhibited a 55% reduction in mean xenograft tumor weight compared with mice in the control group (P < 0.05). In addition, tumor-specific lipid peroxidation was observed in the in vivo model.CONCLUSIONLinalool exhibited an anticancer effect via cancer-specific oxidative stress, and this agent has potential for application in colon cancer therapy.

Anticancer Activity of Linalool Terpenoid: Apoptosis Induction and Cell Cycle Arrest in Prostate Cancer Cells

Purpose : To evaluate the anticancer activity of linalool against human prostate cancer (DU145) cells. Methods : The anticancer activity of linalool against DU145 cancer cells was evaluated by 3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry, using propidium iodide and Annexin V-FITC, was applied to study apoptosis and cell cycle phase distribution. Inverted light microscopy was used to study the effect of linalool on cell morphology and apoptotic body formation in DU145 cells while gel electrophoresis was employed to evaluate the effect of linalool on DNA fragmentation. Results : Linalool induced a dose-dependent as well as time-dependent growth inhibitory effect on DU145 prostate cancer cells. It induced sub-G1 phase growth arrest which led to increase in sub-G0/G1 cell population after treatment with increasing doses of linalool. DNA ladder appeared to be more evident with increasing linalool concentration. However, no DNA fragments were observed in the control groups. It was observed that 4.36, 11.54, 21.88 and 15.54 % of the cells underwent early apoptosis after treatment with 0 (no linalool treatment), 20, 40, and 80 μM of linalool, respectively. Compared to control cells, linalool treatment resulted in the appearance of cell shrinkage along with membrane blebbing which are characteristic features of cell apoptosis. Conclusion : The findings of this study indicate that linalool can be developed as a plant-based chemotherapeutic agent against prostate cancer Keywords : Prostate cancer, Linalool, Chemotherapy, Cell cycle, Apoptosis, DNA fragmentation, Sub- G1 phase growth

Effects of linalool on inflammation, matrix accumulation and podocyte loss in kidney of streptozotocin-induced diabetic rats

Context: This study aimed to evaluate the renoprotective action of linalool (LIN) on streptozotocin (STZ)-induced diabetic rats.Objective: The pathological changes in diabetic nephropathy (DN) include oxidative stress, renal injury, matrix accumulation and podocyte abnormalities. We investigated the renoprotective actions of LIN, a monoterpene alcohol, present in herbal essential oils in STZ-induced diabetic rats with renal injury.Materials and methods: STZ-diabetic rats were administered LIN (25 mg/kg) for 45 days, after which the activities of key enzymes of glucose metabolism, collagen content, oxidative damage and expression of glucose transporter-1 (GLUT-1), transforming growth factor-β1 (TGF-β1), nuclear factor-κBp65 (NF-κB p65) and nephrin were analyzed.Results: Diabetic rats displayed altered glucose metabolism, collagen accumulation and increased TGF-β1 and NF-κB expression in kidney. LIN treatment restored glucose-metabolizing enzymes, collagen content and GLUT-1 expression and also prevented nephrin loss. LIN also rescued kidney from oxidative stress and inflammation by decreasing the expression of TGF-β1 and NF-κB. Ultrastructural changes such as basement membrane thickening, reduction in podocyte number and loss of filtration barrier integrity in diabetic rats were mitigated by LIN.Discussion and conclusion: The results of this study suggest that LIN can attenuate nephropathic changes induced in kidney of diabetic rats. These findings highlight the utility of LIN as a potential drug to treat renal damage in diabetic subjects.

Abstract 3733: Combined effect of linalool as component of Humulus lupulus on doxorubicin-induced antitumor activity

Abstract [Purpose] Cancer chemotherapy has been applied to advanced tumors and intractable tumors, playing an important role in their treatments. However, there are many problems including the appearance of adverse reactions and acquirement of drug resistance. The increased numbers of medications resulted in a decreased quality of life for the patients. However, food and food components can be used to increase the activity of antitumor agents without increasing the number of medicines. In this study, the effects of some components in Humulus lupulus (Hop) were examined on the doxorubicin (DOX) induced antitumor activity in vitro and in vivo. [Methods] The effects of Hop components (linalool, myrcene, α-humulene, α-caryophyllene) on DOX permeability and DOX cytotoxicity in P388 leukemia cells in vitro were examined. P388 leukemia cells (5 x 105 cells per animal) were transplanted onto the backs of BDF1 mice, and DOX (2.0mg/kg/day x 4 days, i.p.) and linalool (1.0mg/kg/day x 4 days, p.o.) were administered. The solid tumor and normal tissues were removed and measured DOX concentrations in each tissue. [Results and Discussion] In vitro, myrcene, α-humulene and α-caryophyllene did not have beneficial effects on DOX permeability in tumor cells. In contrast, the addition of linalool was shown to significantly promote on DOX influx and increased DOX concentration in tumor cells. The combination of DOX with linalool (0.1 μM) showed 3.5-fold (P&amp;lt;0.05) cytotoxicity, compared to treatment with DOX alone. Therefore, the combined linalool with DOX enhanced DOX cytotoxicity by the increase of DOX concentration in tumor cells. In vivo, the tumor weight in the DOX alone group decreased to 77% of the control level, whereas the combination of linalool with DOX decreased the tumor weight by 53% (P&amp;lt;0.05) of that in DOX alone group. In the tumor, the DOX concentration in the linalool combined group increased by 1.8-fold (P&amp;lt;0.05) compared to DOX alone group. In the normal tissue, the DOX concentration after combined linalool and DOX treatment tended to decrease. In particular, the DOX concentration in the heart decreased by 49% (P&amp;lt;0.05) of that in DOX alone group, expecting that linalool may decrease DOX-induced cardiotoxicity. Thus, the combination of linalool with DOX increased DOX concentration in the tumor, consequently enhanced antitumor activity of DOX. In conclusion, linalool is expected effectiveness as DOX modulator. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3733. doi:1538-7445.AM2012-3733

Repellency of Various Oils and Pine Oil Constituents to House Flies (Diptera: Muscidae)

Comparative repellency of pine, mineral, motor, and silicon oil to house flies, Musca domestica L., was tested. In binary choice bioassays with flies feeding on 20 microliter of watery honey solutions mixed with (treatment) or without (control) 10 microliter of one of the oils under investigation, only pine oil completely suppressed feeding and remained inhibitory even after 24 h. Approaching pine oil-treated honey solution, 95% of flies were repelled at a distance >6 mm from the source. Analysis of pine oil volatiles by coupled gas chromatographic-electroantennographic detection (GC-EAD) analysis revealed 5 antennally active compounds, 4 of which were identified by coupled GC-mass spectrometry as myrcene, p-cymene, gamma-terpinene, and (+/-)-linalool. Treatment of honey solution with pine oil, the 4 compounds singly, or in quaternary combination at 10 microliter each, equally and significantly reduced the number of feeding flies compared with untreated honey solution. At an amount of 1 microliter, only the linalool treatment inhibited feeding. In binary choice experiments both feeding and oviposition were significantly reduced on linalool-treated sources. Because fly maggots naturally develop in and rely on microbe-rich organic sources, gravid females may perceive and avoid potential oviposition sites that are rich in antimicrobial compounds such as linalool.