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Aim: Geraniol is an acyclic monoterpenoid that is abundant in many plants, including rose, lemongrass, and lavender. As geraniol has various beneficial functions, rose oil rich in geraniol is not only used for aromatherapy but also as a supplement to promote health benefits. However, the beneficial effects of geraniol on age-related pathologies are unknown. In this study, we aimed to clarify the effects of geraniol intake on age-related pathologies., Methods: We orally administered geraniol to aged mice (age: 24-29 months) five times a week for 4 weeks and sampled their blood and various organs. We investigated age-related changes in the blood and organ samples. Furthermore, we treated HepG2 cells with geraniol and examined the expression level of the ALB gene and the amount of secreted albumin in vitro., Results: Geraniol significantly increased blood albumin, total cholesterol, and red blood cell counts, indicating an improvement in nutritional markers in aged mice. Geraniol also transcriptionally increased the Alb gene expression in the liver of aged mice. Furthermore, treatment with geraniol significantly upregulated the ALB gene expression and the secretion of albumin in the conditioned medium of HepG2 cells., Conclusion: Geraniol increases serum albumin levels at the transcriptional level. Geraniol intake can be an effective strategy for age-related malnutrition. Geriatr Gerontol Int 2024; 24: 1233-1240., (© 2024 Japan Geriatrics Society.)

Sleep insufficiency is a significant health problem worldwide, and adolescent sleep restriction (SR) could induce multiple neurodevelopmental disorders in the central nervous system (CNS). Microglial-mediated neuroinflammation plays a vital role in multiple neurological diseases, and recent research showed the regulation effect of immunoproteasome on microglia functions. Geraniol (GER), an important ingredient in many essential oils, possesses diverse pharmacological properties like anti-inflammatory and antioxidant. The present study was designed to evaluate the neuroprotective effect of GER on SR in adolescent mice and further investigate the underlying mechanisms. Our results displayed that 14 days of chronic sleep restriction (CSR) induced cognitive decline, and anxiety-like and attention-deficit behaviors, which were mitigated by GER pretreatment. GER administration also reversed microglial pro-inflammatory response under CSR stimulation in the anterior cingulate cortex (ACC) regions by reducing the expression and secretion of cytokines like IL-1β and TNF-α. Mechanism research showed that LMP7 mRNA was selectively up-regulated under CSR treatment but down-regulated by GER administration. Proteasome activity and protein expression of LMP7 were consistent with mRNA data. ONX-0914 was applied to inhibit LMP7 selectively, and data validated that GER might alleviate CSR-induced neuroinflammation by regulating LMP7. Our study provides evidence that LMP7 is a critical regulator of CSR-induced proinflammation, and geraniol might be a promising therapy against CSR-induced neurodevelopmental disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The clinical use of gentamicin (GM) is restricted by its nephrotoxic effects. This study aimed for the first time to elucidate the ameliorative effects of the monoterpene linalool (Lin) against GM-mediated acute kidney injury in rats. A total of thirty-two rats were subdivided into four equal groups: control (saline), Lin (100 mg/kg/day), GM (100 mg/kg/day), and GM + Lin (100 and 100 mg/kg/day). Lin and GM were intraperitoneally administered for 12 days. Our results illustrated that Lin ameliorated GM-mediated renal histopathological abnormalities and reduced serum urea and creatinine levels in rats exposed to GM. Lin treatment mitigated oxidative stress in nephrotoxic animals as manifested by reducing serum and renal levels of malondialdehyde and increasing the activities of serum and renal glutathione peroxidase and renal catalase. Moreover, Lin markedly inhibited GM-triggered inflammation by downregulating NF-κB, iNOS, TNF-α, and IL-1β and reducing renal myeloperoxidase activity and nitric oxide levels. Interestingly, Lin repressed GM-induced apoptosis, as reflected by a marked downregulation of Bax and caspase-3 expression, concurrent with the upregulation of Bcl2 expression. Finally, Lin administration led to a significant downregulation of TGF-β expression in nephrotoxic animals. In summary, Lin ameliorated GM-mediated nephrotoxicity in rats, at least through its antioxidant, anti-inflammatory, and anti-apoptotic activities and by modulating TGF-β., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This comprehensive review endeavors to illuminate the nuanced facets of linalool, a prominent monoterpene found abundantly in essential oils, constituting a massive portion of their composition. The biomedical relevance of linalool is a key focus, highlighting its therapeutic attributes observed through anti-nociceptive effects, anxiolytic properties, and behavioral modulation in individuals affected by dementia. These findings underscore the compound's potential application in biomedical applications. This review further explores contemporary formulations, delineating the adaptability of linalool in nano-emulsions, microemulsions, bio-capsules, and various topical formulations, including topical gels and lotions. This review covers published and granted patents between 2018-2024 and sheds light on the evolving landscape of linalool applications, revealing advancements in dermatological, anti-inflammatory, and antimicrobial domains., Competing Interests: The authors declare that there are no conflicts of interest., (Thieme. All rights reserved.)

Adaptation to psychosocial stress is psychologically distressing, initiating/promoting comorbidity with alcohol use disorders. Emerging evidence moreover showed that ethanol (EtOH) exacerbates social-defeat stress (SDS)-induced behavioral impairments, neurobiological sequelae, and poor therapeutic outcomes. Hence, this study investigated the effects of geraniol, an isoprenoid monoterpenoid alcohol with neuroprotective functions on EtOH escalated SDS-induced behavioral impairments, and neurobiological sequelae in mice. Male mice chronically exposed to SDS for 14 days were repeatedly fed with EtOH (2 g/kg, p. o.) from days 8-14. From days 1-14, SDS-EtOH co-exposed mice were concurrently treated with geraniol (25 and 50 mg/kg) or fluoxetine (10 mg/kg) orally. After SDS-EtOH translational interactions, arrays of behavioral tasks were examined, followed by investigations of oxido-inflammatory, neurochemicals levels, monoamine oxidase-B and acetylcholinesterase activities in the striatum, prefrontal-cortex, and hippocampus. The glial fibrillary acid protein (GFAP) expression was also quantified in the prefrontal-cortex immunohistochemically. Adrenal weights, serum glucose and corticosterone concentrations were measured. EtOH exacerbated SDS-induced low-stress resilience, social impairment characterized by anxiety, depression, and memory deficits were attenuated by geraniol (50 and 100 mg/kg) and fluoxetine. In line with this, geraniol increased the levels of dopamine, serotonin, and glutamic-acid decarboxylase enzyme, accompanied by reduced monoamine oxidase-B and acetylcholinesterase activities in the prefrontal-cortex, hippocampus, and striatum. Geraniol inhibited SDS-EtOH-induced adrenal hypertrophy, corticosterone, TNF-α, IL-6 release, malondialdehyde and nitrite levels, with increased antioxidant activities. Immunohistochemical analyses revealed that geraniol enhanced GFAP immunoreactivity in the prefrontal-cortex relative to SDS-EtOH group. We concluded that geraniol ameliorates SDS-EtOH interaction-induced behavioral changes via normalization of neuroimmune-endocrine and neurochemical dysregulations in mice brains., Competing Interests: Declaration of competing interest Authors declare that they have no conflict of interest and all experiments were approved and performed under the guidelines of Faculty of Basic Medical Sciences, Delta State University Animals Ethic Committee (REC/FBMS/DELSU/22/148) and the National Institutes of Health Guide for Care and Use of Laboratory Animals (Publication number: 85–23, revised 1985)., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

About 10 million people are diagnosed with cancer each year. Globally, it is the second leading cause of death after heart disease, and by 2035, the death toll could reach 14.6 million. Several drugs and treatments are available to treat cancer, but survival rates remain low. Many studies in recent years have shown that plant-derived monoterpenes, particularly geraniol and citral, are effective against various cancers, including breast, liver, melanoma, endometrial, colon, prostate, and skin cancers. This trend has opened new possibilities for the development of new therapeutics or adjuvants in the field of cancer therapy. These monoterpenes can improve the efficacy of chemotherapy by modulating many signaling molecules and pathways within tumors. Analysis of reports on the anticancer effects published in the past 5 years provided an overview of the most important results of these and related properties. Also, the molecular mechanisms by which they exert their anticancer effects in cell and animal studies have been explained. Therefore, this review aims to highlight the scope of geraniol and citral as complementary or alternative treatment options in cancer therapy., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Geraniol (GE), an acyclic monoterpene, is a chief constituent of essential oils of herbs and fruits. It possesses diverse pharmacological actions like antioxidant, anti-inflammatory, anti-apoptotic, and anti-parkinson. However, its neuroprotective potential in stroke is yet to be explored at large. The present study evaluated the neuroprotective potential of GE against the global model of cerebral ischemia/reperfusion (I/R)-injury in rats. Bilateral common carotid artery (BCCA) occlusion for 30 min followed by 7 days of reperfusion caused varied biochemical/enzymatic alterations viz. increase in levels of lipid peroxidation (LPO), nitric oxide (NO), xanthine oxidase (XO), and decrease in the levels of cerebroprotectives like superoxide dismutase (SOD), catalase (CAT), total thiols, and glutathione (GSH). GE-pretreatment markedly reversed these changes and restored the levels of protective enzymatic and non-enzymatic antioxidants near to normal compared to I/R group. Besides, GE treatment showed marked improvement in anxiety-related behavior and neuronal deficits in animals subjected to I/R injury. Moreover, 2,3,5-triphenyl tetrazolium chloride (TTC)-stained rat brain coronal sections and histopathological studies revealed neuronal protection against I/R-injury, as evidenced by a reduction in infarct area (%) and an increase in hippocampal CA1 neuronal density in the GE-treated groups. The results of this study revealed that GE exhibited potential neuroprotective activity by reducing oxidative stress and infarction area, and protecting hippocampal CA1 neurons against I/R-injury in the global stroke model in rats., (© 2023 John Wiley & Sons Ltd.)

Depression is a prevalent disease worldwide, limiting psychosocial functioning and thequality of life. Linalool is the main constituent of some essential oils from aromatic plants, representing about 70% of these volatile concentrates. Evidence of the linalool activity on the central nervous system, mainly acting as an antidepressant agent, is increasingly abundant. This review aimed to extend the knowledge of linalool's antidepressant action mechanisms, which is fundamental for future research, intending to highlight this natural compound as a new antidepressant phytomedication. A critical analysis is proposed here with probable hypotheses of the synergic mechanisms that support the evidence of antidepressant effects of the linalool. The literature search has been conducted in databases for published scientific articles before December 2020, using relevant keywords. Several pieces of evidence point to the anticonvulsant, sedative, and anxiolytic actions. In addition to these activities, other studies have revealed that linalool acts on the monoaminergic and neuroendocrine systems, inflammatory process, oxidative stress, and neurotrophic factors, such as BDNF, resulting in considerable advances in the knowledge of the etiology of depression. In this context, linalool emerges as a promising bioactive compound in the therapeutic arsenal, capable of interacting with numerous pathophysiological factors and acting on several targets. This review claims to contribute to future studies, highlighting the gaps in the linalool knowledge, such as its kinetics, doses, routes of administration, and multiple targets of interaction, to clarify its antidepressant activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Anti-inflammatory molecules, such as rose oxide (RO), are likely to exert therapeutic effects in systemic arterial hypertension (SAH), a disease associated with abnormal immune responses. We aimed to investigate acute autonomic effects of RO on hemodynamic parameters of Wistar and spontaneously hypertensive rats (SHR)., Methods: Rats were anesthetized and femoral artery and veins were cannulated. Next day, blood pressure (BP) and heart rate (HR) were recorded. Acute effects of RO (1.25, 2.5, or 5.0 mg/kg; iv) on BP, HR, and variability of systolic arterial pressure (SAP) and pulse interval (PI) were assessed. The effects of RO were also investigated in SHR, which received atropine (2 mg/kg), propranolol (4 mg/kg), or hexamethonium (20 mg/kg) 15 min before receiving RO. Vasorelaxant effects of RO (10-10 to 10-4 M) on aortic rings of rats were also assessed., Key Findings: In Wistar rats, none of the RO doses evoked significant changes in BP, HR, and variability of SAP and PI. On the other hand, in SHR, RO elicited reduction in mean arterial pressure (MAP), and prevented the increase in the low frequency power (LF) of the SAP spectra. Pretreatment with atropine or propranolol did not alter hypotension, but attenuated RO-induced bradycardia. Hexamethonium prevented RO-induced hypotension and bradycardia. RO exerted vasorelaxant effects on aortic rings with (Wistar and SHR) or without functional endothelium (SHR only)., Significance: Rose oxide, a monoterpene with anti-inflammatory properties, acts as an antihypertensive molecule due to its ability to acutely promote hypotension and bradycardia in spontaneously hypertensive rats., (Copyright © 2021. Published by Elsevier Inc.)

Background: Geraniol, a natural monoterpene, is a component of many plant essential oils. It contains many medicinal and pharmacological properties. Doxorubicin is an anticancer drug; however, its clinical usage is limited due to its cumulative and dose-dependent cardiotoxicity. This study investigates geraniol as a protective agent against doxorubicin-induced cardiotoxicity and explores possible underlying mechanisms of action., Methods: Male Sprague-Dawley rats were allocated into five groups. Groups 1 and 2 were administered saline and geraniol 200 mg/kg/day/orally, respectively, for 15 days. Group 3 was administered intraperitoneal doxorubicin (5 mg/kg/IP on the 5th, 10th and 15th days to achieve a cumulative dose of 15 mg/kg) to induce cardiotoxicity. The fourth and fifth groups were treated with either geraniol 100 mg/kg or 200 mg/kg orally and doxorubicin to equal the doxorubicin dose administered to Group 3., Results: Treatment with geraniol significantly ameliorated cardiac damage and restored serum cardiac injury marker levels in doxorubicin treated animals. Geraniol upregulated Nrf2 and HO-1 expression, elevated total antioxidant capacity, decreased the nuclear accumulation of kappa-light-chain enhancer of activated B cells (NF-κB), decreased the phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), suppressed tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin-18 (IL-18) levels, and restored the levels of Bax and caspase-3 and 9 in heart tissue., Conclusion: Geraniol may function as a potential activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently improves Nrf2-dependent antioxidative signaling, diminishes apoptosis and subdues the inflammatory response. The downstream result is protection of the heart from doxorubicin-induced cardiotoxicity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Nerol, a monoterpene is evident to possess diverse biological activities, including antioxidant, anti-microbial, anti-spasmodic, anthelmintic, and anti-arrhythmias. This study aims to evaluate its hepatoprotective effect against paracetamol-induced liver toxicity in a rat model. Five groups of rats (n = 7) were orally treated (once daily) with 0.05% tween 80 dissolved in 0.9% NaCl solution (vehicle), paracetamol 640 mg/kg (negative control), 50 mg/kg silymarin (positive control), or nerol (50 and 100 mg/kg) for 14 days, followed by the hepatotoxicity induction using paracetamol (PCM). The blood samples and livers of the animals were collected and subjected to biochemical and microscopical analysis. The histological findings suggest that paracetamol caused lymphocyte infiltration and marked necrosis, whereas maintenance of the normal hepatic structural was observed in group pre-treated with silymarin and nerol. The rats pre-treated with nerol significantly and dose-dependently reduced the hepatotoxic markers in animals. Nerol at 100 mg/kg significantly reversed the paracetamol-induced altered situations, including the liver enzymes, plasma proteins, antioxidant enzymes and serum bilirubin, lipid peroxidation (LPO) and cholesterol [e.g., total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c)] levels in animals. Taken together, nerol exerted significant hepatoprotective activity in rats in a dose-dependent manner. PCM-induced toxicity and nerol induced hepatoprotective effects based on expression of inflammatory and apoptosis factors will be future line of work for establishing the precise mechanism of action of nerol in Wistar albino rats., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ethnopharmacological Relevance: Cymbopogon citratus (DC.) Stapf (C. citratus) is consumed as an infusion in folk medicine due to its pharmacological properties and action in the central nervous system. Epilepsy is a neurological disorder that affects millions of people. Since the currently available antiepileptic drugs often cause undesirable side effects, new alternative therapeutic strategies based on medicinal plants have been proposed., Aim of the Study: This study aimed to investigate the anticonvulsant and neuroprotective effects of C. citratus essential oil (EO) and hydroalcoholic extract (E1) from its leaves, as well as of its related compounds citral (CIT) and geraniol (GER) against the effects of pentylenetetrazole (PTZ) induced seizures in zebrafish (Danio rerio)., Materials and Methods: To evaluate the anticonvulsant properties of the samples, adult animals were pre-treated (by immersion) and subsequently exposed to PTZ solution. The involvement of GABA A receptors in the antiepileptic effects was investigated by the coadministration of flumazenil (FMZ), a known GABA A receptor antagonist. Oxidative stress markers malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and nitric oxide (NO) were assessed in zebrafish brain homogenates after PTZ exposure., Results: All samples increased the latency time for the first seizure, which was reduced when animals were pretreated with FMZ, suggesting the involvement of GABA A receptors in the observed properties. The association between CIT and GER at the lowest concentration studied showed a synergistic effect on the anticonvulsant activity. Decreases in MDA and NO levels and increases in GSH and CAT levels in the brain of treated animals suggested the neuroprotective effect of the compounds investigated., Conclusions: Our results proved that C. citratus EO, E1, CIT and GER have anticonvulsant effects in zebrafish and could be used as a promising adjuvant therapeutic strategy for epilepsy treatment. Furthermore, zebrafish demonstrated to be an alternative animal model of epilepsy to evaluate the anticonvulsant and neuroprotective effects of C. citratus., (Copyright © 2021. Published by Elsevier B.V.)

Background : Nicotine is the addictive agent in tobacco products. The monoterpene linalool is the main ingredient in the essential oils of various aromatic plants. It has previously been demonstrated that linalool has beneficial effects on some mechanisms that are important in drug addiction. Objectives : The goal of the current study was to investigate the effect of linalool on nicotine-induced conditioned place preference (CPP) in male mice. Methods : CPP was induced by administering intraperitoneal (i.p.) injection of nicotine (0.5 mg/kg) during the conditioning phase. The effects of nicotinic acetylcholine receptor partial agonist varenicline and linalool on the rewarding characteristics of nicotine were tested in mice with administration of linalool (12.5, 25, and 50 mg/kg, i.p.), varenicline (2 mg/kg, i.p.) or saline 30 minutes before nicotine injection. CPP was extinguished by repeated testing, during which conditioned mice were administered varenicline and linalool every day. One day after the last extinction trial, mice that received linalool, varenicline or saline 30 minutes before a priming injection of nicotine (0.1 mg/kg, i.p.) were immediately tested for reinstatement of CPP. Results : Linalool attenuated nicotine acquisition (50 mg/kg, p < .01) and reinstatement (25 and 50 mg/kg, respectively p < .05, p < .01) and accelerated the extinction of nicotine-induced CPP (50 mg/kg, p < .05). Linalool exhibited similar effects on the reference drug varenicline in the CPP phases. Conclusion : These results suggest that linalool may be helpful as an adjuvant for the treatment of nicotine use disorder.

Complex regional pain syndrome type 1 (CRPS-1) is a painful syndrome without effective treatment. In order to explore possible new treatments, we used an animal model of CRPS-1 to examine the effects of β-Citronellol (βCT), a monoterpene found in a variety of plants that has been shown to have analgesic effects. We aimed to assess its effects alone, and complexed with β-cyclodextrin (βCD), which has been previously used to enhance the effects of a number of medicines. The βCT-βCD was characterized physiochemically using high performance liquid chromatography (HPLC) and differential scanning calorimetry (DSC) and shown to have 80% efficiency. In the animal model, Swiss mice were treated with βCT, βCT-βCD, vehicle, pregabalin or sham and evaluated for hyperalgesia and motor coordination. Inflammatory mediators were measured by Western blot or ELISA and the descending pain pathway by immunofluorescence. βCT was shown to have an anti-hyperalgesic effect (without affecting motor coordination) that reduced inflammatory mediators and activated the descending pain pathway, and these effects were increased with complexation in βCD. Our results showed βCT-βCD to be a promising treatment for CRPS-1., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Rhabdomyosarcoma (RMS) is a rare type of soft tissue sarcoma most commonly found in pediatric patients. Despite progress, new and improved drug regimens are needed to increase survival rates. Citral, a natural product plant oil can induce cell death in cancer cells. Another compound, metformin, isolated originally from French lilac and used by diabetics, has been shown to reduce the incidence of cancer in these patients. Application of citral to RMS cells showed increase in cell death, and RD and RH30 cells showed half maximal inhibitory concentration (IC 50 ) values as low as 36.28 μM and 62.37 μM, respectively. It was also shown that the citral initiated cell apoptosis through an increase in reactive oxygen species (ROS) and free calcium. In comparison, metformin only showed moderate cell death in RMS cell lines at a very high concentration (1,000 μM). Combinatorial experiments, however, indicated that citral and metformin worked antagonistically when used together. In particular, the ability of metformin to quench the ROS induced by citral could lead to the suppression of activity. These results clearly indicate that while clinical use of citral is a promising anti-tumor therapy, caution should be exercised in patients using metformin for diabetes., (© 2020 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.)

The volatile components of kuromoji oil (Lindera umbellata Thunb.) obtained in Shizuoka Pref. were analyzed by GC/MS. Linalool, α-pinene, limonene, camphene, cis- and trans-dihydrocarvone, 1,8-cineol, 4-terpinenol, α-terpineol, piperitone, geranyl acetate, geraniol, and trans-nerolidol were identified as major components. Using enantio-MDGC-MS, the enantiomeric ratio ((R)-(-) vs (S)-(+)) of linalool in this oil was determined to be 67.8/32.2. Touch care treatment while sniffing this oil was done on cancer patients. We found that the relaxation effect persisted longer after the treatment compared to treatment without aroma.

Deregulated activity of protein kinase B/mammalian target of rapamycin complex-1 (Akt/mTORC1) incites crucial pathological characteristics of diabetic nephropathy. The acyclic monoterpene geraniol has been recently reported to possess antidiabetic effects; however, its potential renoprotective effect in diabetes has not yet been elucidated. This study aimed to assess the possible modulatory effect of geraniol on the Akt/mTORC1 pathway in diabetes-induced nephropathy in rats compared to the standard antidiabetic drug gliclazide. Geraniol and gliclazide was administered daily to diabetic rats for 6 weeks starting on the 3rd-day post diabetes induction by streptozotocin (STZ). Geraniol amended the deteriorated renal function (serum creatinine; blood urea nitrogen). It exerted a remarkable antihyperglycemic effect that is comparable to that of gliclazide and suppressed the fibrotic marker, transforming growth factor-β. Geraniol restored redox balance and inhibited lipid peroxidation by reducing nicotine amide adenine dinucleotide phosphate oxidase and enhancing the antioxidant enzyme, superoxide dismutase. These beneficial effects were associated with a robust downregulation of miRNA-21 and consequently, reversion of tumor suppressor protein phosphatase and tension homolog (PTEN)/Akt/mTORC1 cue and its downstream proteins required for mesangial cell proliferation and matrix protein synthesis. The current study indicates that geraniol interfered with miRNA-21/ PTEN/AKT/mTORC1 pathway signaling that contributes largely to the progression of mesangial expansion and extracellular matrix deposition in diabetic nephropathy.

Background: Epithelial ovarian cancer (EOC) is a fatal gynecologic malignancy that is usually treated with chemotherapy after surgery. However, patients who receive chemotherapy experience severe side effects because of the inherent toxicity and high dose of chemotherapeutics. To overcome these issues, we suggest a combination therapeutic strategy using liposomes encapsulating linalool nanoemulsions (LN-NEs) and doxorubicin (DOX), a chemotherapeutic drug, to increase their synergistic antitumor efficacy and reduce the incidence of side effects from chemotherapeutics for EOC., Methods: The physical properties of LN-NE-DOX-liposomes were characterized by light scattering with a particle size analyzer. Cell viability was determined by MTT assay. Therapeutic efficacy was evaluated in a mouse HeyA8 EOC tumor model of ovarian carcinoma. Additionally, biochemical toxicity was analyzed for levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood urea nitrogen (BUN) using BALB/c nude mice., Results: The size of the liposomes encapsulating LN-NEs and DOX (LN-NE-DOX-liposomes) was 267.0 ± 4.6 nm, with a loading efficiency of 55.1 ± 3.1% and 27.2 ± 0.9% for linalool and DOX, respectively. Cell viability after treatment with LN-NE-DOX-liposomes was significantly decreased compared to that of cells treated with DOX liposomes, and apoptosis was significantly increased. Additionally, LN-NE-DOX-liposomes significantly inhibited HeyA8 EOC tumor growth compared to that of the control ( p < 0.01) and DOX-liposome-treated groups ( p < 0.05), while decreasing cell proliferation (Ki67) and microvessel density (CD31), and promoting apoptosis (caspase-3) compared to the control ( p < 0.05). Moreover, the liposomal formulations induced no significant differences in biochemical toxicity (AST, ALT, and BUN) compared to healthy control mice, indicating that the liposomal formulations showed no overt toxicity in mice., Conclusion: This study demonstrates that the production of LN-NE-DOX-liposomes is a pivotal approach for EOC treatment, suggesting a novel combination therapeutic strategy., Competing Interests: The authors declare that they have no competing financial or non-financial interests., (© 2020 Wi et al.)

Geraniol (GOH) is a natural essential oil that possesses antioxidant, anti-inflammatory, and antiapoptotic properties by various signaling pathways. Liver ischemia-reperfusion injury (IRI) is a serious event that triggers liver dysfunction or even failure. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional factor, maintains cellular defense mechanism through antioxidant and anti-inflammatory properties. To detect GOH effect against liver IRI through the activation of the Nrf2/HO-1 antioxidant pathway, five groups of rats were randomized to normal, sham, IR, GOH, and GOH/IR. Blood samples and liver tissues were collected to measure various biochemical parameters related to liver function, and oxidative stress as well as inflammatory and apoptotic indicators besides liver tissue histopathology was evaluated by light microscopy. GOH induces activation of Nrf2 along with the upregulation of HO-1 expression. Also, the antioxidant activity of GOH was shown by the elevation of total antioxidant capacity and GSH levels, together with normalizing malondialdehyde. Regarding the anti-inflammatory effect of GOH, it suppresses the levels of TNF-α, iNOS, and COX-2. Additionally, the antiapoptotic effect of GOH, Bax, and caspase-3, 9 were reduced in liver tissue. GOH is a promising hepatoprotective agent in liver IRI through the activation of Nrf2/HO-1 antioxidant pathway.

Hepatocellular carcinoma (HCC) ranks the sixth position among various cancers worldwide. Recent research shows that natural and dietary compounds possess many therapeutic effects. Citral is a monoterpene aldehyde that contains geranial and neral. The present study was considered to study the role of citral against N-nitrosodiethylamine (NDEA)-induced HCC via modulation of antioxidants and xenobiotic-metabolizing enzymes in vivo. NDEA-alone-administered group II animals profoundly showed increased tumor incidence, reactive oxygen species, liver marker enzyme levels, serum bilirubin levels, tumor markers of carcinoembryonic antigen, α-fetoprotein, proliferative markers of argyrophilic nucleolar organizing regions, proliferating cell nuclear antigen (PCNA) expressions, phase I xenobiotic-metabolic enzymes and simultaneously decreased antioxidants, and phase II enzymes levels. Citral (100 mg/kg b.w.) treatment significantly reverted the levels in group III cancer-bearing animals when compared to group II cancer-bearing animals. In group IV animals, citral-alone administration did not produce any adverse effect during the experimental condition. Based on the results, citral significantly inhibits the hepatocellular carcinogenesis through restoring the antioxidants and phase II xenobiotic-enzyme levels; thereby, it strongly proves as an antiproliferative agent against rat HCC., (© 2020 Wiley Periodicals, Inc.)

Current antiepileptic drugs (AEDs) are undesirable for many reasons including the inability to reduce seizures in certain types of epilepsy, such as Dravet syndrome (DS) where in one-third of patients does not respond to current AEDs, and severe adverse effects that are frequently experienced by patients. Epidiolex, a cannabidiol (CBD)-based drug, was recently approved for treatment of DS. While Epidiolex shows great promise in reducing seizures in patients with DS, it is used in conjunction with other AEDs and can cause liver toxicity. To investigate whether other cannabis-derived compounds could also reduce seizures, the antiepileptic effects of CBD, Δ9-tetrahydrocannabinol (THC), cannabidivarin (CBDV), cannabinol (CBN), and linalool (LN) were compared in both a chemically-induced (pentylenetetrazole, PTZ) and a DS (scn1Lab -/- ) seizure models. Zebrafish (Danio rerio) that were either wild-type (Tupfel longfin) or scn1Lab -/- (DS) were exposed to CBD, THC, CBDV, CBN, or LN for 24 h from 5 to 6 days postfertilization. Following exposure, total distance traveled was measured in a ViewPoint Zebrabox to determine if these compounds reduced seizure-like activity. Cannabidiol (0.6 and 1 μM) and THC (1 and 4 μM) significantly reduced PTZ-induced total distance moved. At the highest THC concentration, the significant reduction in PTZ-induced behavior was likely the result of sedation as opposed to antiseizure activity. In the DS model, CBD (0.6 μM), THC (1 μM), CBN (0.6 and 1 μM), and LN (4 μM) significantly reduced total distance traveled. Cannabinol was the most effective at reducing total distance relative to controls. In addition to CBD, other cannabis-derived compounds showed promise in reducing seizure-like activity in zebrafish. Specifically, four of the five compounds were effective in the DS model, whereas in the PTZ model, only CBD and THC were, suggesting a divergence in the mode of action among the cannabis constituents., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Osteoarthritis (OA) is a degenerative disease that has received increasing attention among the elderly. Its clinical manifestation is primarily long-term joint pain. Evidence for the pharmacological effects of geraniol in various diseases is accumulating. However, whether geraniol has a therapeutic effect against OA remains to be determined. In this study, we discussed the anti-inflammatory effects of geraniol in IL-1β-induced chondrocytes and the anti-cartilage degradation effects in a mouse model of destabilization of the medial meniscus (DMM). In cell experiments, we found that the treatment of geraniol inhibited the expression of IL-1β-induced PGE2, NO, COX-2, iNOS, TNF-α and IL-6 by western blot, qRT-PCR and immunofluorescence staining. Besides, geraniol inhibited the expression of MMP-9 and ADAMTS-5, and reversed the degradation of aggrecan and type II collagen. Mechanistically, we revealed that geraniol suppressed IL-1β-stimulated PI3K/Akt/NF-κB and MAPK activation. Importantly, we have found in animal experiments that oral treatment of geraniol was beneficial in protecting articular cartilage from degradation. Overall, these data indicated that geraniol may have the potential to be developed as an effective treatment for OA., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Fibromyalgia (FM) is a chronic disease that has as main characteristic generalized musculoskeletal pain, which can cause physical and emotional problems to patients. However, pharmacological therapies show side effects that hamper the adhesion to treatment. Given this, (-)-linalool (LIN), a monoterpene with several therapeutic properties already reported in scientific literature as anti-depressive, antinociceptive, anti-inflammatory, and antihyperalgesic also demonstrated therapeutic potential in the treatment of FM. Nevertheless, physicochemical limitations as high volatilization and poor water-solubility make its use difficult. In this perspective, this present research had performed the incorporation of LIN into polymeric nanocapsules (LIN-NC). Size, morphology, encapsulation efficiency, cytotoxicity, and drug release were performed. The antihyperalgesic effect of LIN-NC was evaluated by a chronic non-inflammatory muscle pain model. The results demonstrated that the polymeric nanocapsules showed particle size of 199.1 ± 0.7 nm with a PDI measurement of 0.13 ± 0.01. The drug content and encapsulation efficiency were 13.78 ± 0.05 mg/mL and 80.98 ± 0.003%, respectively. The formulation did not show cytotoxicity on J774 macrophages. The oral treatment with LIN-NC and free-LIN increased the mechanical withdrawal threshold on all days of treatment in comparison with the control group. In conclusion, LIN-NC is a promising proposal in the development of phytotherapy-based nanoformulations for future clinical applications.

Linalool (LIN) is a monoterpene, responsible for the aroma of essential oils in some species. It presents a sedative and anxiolytic potential, enhancing GABAergic currents and behaving as a benzodiazepine-type of drug. The objectives of the present work were to study the neuroprotective effects of LIN on a model of Parkinson's disease. For that, male Wistar rats were divided into the following groups: sham-operated (SO), 6-OHDA-lesioned, and 6-OHDA-lesioned and treated with LIN (25, 50, and 100 mg/kg, p.o.) for 2 weeks. Afterwards, the animals were subjected to behavioral tests (apomorphine-induced rotations, open field, and forced swimming tests). Then, the animals were euthanized, and the striatum, hippocampus, and prefrontal cortex were processed for neurochemistry (nitrite and lipoperoxidation measurements) and immunohistochemistry (TH and DAT) assays. The results were analyzed by ANOVA and Tukey's test for multiple comparisons and considered significant at p < 0.05. LIN significantly improved the behavioral alterations of the 6-OHDA-lesioned group, as evaluated by the apomorphine-induced rotations, open field, and forced swimming tests. In addition, LIN partially reversed the decreased DA, DOPAC, and HVA contents observed in the 6-OHDA-lesioned striatum. The untreated 6-OHDA group presented increased nitrite contents and lipoperoxidation in all the brain areas studied, and these changes were completely reversed after LIN treatments. Finally, LIN significantly prevented the reduction in TH and DAT expressions demonstrated in the right 6-OHDA-lesioned striatum. All these data strongly suggest that LIN presents a neuroprotective action in hemiparkinsonian rats, probably related to the drug anti-inflammatory and antioxidant activities.

Candida albicans invasion is one of the most serious fungal infections in clinical history. In recent years, because of the widespread use of immunosuppressive drugs, chemotherapy drugs, glucocorticoids, and broad-spectrum antibiotics, serious drug resistance has been reported; therefore, a new type of antifungal drug needs to be developed. In this study, we found that Nerol (NEL) had strong antimicrobial activity and 0.77 μL/mL NEL was the minimum inhibitory concentration (MIC) effective against C. albicans. We determined the change of the growth curve of NEL for C. albicans, to identify the trend of NEL activity against C. albicans. Through the determination of the ergosterol content and glucose-induced extracellular fluid acidification of NEL on C. albicans, we found that NEL inhibits the growth of C. albicans by destroying cell membranes. This finding was also supported by the expression of SAP (secreted aspartyl proteinase) involved in cell membrane synthesis. Finally, demonstrations of phenotype investigation, colony-forming unit (CFU) counts, and PAS (periodic acid-Schiff) staining were conducted to prove that NEL had the ability to treated mouse oral C. albicans infection and vaginal C. albicans infection. This research may help us to investigate new antimicrobial agents for treating C. albicans infections. KEY POINTS: • NEL can inhibit the growth of C. albicans. • NEL destroys the cell membrane formation and permeability of C. albicans. • NEL can treat vulvovaginal candidiasis and oropharyngeal candidiasis in mice. • NEL could be used as a possible antifungal agent.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Treatment of Psoroptes ovis in cattle is limited to topical acaricides or systemic treatment with macrocyclic lactones. Treatment failure of macrocyclic lactones has been reported. The aim of this study was to evaluate a potential alternative treatment against P. ovis., Methods: The acaricidal activity against P. ovis of four plant-derived essential oil components, i.e. geraniol, eugenol, 1,8-cineol and carvacrol, was assessed in vitro and in vivo. In vitro contact, fumigation and residual bioassays were performed. In addition, 12 Belgium Blue cattle were artificially infested and treated topically once a week for three successive weeks with carvacrol in Tween-80 (treatment group) or with Tween-80 alone (control). The efficacy of carvacrol was determined by the reduction in lesion size and mite counts. Six additional animals were topically treated with carvacrol to assess local adverse reactions., Results: Three components showed a concentration-dependent acaricidal activity in a contact assay, with LC 50 of 0.56, 0.38 and 0.26% at 24 h for geraniol, eugenol, and carvacrol, respectively. However, 1,8-cineol showed no activity at any of the tested concentrations in a contact bioassay. In a fumigation bioassay, carvacrol killed all mites within 50 min after treatment, whereas geraniol, eugenol and 1,8-cineol needed 90 to 150 min. Following a 72 h incubation period in a residual bioassay, carvacrol killed all mites after 4 h of exposure to LC 90, while geraniol and eugenol killed all mites only after 8 h exposure. Based on these results, carvacrol was further assessed in vivo. Mite counts in the treatment group were reduced by 98.5 ± 2.4% at 6 weeks post-treatment, while in the control group the mite population had increased. Topical application of carvacrol only caused mild and transient erythema 20 min after treatment. No other side effects were observed., Conclusions: Considering the strong acaricidal activity of carvacrol in vitro and in vivo and the mild and transient local side effects, carvacrol shows potential as an acaricidal agent in the treatment of P. ovis in cattle.