Menthol Group Research Articles

Dispersion Forces-Driven Hierarchical Assembly of Protein-Like Lanthanide Octamers and Emergent CPL.

Hierarchical self-assembly driven by non-covalent interactions is a prevalent strategy employed by nature to construct sophisticated biomacromolecules, such as proteins. However, the construction of protein-like superstructures that rely on weaker dispersion forces-driven hierarchical assembly remains largely unexplored. Here, we report the first example of dispersion forces driving the high-order assembly of the lanthanide trinuclear circular helicate [HNEt₃]₃[Eu₃(LL)₆] (ΔΔΔ-1) into a protein-like lanthanide octamer ((ΔΔΔ-1)₈-2). Within the octamer, the forty-eight (48) menthol groups on the ligands and eighty-four (84) 1,4-dioxane solvent molecules contribute to enhanced dispersion forces through conformational adaptation and size-matching effects. These enhanced dispersion forces not only drive the formation of the hierarchical superstructure but also result in a four-level chirality transfer from the menthol to the octamer. Benefiting from the homochirality of Eu³⁺, the octamer is endowed the strong circularly polarized emission (|glum| = 0.34, Φoverall = 41%). This understanding of how dispersion forces drive hierarchical self-assembly provides a foundation for the directed fabrication of more fascinating superstructures.

Transient Receptor Potential Melastatin 8 Contributes to Cystitis-Induced Neuronal Sprouting and Pain Hypersensitivity Through AKT/mTOR Signaling Pathway in Interstitial Cystitis/Bladder Pain Syndrome.

The aim of this study was to investigate the mechanism of TRPM8 in neuroproliferation and pain, as well as the relevance of the Akt/mTOR signaling pathway in mice with IC/BPS. The model of IC/BPS was established in wild and TRPM8-/- mice. The mechanical sensitivity was measured. The number of neurite segments, length of neurites, and density of neurites were all counted. IL-6 and norepinephrine levels were detected by ELISA, Western blot was used to detect protein levels of TRPM8, Akt, p-Akt, mTOR, p-mTOR. Immunofluorescence was used to detect TRPM8 expression and distribution in neurites, neurons, and sensory nerves in mouse bladder tissue. Pain threshold in the IC/BPS group was decreased, and neurite segments, length, and density were all significantly enhanced when compared to the control group. The parameters in the IC/BPS model + Menthol group were more statistically significant. Neurite number and density were lower in TRPM8 knockout-model mice than in IC/BPS model mice. The expression of TRPM8 and the ratios of p-Akt/Akt and p-mTOR/mTOR rose in the IC/BPS model group. In TRPM8 knockout-model mice, the ratios of p-Akt/Akt and p-mTOR/mTOR were not substantially different from those in the control group. TRPM8 knockout-model mice had considerably lower levels of serum IL-6 and urine norepinephrine than IC/BPS model mice. TRPM8 can induce pain hypersensitivity and sensory nerve proliferation by activating Akt/mTOR pathway and raising the expression of IL-6 and norepinephrine in IC/BPS models. These findings offer new perspectives on IC/BPS treatment.

Assessment of Abuse Liability and Nicotine Pharmacokinetics of glo Heated Tobacco Products in a Randomized, Crossover Study.

Heated tobacco products (HTPs) are a class of non-combustible, inhaled tobacco products with the potential to reduce the harm associated with cigarette smoking due to reduced cigarette smoke toxicant exposure. Subjective and nicotine pharmacokinetics measures taken over the course of product use provide a framework for abuse liability (AL) assessment of tobacco and nicotine products as well as information on adoption potential for a new tobacco product, which are important aspects for premarket tobacco product authorization by the US Food and Drug Administration. This study aimed to assess the AL of glo HTPs, operated in either Standard or Boost Modes, compared with high- and low-AL comparators (subjects' usual brand cigarettes and nicotine gum, respectively). Nicotine uptake and pharmacodynamics measures (including subjective and physiological measures) were assessed in a clinical study of 75 healthy adult non-menthol or menthol smokers using an open-label, randomized crossover study design. Comparisons were made between glo HTPs (Standard or Boost Modes) and each of usual brand (UB) cigarettes and nicotine gum to evaluate nicotine exposure and subjective effects measures. Nicotine uptake, as reflected in the area under the curve (AUC) at 15 and 240 min after product use (AUC0-15 and AUC0-240, respectively) and maximum nicotine concentration (Cmax) were significantly lower for all glo HTPs compared to UB cigarettes, regardless of the glo device mode. AUC0-15 values for glo HTPs ranged from 41.26 to 75.71 ng × min/mL, versus 158.04 to 165.53 ng × min/mL for UB cigarettes. Similarly, AUC0-240 values for glo HTPs ranged from 379 to 596 ng × min/mL, compared to 1123.73 and 1283.37 ng × min/mL for UB cigarettes. The Cmax for glo HTPs ranged from 5.46 to 9.00 ng/mL, whereas UB cigarettes had Cmax values of 16.29 to 16.76 ng/mL. The time to reach maximum nicotine concentration (Tmax) was significantly shorter for glo HTPs (4-5 min) compared to UB cigarettes (6-7 min), except for one variant of glo HTP in Standard Mode. Nicotine gum exhibited a slower nicotine absorption profile, with a Tmax of 45 min and Cmax of 4.60 ng/mL. AUC0-15 and AUC0-240 values for nicotine gum were 6.18 and 5.22 ng × min/mL, and 647.80 and 687.68 ng × min/mL for non-menthol and menthol groups, respectively. Subjective measures indicated that glo HTPs were rated significantly lower than UB cigarettes in terms of product liking, smoking urge reduction, product effects, and intent to use again, but were comparable to nicotine gum. glo HTPs demonstrated lower AL than combustible cigarettes while delivering sufficient nicotine to support product adoption among current smokers. This positions glo HTPs as a potential tool in tobacco harm reduction, offering a less harmful alternative to traditional cigarettes. Clinical trial ID NCT05114863.

Effect of TRPM8 on pain symptom and neuronal proliferation in mice with interstitial cystitis/bladder pain syndrome

Objective: To explore the effects between transient receptor potential melastatin 8 (TRPM8) on pain symptom and neuronal proliferation in mice with interstitial cystitis/bladder pain syndrome (IC/BPS). Methods: Female wild-type C57BL/6 mice (8-10 weeks old) were divided into control group, IC/BPS model group, and IC/BPS model+menthol group (6 mice each) by random number table method; TRPM8 knockout mice were randomly divided into TRPM8 knockout group and TRPM8 knockout model group (6 mice each). The IC/BPS model group, the IC/BPS model+menthol group, and the TRPM8 knockout model group were injected subcutaneously with residues 65-84 of murine uroplakin 3A (UPK3A65-84). The IC/BPS model+menthol group continued to be injected with menthol. After successful modeling, the differences in pain thresholds between the groups were assessed by mechanosensitivity. The bladder wall was injected with a cell membrane red fluorescent probe (Dil), and the dorsal root ganglion (DRG) tissues were collected 10 days later. The differences in the protein and mRNA levels of TRPM8 and GAP43 in the groups were detected by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Immunofluorescence was used to detect the distribution of TRPM8 expression with GAP43 or Dil in DRG tissues. The relationship between TRPM8 and pain symptom and its role in neuronal proliferation in IC/BPS mice were analyzed. Results: The models were all constructed successfully. Compared with the control group, the pain thresholds of mice in the IC/BPS model group and IC/BPS model+menthol group were reduced [(8.50±1.22), (5.50±1.05) vs (11.67±2.16), respectively, all P<0.001]. Compared with the control group, the expression of TRPM8 mRNA was elevated in the IC/BPS model group and IC/BPS model+menthol group, while TRPM8 was not expressed in the TRPM8 knockout group [(3.16±0.05), (6.46±0.21), and 0 vs (1.00±0.06), respectively, all P<0.001]. The expression of TRPM8 protein and mRNA in each group had the same trend (P<0.001). Compared with the control group, the expression of GAP43 mRNA in the DRG of the IC/BPS model group and the IC/BPS model+menthol group was increased, whereas the expression of GAP43 mRNA in the TRPM8 knockout model group was decreased (all P<0.001). The trend of GAP43 protein expression was the same as that of mRNA expression (P<0.001). Immunofluorescence results showed an increase in the number of GAP43-positive neurons in the DRG of the IC/BPS model group and the IC/BPS model+menthol group, and a decrease in the TRPM8 knockout group compared with the control group (all P<0.001). Compared with the control group, the number of Dil-positive neurons in the DRG of the IC/BPS model group and the IC/BPS model+menthol group was increased, while the TRPM8 knockout group was decreased (all P<0.001). Conclusion: TRPM8 can exacerbate pain symptom in IC/BPS mice, and the mechanism may be related to the induction of sensory nerve proliferation at the DRG level.

New benzotriazole-derived α-substituted hemiaminal ethers with enhanced cholinesterase inhibition activity: Synthesis, structural, and biological evaluations

A new series of benzotriazole-derived α-substituted hemiaminal ethers have been synthesized as human cholinesterase (hChE)inhibitors with enhanced activity. The synthesized compounds were extensively characterized by 1H NMR and 13C NMR spectroscopy, mass spectrometry, and SC-XRD studies. All the compounds demonstrated dual inhibition potential against acetyl and butylcholinesterases(AChE and BChE) in the in-vitro studies. Results revealed that compounds carrying the optically active (R)-menthol group demonstrated more activity than the bicyclic (R)-fenchol moiety. For instance, α-butyl-(R)-menthyl-benzotriazole derivative (5a-iii) exhibited the best AChE inhibition with an IC50 value of 44.03 nM, while its α-methyl analog (5a-i) showed promising results against BChE inhibition (IC50 = 80.74 nM). Themolecular modeling study was carried out to assess the binding interactions with the target proteins to rationalize the structural–activity relationship. Subsequently, the stability of the protein–ligand complex was verified through molecular dynamics (MD) simulations. Pharmacokinetic and bioavailability parameters further supported the suitability of the new inhibitors as lead compounds for neurological disorders.

Menthol application on healthy and inflamed goat udders changes antimicrobial components in milk.

Mammary glands with mastitis are usually treated with antibiotics in combination with anti-inflammatory drug application on the udder skin. Menthol is an anti-inflammatory drug. The aim of the present study was to investigate the effect of surface application of menthol on goat udders on the production of antimicrobial components in milk. Goats (5 Shiba and 11 Tokara goats) were subjected to menthol application to the udder under both healthy and inflammatory conditions. An intramammary infusion of lipopolysaccharides was carried out to induce inflammatory conditions in the udder. Milk samples were collected to determine somatic cell count (SCC) and sodium ion (Na+ ), antimicrobial component and cytokine concentrations. In healthy udders, menthol application increased the concentration of antimicrobial components (S100A7 and S100A8), but not in the control. In the inflamed udder, antimicrobial component (lactoferrin, S100A7, and S100A8) and inflammatory cytokine (IL-1β) concentrations were higher in the menthol group than in the control group. These results suggest that menthol application on udders augments the antimicrobial component concentration in the mammary gland under both healthy and inflammatory conditions.

Oxidative stress response biomarker gene expression in Piaractus brachypomus (Characiformes: Serrasalmidae)

ABSTRACT Oxidative stress may occur in the fish brain under several conditions, including tissue reoxygenation during anaesthesia, injury and toxic exposure. An imbalance in oxidative homeostasis can lead to oxidative stress, triggering several adaptive mechanisms at both the genetic and protein levels. The aim of this study was to assess the transcription levels of five oxidative stress-related genes in the Colombian native fish red-bellied pacu, Piaractus brachypomus, under anaesthesia with menthol (50 mg/L) and eugenol (40 mg/L), as well as in models of acute brain injury and organophosphate toxicity. Relative gene expression was assessed in the brain, gill and liver tissues of fish under anaesthesia and in the brain tissues of fish in the brain injury and toxicity experiments. It was found that glutathione reductase (GSR) mRNA levels in the brain were significantly higher in the eugenol group than in the menthol group, ATP synthase subunit 6 (ATP6) transcription was downregulated after brain injury, and the GSR, ATP6 and superoxide dismutase 2 (SOD2) genes were upregulated in fish exposed to the organophosphate chlorpyrifos. This is the first evaluation of the relative gene expression of oxidative response biomarkers in P. brachypomus.

Animal Experimental Study of the Role of Menthol and Cineole, Two Tobacco Additives, on Nicotine Dependence

To establish a nicotine intravenous self-administration rat model, and to examine, with this model, the effects of two flavoring additives, menthol and cineole, on nicotine dependence. Thirty male Sprague-Dawley (SD) rats were included in the study. After jugular venous catheterization was performed, fixed concentration of nicotine was administered in order to train the rats and establish the rat model of intravenous self-administration groups, receiving intraperitoneal injection of menthol, cineole, and dimethyl sulfoxide (DMSO), the vehicle that was used for the control group. The rats were tested with different fixed-ratio (FR) schedules, including FR1 schedule, in which the rat received one nicotine infusion for every active nose poke, FR2 schedule, in which the rat received one nicotine infusion for every two active nose pokes, and FR5 schedule, in which the rat received one nicotine infusion for every five active nose pokes. The number of active and inactive poke responses and the number of nicotine infusion were documented accordingly. After 10 days of training in nicotine self-administration, the 30 rats demonstrated significant increase in the number of active poke responses and the number of nicotine infusion, which were maintained at a stable and relatively high level. The number of active poke responses was significantly higher that of inactive poke responses ( P< 0.001). The rat model of intravenous nicotine self-administration was successfully established. In the testing phase, under the FR2 schedule, the menthol group showed a reduced number of active poke responses ( P=0.020). Under the FR5 schedule, the groups showed obvious interaction between time and the number of active poke responses ( P<0.011), with the menthol group showing reduced number of active poke responses on day three ( P=0.011) and the cineole group showing rising number of active poke responses on day three ( P=0.003). The DMSO control group did not show any significant change. Menthol and cineole are shown to have an effect on nicotine dependence. When there is relative difficulty involved in obtaining nicotine, menthol suppresses nicotine dependence, whereas cineole enhances nicotine dependence.

Menthol-induced cutaneous stimulation combined with self-paced walking training improves knee extension performance in untrained older healthy females.

[Purpose] The present study aimed to investigate whether self-paced walking training utilizing the facilitating effect of skin cooling with menthol gel application was effective in untrained older healthy females. [Participants and Methods] Forty-two untrained healthy older females (aged 60–69 years) were divided into the following three groups: (i) Walking training with menthol group: GM, (ii) Walking training group: GW, and (iii) Control group: GC. The participants in GM and GW performed self-paced walking for 30 minutes a day, 2 times a week, for 6 weeks. Menthol gel was applied to the front of the thigh of the participants in GM. Maximal voluntary contraction and rate of force development were measured pre- and post-training and walking speed was measured during the training. The number of steps taken and walking speed in daily activity were measured and the average of these parameters per day were calculated. [Results] The main findings were [1] knee extension muscle strength increased in GM and GW, and [2] rate of force development only improved in GM. [Conclusion] These results suggest that walking training utilizing the facilitating effect of skin cooling enhances muscle function in untrained older healthy females and that the present skin cooling method with menthol gel application may be recommended as a training strategy.

Role of mammalian target of rapamycin activation in menthol-induced expressions of airway inflammation-related factors in human bronchial epithelial cells in vitro

To investigate the role of mammalian target of rapamycin (mTOR) activation in menthol-induced expression of airway inflammation- related factors in human bronchial epithelial cells and explore its mechanism. Cultured human bronchial epithelial cells (BEAS-2B) were divided into normal control group, menthol group, rapamycin group, and menthol+rapamycin group with corresponding treatments. The cell viability was measured with CCK-8 method. The mRNA levels of transient receptor potential melastatin 8 (TRPM8), tumor necrosis factor (TNF)-α and interleukin (IL)-1β were detected by RT-PCR, and the protein expressions of phosphorylated mTOR (p-mTOR), TRPM8, TNF-α and IL-1β were determined using Western blotting. The intracellular Ca2+ fluorescence intensity was measured by flow cytometry. Compared with the normal control cells, menthol- treated cells showed significantly increased TNF-α, IL-1β, and p-mTOR expression and elevated intracellular Ca2+ concentration (P < 0.05), and the rapamycin-treated cells exhibited significantly decreased p-mTOR expression (P < 0.05). No significant difference was found in TNF-α, IL-1β or intracellular Ca2+ concentration between the normal control and rapamycin-treated cells (P>0.05). Compared with the menthol-treated cells, the cells treated with both menthol and rapamycin showed significantly decreased TNF- α, IL-1β, and p-mTOR expression and obviously lowered intracellular Ca2+ concentration (P < 0.05). Menthol promotes the expressions of airway inflammationrelated factors IL-1β and TNF-α possibly by activating mTOR to cause the increase of intracellular Ca2+ concentration.

Topically applied hypericin exhibits skin penetrability on nude mice.

Hypericin, a powerful natural photosensitizer in photodynamic therapy (PDT), is suitable for treating skin diseases involving excess capillary proliferation. In the present study, we aimed to evaluate the skin penetrability of topically applied hypericin, expecting a reduced risk of prolonged skin photosensitivity, which often occurs after systemic administration. Firstly, the Franz diffusion cell assays were performed to evaluate the penetration effects of different enhancers, including menthol, propylene glycol, camphanone, azone, and carbamide. In view of above evaluation results, we selected menthol as the enhancer in the subsequent in vivo studies. The setting groups were as follows: the blank control group, the light-exposure control group, the gel-base control group, the hypericin gel group, and a hypericin gel-containing menthol group. Except for the blank control, all other animals were irradiated by a LED light. Then, fluorescence microscopy was performed to examine the distribution of hypericin in the skin of nude mouse. Macroscopic and microscopic analyses were also carried out to detect pathological changes in the skin after topical hypericin-PDT treatment. Immunohistochemistry was used to determine the expression change of PECAM-1. As shown in the results, menthol facilitated hypericin penetrate the skin of nude mice most. The results of in vivo assays revealed that hypericin penetrated nude mouse skin, spread to the dermis, and resulted in obvious photosensitivity reaction on the dermal capillaries. Moreover, skin injured by the photosensitive reaction induced by hypericin-PDT treatment was replaced by normal skin within 7days. We concluded that topical applied hypericin could penetrate nude mouse skin well and has a great potential in PDT treatment of skin diseases.

“Pinwheel-like” phthalocyanines with four non-peripheral chiral menthol units: Synthesis, spectroscopy, and electrochemistry

A pair of “pinwheel-like” metal free phthalocyanines, (d)- and (l)-1,8,15,22-tetrakis(2-isopropyl-5-methylcyclohexoxyl)phthalocyanine (1) were isolated for the first time from cyclic tetramerization of (d)- and (l)-3-(2-isopropyl-5-methylcyclohexoxyl)-1,2-dicyanobenzene (2), respectively, in refluxing n-pentanol in the presence of lithium pentanoate followed by treatment with acetic acid. Owing to the steric hindrance of the bulky menthol groups, C4 tetra-α-substituted phthalocyanine 1 is the main phthalocyanine product generated and then could be purified readily by column chromatography. The newly prepared phthalocyanine has been characterized by a series of spectroscopic technique including MALDI-TOF mass, NMR, electronic absorption and IR spectroscopy in addition to elemental analysis. In addition, their electrochemical properties have also been studied by cyclic voltammetry measurement.

Effects of Menthol-Containing Artificial Tears on Tear Stimulation and Ocular Surface Integrity in Normal and Dry Eye Rat Models

ABSTRACTPurpose: To evaluate the effects of menthol-containing artificial tears on tear stimulation and ocular surface integrity in normal and dry eye rat models.Methods: A total of 54 male Lewis rats were used. The levels of tear secretion and tear MUC5AC concentrations were compared between the menthol-containing artificial tear-treated group (menthol group) and the vehicle-treated group (vehicle group). The groups were compared after a single instillation to evaluate the immediate effects, and after repeated instillation (five times a day for 5 days) to evaluate the longer-term effects. Tear lactate dehydrogenase (LDH) activity was measured to evaluate eye drop instillation-induced ocular surface damage. The effects of menthol-containing artificial tears were also evaluated in a dry eye rat model.Results: After a single instillation of menthol-containing artificial tears, tear secretion increased from 4.37 (±0.75) mm at baseline to 7.37 (±1.60) mm. However, after repeated instillations, the effects of tear stimulation decreased. The tear MUC5AC concentration was significantly lower in the menthol group than in the vehicle group after a single instillation, but not after repeated instillation. However, the tear LDH concentration was significantly increased in the menthol group after repeated instillation. In the dry eye rat model, the extent of menthol-induced tear stimulation was reduced.Conclusions: Menthol-containing artificial tears increased tear secretion, but lowered the tear MUC5AC concentration. Menthol-induced tear stimulation was reduced after repeated instillation for 5 days and in the dry eye rat model. Conversely, repeated instillation of menthol-induced ocular surface damage, resulting in increased tear LDH activity.

Menthol enhances nicotine-induced locomotor sensitization and in vivo functional connectivity in adolescence.

Mentholated cigarettes capture a quarter of the US market, and are disproportionately smoked by adolescents. Menthol allosterically modulates nicotinic acetylcholine receptor function, but its effects on the brain and nicotine addiction are unclear. To determine if menthol is psychoactive, we assessed locomotor sensitization and brain functional connectivity. Adolescent male Sprague Dawley rats were administered nicotine (0.4 mg/kg) daily with or without menthol (0.05 mg/kg or 5.38 mg/kg) for nine days. Following each injection, distance traveled in an open field was recorded. One day after the sensitization experiment, functional connectivity was assessed in awake animals before and after drug administration using magnetic resonance imaging. Menthol (5.38 mg/kg) augmented nicotine-induced locomotor sensitization. Functional connectivity was compared in animals that had received nicotine with or without the 5.38 mg/kg dosage of menthol. Twenty-four hours into withdrawal after the last drug administration, increased functional connectivity was observed for ventral tegmental area and retrosplenial cortex with nicotine+menthol compared to nicotine-only exposure. Upon drug re-administration, the nicotine-only, but not the menthol groups, exhibited altered functional connectivity of the dorsal striatum with the amygdala. Menthol, when administered with nicotine, showed evidence of psychoactive properties by affecting brain activity and behavior compared to nicotine administration alone.

Comparison of the Effect of Topical Application of Rosemary and Menthol for Musculoskeletal Pain in Hemodialysis Patients.

Background:Pain is the most common problem experienced by hemodialysis patients, especially musculoskeletal pain in lower extremities, which is usually not completely treated and adversely affects their quality of life. The present study was conducted with the aim to determine and compare the effects of topical application of menthol and rosemary for musculoskeletal pain in hemodialysis patients.Materials and Methods:The present single-blind clinical trial recruited 105 eligible patients undergoing hemodialysis in selected hospitals affiliated to Isfahan University of Medical Sciences; patients were selected by convenient sampling. Participants’ severity of pain was determined prior to intervention. They were then randomly divided into rosemary, menthol, and placebo groups. All three groups applied medication on the site of pain on their legs three times a day for three days and recorded the severity of pain four hours after morning and afternoon applications. The statistical analysis of data was performed using SPSS 18.Results:The mean score of severity of pain before the intervention was not significantly different among the three groups (p = 0.83), but it became significantly different after intervention (p = 0.001). Significant differences were observed in mean severity of pain before and after intervention in rosemary and menthol groups (p < 0.001), but not in the placebo group (p = 0.21).Conclusions:Topical application of menthol and rosemary can alleviate severity and frequency of recurrence of musculoskeletal pain in hemodialysis patients; however, according to the results of the study, none had precedence over the other.

Influence of puerarin, paeoniflorin, and menthol on structure and barrier function of tight junctions in MDCK and MDCK-MDR1 Cells

ObjectiveIn this study, the influence of puerarin, paeoniflorin, and menthol on the structure and barrier function of tight junctions (TJs) in Madin–Darby canine kidney epithelial (MDCK) and MDCK-multi-drug resistance 1 (MDR1) cells was evaluated to determine the mechanisms by which the drugs cross the blood–brain barrier (BBB). MethodCells were treated with puerarin, paeoniflorin, and menthol followed by immunohistochemical staining with occludin, claudin-1, and F-actin. The cells were then observed using laser-scanning confocal microscopy. Average optical density (AOD) of the immunofluorescence images of the proteins were analyzed using ImageJ software while Transepithelial electrical resistance (TEER) was measured using an epithelial voltohmmeter. ResultsConfocal microscopy revealed that puerarin- and paeoniflorin-treated tight junction proteins were conspicuous while menthol suppressed their expression. Correspondingly, AOD values of cells treated with puerarin or paeoniflorin, or both showed no difference compared to the control group (P > .05) while the menthol group value was downregulated. In 3 h, TEER of cells not treated with menthol were similar to the control group, while treatment with menthol significantly decreased TEER value (P < .05). In addition, application of menthol decreased TEER in MDCK cells earlier than in MDCK-MDR1 cells. ConclusionMenthol but not puerarin and paeoniflorin may enhance paracellular transport and improve drug penetration of the BBB by disrupting the structure and, thereby, weakening the barrier function of TJs.

Twisted baskets.

A preparative procedure for obtaining a pair of twisted molecular baskets, each comprising a chiral framework with either right ((P)-1syn) or left ((M)-1syn) sense of twist and six ester groups at the rim has been developed and optimized. The racemic (P/M)-1syn can be obtained in three synthetic steps from accessible starting materials. The resolution of (P/M)-1syn is accomplished by its transesterification with (1R,2S,5R)-(-)-menthol in the presence of a Ti(IV) catalyst to give diastereomeric 8(P) and 8(M). It was found that dendritic-like cavitands 8(P) and 8(M), in CD2Cl2, undergo self-inclusion ((1)H NMR spectroscopy) with a menthol moiety occupying the cavity of each host. Importantly, the degree of inclusion of the menthol group was ((1)H NMR spectroscopy) found to be greater in the case of 8(P) than 8(M). Accordingly, it is suggested that different folding characteristic of 8(P) and 8(M) ought to affect the physicochemical characteristics of the hosts to permit their effective separation by column chromatography. The absolute configuration of 8(P)/8(M), encompassing right- and left-handed "cups", was determined with the exciton chirality method and also verified in silico (DFT: B3LYP/TZVP). Finally, the twisted baskets are strongly fluorescent due to three naphthalene chromophores, having a high fluorescence quantum yield within the rigid framework of 8(P)/8(M).

Effects of Antagonists and Heat on TRPM8 Channel Currents in Dorsal Root Ganglion Neuron Activated by Nociceptive Cold Stress and Menthol

Transient receptor potential ion channel melastatin subtype 8 (TRPM8) is activated by cold temperature and cooling agents, such as menthol and icilin. Compounds containing peppermint are reported to reduce symptoms of environmental cold stress such as cold allodynia in dorsal root ganglion (DRG) neuron; however, the underlying mechanisms of action are unclear. We tested the effects of physiological heat (37°C), anthralic acid (ACA and 0.025 mM), 2-aminoethyl diphenylborinate (2-APB and 0.05) on noxious cold (10°C) and menthol (0.1 mM)-induced TRPM8 cation channel currents in the DRG neurons of rats. DRG neurons were freshly isolated from rats. In whole-cell patch clamp experiments, TRPM8 currents were consistently induced by noxious cold or menthol. TRPM8 channels current densities of the neurons were higher in cold and menthol groups than in control. When the physiological heat is introduced by chamber TRPM8 channel currents were inhibited by the heat. Noxious cold-induced Ca(2+) gates were blocked by the ACA although menthol-induced TRPM8 currents were not blocked by ACA and 2-APB. In conclusion, the results suggested that activation of TRPM8 either by menthol or nociceptive cold can activate TRPM8 channels although we observed the protective role of heat, ACA and 2-APB through a TRPM8 channel in nociceptive cold-activated DRG neurons. Since cold allodynia is a common feature of neuropathic pain and diseases of sensory neuron, our findings are relevant to the etiology of neuropathology in DRG neurons.

Role of menthol in treatment of candidial napkin dermatitis

The antibacterial, antifungal and probable anti-inflammatory effects of menthol were evaluated in the treatment of napkin dermatitis (ND). A pilot clinical trial was conducted in Iran at the Tehran University of Medical Sciences. Eligible neonates with a diagnosis of candidial ND who did not require critical care or systematic antifungal and anti-inflammatory drugs were included in the study. Overall, 84 patients were randomly allocated into two groups: menthol group (n=42) receiving standard therapy (topical clotrimazole) plus menthol drops applied topically and control group (n=42) receiving standard therapy plus a placebo. Thirty-five neonates in each group finished the course of study and were analyzed for skin rash using Munz and Concannon rash scoring methods before therapy and on the 1st, 3rd, 5th and 7th day after the treatments. Demographic data and the baseline total skin rash score were not significantly different between the menthol and control groups. The total course of therapy for complete healing was found to be shorter in the menthol group (4.3±1.6 vs. 6.9±1.8 days, P=0.0001) and erythema and pustules had a significant (P=0.0001) relief in this group. During the study no severe adverse effects of the drug were observed. Topical application of menthol may be effective in treatment of candidial ND.