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The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca2+)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring C-terminal amides and diversely substituted N′-terminal monobenzyl groups in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca2+ entry, thereby establishing critical structure–activity relationships. While the substitution of the tert-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the N′-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the transient receptor potential (TRP) ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein. While the four main populated poses are located by the pore zone, a similar location to that described for the N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist cannot be discarded. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin (OXA). [ABSTRACT FROM AUTHOR]

The history of discovery by Rosetta Reusch of oligo‐ and poly‐β‐hydroxybutyrates (OHBs and PHBs) consisting of less than ca. 150 HB units is described. These 'short‐chain' biopolymers can be detected in all living organisms and have numerous physiological activities of fundamental importance for the chemistry of life. The largest are components of ion channels such as Ca2+‐polyphosphate‐PHB (Ca‐PPi‐PHB) in genetically competent E. coli and in mammalian mitochondria. Sequences with chain lengths < ca. 30 occur covalently attached to proteins (post‐translational PHBylation), and methyl esters of the dimer and trimer are used by certain bacteria as highly efficient antioxidants. With synthetic monodisperse OHBs (up to 128mer) our group has contributed structural investigations, and we have shown that OHBs≥16 alone make phospholipid bilayer vesicles permeable to Ca ions. An extensive biochemical analysis of the TRPM8 protein channel, responsible for the sense of heat in our skin, proved to be fully active only when PHBylated. Reasons for the difficulty of detecting OHBs and PHBs are discussed: the polyester chain is highly flexible, and there is ester cleavage by base, acid, nucleophiles, Lewis acids, and heat – in stark contrast to peptides. PHBs may be called a ubiquitous but fleeting species in the chemistry of life – worth being appreciated and studied much more intensively in the future! A speculation about PHB's possible role in prebiotic compartmentalization is presented, and recent uses of compartmentalization in organic synthesis are briefly mentioned. Portions of the figures used herein were presented in a lecture at the International Symposium on Biopolymers on September 13, 2022, in Sion (Switzerland). [ABSTRACT FROM AUTHOR]

Functional biomechanical parameters of muscle soleus contraction in rats as well as selected blood biochemical parameters were studied during the first 3 days of post-traumatic syndrome progression caused by the destruction of muscle cells by compression. Single administration of the antioxidant C60 fullerene and the selective agonist of TRPM8 channels menthol were used as therapeutic agents. Injection of C60 fullerene at a concentration of 1 mg/kg into the damaged muscle improved its contractile function by 25–28%. The use of combined injections of C60 fullerene and menthol (at the concentration 1 mg/kg) improved this index by additional 27–39% and simultaneously stabilized the decrease in muscle strength observed throughout the experiment. A tendency towards a decrease in the indexes of the above described biochemical parameters by 10–15% were found with the therapeutic administration of C60 fullerene. With combined injections of C60 fullerene and menthol, the above described biochemical parameters decreased by an additional 17–24%. The synergism between the action of menthol and C60 fullerene on the post-traumatic recovery of skeletal muscle function opens up new perspectives for the clinical application of this combination therapy. [ABSTRACT FROM AUTHOR]

Aims: The transient receptor potential melastin‐8 (TRPM8) channel is a "cooling" receptor expressed in primary sensory neurons and can be activated by compounds like menthol or icilin. TRPM8 is involved in the regulation of urinary bladder sensory function and contraction, but the role of TRPM8 in the ureter, particularly in the human ureter, is poorly understood. The aim of this study is to examine the effects of TRPM8 activation on human ureter contraction. Methods: Human ureters were acquired from 20 patients undergoing radical nephrectomy. Contractions of ureter strips were recorded by an isometric transducer in the organ bath. Ureteral TRPM8 expression in the human ureter was examined by immunofluorescence and western blot. Results: The two TRPM8 agonists menthol and icilin both reduced the frequency of spontaneous, electrical field stimulation, or neurokinin A‐evoked ureteral contractions in a dose‐dependent manner. The inhibitory effects were decreased by 10‐fold in mucosa‐denuded strips. The inhibitory effects of TRPM8 agonists were mimicked by calcitonin gene‐related peptide (CGRP), and were blocked by KRP2579 (a TRPM8 antagonist), tetrodotoxin (a sodium channel blocker), olcegepant (BIBN, a CGRP receptor antagonist), SQ22536 (an adenylate cyclase antagonist), or H89 (a nonspecific cAMP‐dependent protein kinase A inhibitor). TRPM8 was coexpressed with CGRP on the nerves located in the suburothelial and intermuscular regions and was not expressed in the urothelium. Conclusions: The TRPM8 channel expressed on sensory nerve terminals of the human ureter is involved in the inhibitory sensory neurotransmission and modulate ureter contraction via the CGRP–adenylyl cyclase–protein kinase A pathway. TRPM8 may be involved in stone‐induced changes in ureter contraction or pain. [ABSTRACT FROM AUTHOR]

Various families of ion channels have been characterized in mesenchymal stem cells (MSCs), including some members of transient receptor potential (TRP) channels family. TRP channels are involved in critical cellular processes as differentiation and cell proliferation. Here, we analyzed the expression of TRPM8 channel in human bone marrow MSCs (hBM-MSCs), and its relation with osteogenic differentiation. Patch-clamp recordings showed that hBM-MSCs expressed outwardly rectifying currents which were increased by exposure to 500 μM menthol and were partially inhibited by 10 μM of BCTC, a TRPM8 channels antagonist. Additionally, we have found the expression of TRPM8 by RT-PCR and western blot. We also explored the TRPM8 localization in hBM-MSCs by immunofluorescence using confocal microscopy. Remarkably, hBM-MSCs treatment with 100 μM of menthol or 10 μM of icilin, TRPM8 agonists, increases osteogenic differentiation. Conversely, 20 μM of BCTC, induced a decrease of osteogenic differentiation. These results suggest that TRPM8 channels are functionally active in hBM-MSCs and have a role in cell differentiation.

Abstract Transient receptor potential (TRP) channels are a family of non-selective cation channels that are functionally expressed in various organs and cells. Among them, transient receptor potential vanilloid (TRPV) 1 and TRPV4 channels are expressed in T cells, where they serve as Ca2+ channels for T-cell receptor signaling [Bertin et al., 2014, Majhi et al., 2015]. Here, we show that not only TRPV1 and TRPV4 channel inhibitors, but also a transient receptor potential melastatin (TRPM) 8 channel inhibitor can suppress murine T-cell activation. Mouse splenic lymphocytes pretreated with N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)benzamide hydrochloride (AMTB), a TRPM8 channel-selective inhibitor, showed significantly reduced IL-2 and IL-6 release from T cells after stimulation with anti-CD3ε/anti-CD28 antibodies or concanavalin A. AMTB also suppressed IL-2 mRNA expression and activation of extracellular signal-regulated kinase 1/2, which is involved in IL-2 production. Further, the increase of CD25 (IL-2 receptor alpha chain) expression after T-cell activation was suppressed by AMTB. TRPM8 channel was expressed in CD4+ T cells isolated from splenocytes, and we confirmed that the release of IL-2 from isolated CD4+ T cells was significantly suppressed by AMTB. In vitro re-stimulation of splenocytes from external antigen-immunized mice with the same antigen induced IL-2 and IL-6 production, which was significantly suppressed by AMTB. Thus, the TRPM8 channel inhibitor AMTB suppresses T-cell activation induced by various stimulants. Highlights • We examined the effect of TRPM8 channel inhibitor on T cell activation. • TRPM8 inhibitor AMTB suppressed cytokine production in activated CD4 T cells. • AMTB suppressed increase of CD25 expression and ERK1/2 activation. • AMTB suppressed cytokine production in antigen-restimulated lymphocytes. • TRPM8 channel may be a novel therapeutic target for immune diseases. [ABSTRACT FROM AUTHOR]

1,8-Cineole is a cyclic monoterpenoid used in folk medicine for treatment of numerous respiratory diseases and other infections. 1,8-Cineole has anti-inflammatory, antioxidant, and myorelaxant effects, as well as low toxicity. In the present study, the effects of 1,8-cineole on contractility and voltage-gated calcium channels (VGCC) in tracheal smooth muscle were investigated. Intact and dissociated tracheal smooth muscle were used for muscle contraction and patch-clamp recordings, respectively. In experiments involving muscle contraction, 1,8-cineole potentiated contractions at low concentrations and relaxed contractions induced by isotonic K+ at high concentrations. AMTB (a TRPM8 channel blocker) reduced the potentiation induced by 1,8-cineole while indomethacin (a COX inhibitor) did not block this effect. In dissociated myocytes, 1,8-cineole partially blocked Ba2+ currents through VGCC in a concentration-dependent manner. 1,8-Cineole shifted the steady-state activation and inactivation curves to the left and also reduced the current decay time constant. In conclusion, 1,8-cineole has a dual effect on tracheal smooth muscle contraction resulting in a biphasic effect. Our data suggest that the potentiation effect is mediated by activation of TRPM8 channels and the relaxation effect is mediated by the blockage of L-type VGCC. [ABSTRACT FROM AUTHOR]

Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an animal model of complex regional pain syndrome-type I, and its underlying mechanisms. Chronic post-ischemia pain (CPIP) was induced by ischemia and reperfusion (IR) injury of the left hind paw. Our findings showed that simvastatin inhibited mechanical hyperalgesia induced by CPIP model in single and repeated treatment schedules, respectively; however simvastatin did not alter inflammatory signs during CPIP model. The mechanisms underlying those actions are related to modulation of transient receptor potential (TRP) channels, especially TRMP8. Moreover, simvastatin oral treatment was able to reduce the nociception induced by acidified saline [an acid-sensing ion channels (ASICs) activator] and bradykinin (BK) stimulus, but not by TRPA1, TRPV1 or prostaglandin-E2 (PGE2). Relevantly, the antinociceptive effects of simvastatin did not seem to be associated with modulation of the descending pain circuits, especially noradrenergic, serotoninergic and dopaminergic systems. These results indicate that simvastatin consistently inhibits mechanical hyperalgesia during neuropathic and inflammatory disorders, possibly by modulating the ascending pain signaling (TRPM8/ASIC/BK pathways expressed in the primary sensory neuron). Thus, simvastatin open-up new standpoint in the development of innovative analgesic drugs for treatment of persistent pain, including CRPS-I.

Transient receptor potential (TRP) channels are known to regulate energy metabolism, and TRPM8 has become an interesting player in this context. Here we demonstrate the role of the cold sensor TRPM8 in the regulation of clock gene and clock controlled genes in brown adipose tissue (BAT). We investigated TrpM8 temporal profile in the eyes, suprachiasmatic nucleus and BAT; only BAT showed temporal variation of TrpM8 transcripts. Eyes from mice lacking TRPM8 lost the temporal profile of Per1 in LD cycle. This alteration in the ocular circadian physiology may explain the delay in the onset of locomotor activity in response to light pulse, as compared to wild type animals (WT). Brown adipocytes from TrpM8 KO mice exhibited a larger multilocularity in comparison to WT or TrpV1 KO mice. In addition, Ucp1 and UCP1 expression was significantly reduced in TrpM8 KO mice in comparison to WT mice. Regarding circadian components, the expression of Per1, Per2, Bmal1, Pparα, and Pparβ oscillated in WT mice kept in LD, whereas in the absence of TRPM8 the expression of clock genes was reduced in amplitude and lack temporal oscillation. Thus, our results reveal new roles for TRPM8 channel: it participates in the regulation of clock and clock-controlled genes in the eyes and BAT, and in BAT thermogenesis. Since disruption of the clock machinery has been associated with many metabolic disorders, the pharmacological modulation of TRPM8 channel may become a promising therapeutic target to counterbalance weight gain, through increased thermogenesis, energy expenditure, and clock gene activation. [ABSTRACT FROM AUTHOR]

Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an animal model of complex regional pain syndrome-type I, and its underlying mechanisms. Chronic post-ischemia pain (CPIP) was induced by ischemia and reperfusion (IR) injury of the left hind paw. Our findings showed that simvastatin inhibited mechanical hyperalgesia induced by CPIP model in single and repeated treatment schedules, respectively; however simvastatin did not alter inflammatory signs during CPIP model. The mechanisms underlying those actions are related to modulation of transient receptor potential (TRP) channels, especially TRMP8. Moreover, simvastatin oral treatment was able to reduce the nociception induced by acidified saline [an acid-sensing ion channels (ASICs) activator] and bradykinin (BK) stimulus, but not by TRPA1, TRPV1 or prostaglandin-E2 (PGE2). Relevantly, the antinociceptive effects of simvastatin did not seem to be associated with modulation of the descending pain circuits, especially noradrenergic, serotoninergic and dopaminergic systems. These results indicate that simvastatin consistently inhibits mechanical hyperalgesia during neuropathic and inflammatory disorders, possibly by modulating the ascending pain signaling (TRPM8/ASIC/BK pathways expressed in the primary sensory neuron). Thus, simvastatin open-up new standpoint in the development of innovative analgesic drugs for treatment of persistent pain, including CRPS-I. [ABSTRACT FROM AUTHOR]

Menthol is a naturally occurring terpene used as a penetration enhancer in topical and transdermal formulations. Literature shows a growing interest in menthol’s interactions with the transient receptor potential melastatin 8. A decrease in extracellular Ca 2+ due to the activation of the transient receptor potential melastatin 8 receptor produces inhibition of E-cadherin expression that is responsible for cell-cell adhesion. Because calcium is present in the entire epidermis, the purpose of this study is to evaluate whether the aforementioned properties of menthol are also related to its penetration-enhancing effects. We formulated 16 gels: (i) drug-alone (diphenhydramine or lidocaine), (ii) drug with menthol, (iii) drug, menthol, and calcium channel blocker (CCB; verapamil or diltiazem), and (iv) drug and CCB. In vitro studies showed no effect of the CCB on the release of the drugs either with or without menthol . In vivo experiments were performed for each drug/menthol/CCB combination gel by applying 4 formulations on a shaved rabbit’s dorsum on the same day. Dermis concentration profiles were assessed with microdialysis. The gels containing menthol showed higher penetration of drugs than those without whereas the addition of the CCB consistently inhibited the penetration-enhancing effects of menthol. In summary, these findings strongly support the involvement of calcium in the penetration-enhancing effect of menthol. [ABSTRACT FROM AUTHOR]

Purpose:Facilitatory and inhibitory responses of spinal motor neurons are influenced by somatosensory input from the skin. The purpose of this study, employing electromyography, was to examine the neuromuscular changes that occur with menthol applied to the skin over the quadriceps muscle. Methods:Forty-two healthy volunteers performed isometric knee extensions at 35% maximum voluntary contraction (MVC) in three groups (Adult Placebo, Adult Menthol, Older Adult Menthol). Stimulation used was application of 5% menthol gel to the skin. Surface electromyography (sEMG) from the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF) was recorded using miniature pair electrodes. Results:Root mean square electromyography (rmsEMG) in VL and VM significantly increased with menthol stimulation both in Adult and Older Adult, but no significant difference was observed between Adult Menthol and Older Adult Menthol. There was a significant decrease in mean power frequency (MPF) in VM with menthol stimulation in Older Adult, but no significant changes were observed in Adult Menthol. Conclusion:Neuromuscular modulation was observed with the application of menthol gel at low loads in the present study. These findings could lead to a new method of muscular training that targets the recruitment of fast type muscle safe for older adults. [ABSTRACT FROM AUTHOR]

Objective To evaluate the role of the transient receptor potential melastatin 8 ( TRPM8) channel on bladder mechanosensory function by using L-menthol, a TRPM8 agonist, and RQ-00203078 ( RQ), a selective TRPM8 antagonist. Materials and methods Female Sprague-Dawley rats were used. In conscious cystometry ( CMG), the effects of intravesical instillation of L-menthol (3 m m) were recorded after intravenous (i.v.) pretreatment with RQ (3 mg/kg) or vehicle. The direct effects of RQ on conscious CMG and deep body temperature were evaluated with cumulative i.v. administrations of RQ at 0.3, 1, and 3 mg/kg. Single-unit mechanosensitive bladder afferent activities ( SAAs) were monitored in a newly established ex vivo rat bladder model to avoid systemic influences of the drugs. Recordings were performed after cumulative intra-aortic administration of RQ (0.3 and 3 mg/kg) with or without intra-vesical L-menthol instillation (3 m m). Results Intravesical L-menthol decreased bladder capacity and voided volume, which was counteracted by RQ-pretreatment. RQ itself increased bladder capacity and voided volume, and lowered deep body temperature in a dose-dependent manner. RQ decreased mechanosensitive SAAs of C-fibres, and inhibited the activation of SAAs induced by intravesical L-menthol. Conclusion Our results suggest that TRPM8 channels have a role in activation of bladder afferent pathways during filling of the bladder in the normal rat. This effect seems, at least partly, to be mediated via mechanosensitive C-fibres. [ABSTRACT FROM AUTHOR]

Both spinal and trigeminal somatosensory systems use the TRPM8 channel as a principal transducer for detecting cold stimuli. It is currently unclear whether this cold transducer may play a role in trigeminal neuropathic pain manifesting cold allodynia and hyperalgesia. In the present study, trigeminal neuropathy was induced by chronic constrictive nerve injury of the infraorbital nerve (ION-CCI). Behavioral responses to cold stimuli in orofacial regions were assessed by the newly developed orofacial operant test in the ION-CCI rats. We tested menthol and capsazepine, two compounds that can activate and inhibit TRPM8 respectively, on orofacial operant responses to cold stimuli in ION-CCI rats. Testing animals performed operant tasks by voluntarily contacting their orofacial regions to a cold stimulation module in order to access sweetened milk as a reward, and contact time and number of the operant behaviors were automatically recorded. Total contact time was significantly reduced at the cooling temperatures of 17°C and 12°C in ION-CCI group in comparison with sham group, indicating the presence of cold allodynia and hyperalgesia in ION-CCI rats. When menthol was administered to ION-CCI rats, total contact time was further reduced and total contact number increased at the cooling temperatures. In contrast, after administration of capsazepine to ION-CCI rats, total contact time was significantly increased at the cooling temperatures. The behavioral outcomes support the idea that TRPM8 plays a role in cold allodynia and hyperalgesia following chronic trigeminal nerve injury. [ABSTRACT FROM AUTHOR]

Aims We determined if THC-002, a galenical produced from Ba-Wei-Die-Huang-Wan, could increase skin temperature and inhibit detrusor overactivity induced by sudden whole body cooling. Further, we determined if THC-002 could decrease expression of transient receptor potential melastatin 8 (TRPM8) channels associated with the cold responses. Methods Hind leg skin temperature of female 10-week-old Sprague-Dawley rats was measured by thermal imaging. Experimental rats (n = 12) were given oral 100 mg/kg THC-002 daily for one week, and controls (n = 12) were similarly treated with THC-002-free solution. Afterwards, thermal imaging and cystometric investigations of the freely moving conscious rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then transferred to a low temperature (LT, 4 ± 2°C) environment during which thermal imaging and cystometric measurements were taken at 5, 10, 20, 30, and 40 min. Afterward, the skin tissues were harvested to estimate expression levels of TRPM8 channels by immunohistochemistry and real-time reverse-transcription polymerase chain reaction. Results The RT skin temperature of THC-002-treated rats was significantly higher than controls. During the first 20 min under LT, the control rats exhibited cold stress-induced detrusor overactivity such as decreased voiding interval and bladder capacity. THC-002 partially inhibited the detrusor overactivity patterns. During the second 20 min, skin temperature was relatively stable, and the detrusor overactivity of both groups slowly disappeared. THC-002 significantly reduced expression of TRPM8 channel protein and mRNA. Conclusions THC-002 inhibited cold stress-induced detrusor overactivity resulting from decreasing skin temperature. Therefore, THC-002 might provide resistance to cold stress-exacerbated lower urinary tract symptoms. Neurourol. Urodynam. 32: 486-492, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Transient receptor potential (TRP) vanilloid-1 (TRPV1) and melastatin-8 (TRPM8) channels play a role in transmitting sensory information in primary-afferent neurons. TRPV1 agonists at high concentrations inhibit action potential conduction in the neurons and thus have a local anesthetic effect. The purpose of the present study was to know whether TRPM8 agonist menthol at high concentrations has a similar action and if so whether there is a structure–activity relationship among menthol-related chemicals. Main methods: Compound action potentials (CAPs) were recorded from the frog sciatic nerve by using the air-gap method. Key findings: (−)-Menthol and (+)-menthol concentration-dependently reduced CAP peak amplitude with the IC50 values of 1.1 and 0.93mM, respectively. This (−)-menthol activity was resistant to non-selective TRP antagonist ruthenium red; TRPM8 agonist icilin did not affect CAPs, indicating no involvements of TRPM8 channels. p-Menthane, (+)-limonene and menthyl chloride at 7–10mM minimally affected CAPs. On the other hand, (−)-menthone, (+)-menthone, (−)-carvone, (+)-carvone and (−)-carveol (in each of which chemicals :glyph name="dbnd" />O group was added to p-menthane and limonene) and (+)-pulegone inhibited CAPs with extents similar to that of menthol. 1,8-Cineole and 1,4-cineole were less effective while thymol and carvacrol were more effective than menthol in inhibiting CAPs. Significance: Menthol-related chemicals inhibited CAPs and were thus suggested to exhibit local anesthetic effects comparable to those of lidocaine and cocaine as reported previously for frog CAPs. This result may provide information to develop local anesthetics on the basis of the chemical structure of menthol. [Copyright &y& Elsevier]

Abstract: The TRPM8 cation channel belongs to the superfamily of transient receptor potential (TRP) channels. It is involved in non-painful cool sensation and triggered by diverse chemical and physical stimuli whose precise activation mechanism is still unknown. The study presents a set of targeted molecular dynamics (MD) simulations involving selected complexes of the TRPM8 channel whose homology model was recently generated by some of us. More in detail, the MD simulations concerned the TRPM8 alone and in complex with agonists and antagonists. These simulations were focused on voltage sensor module and designed to validate the ligand induced activation mechanism as hypothesized in our previous study. The obtained results are in encouraging agreement with the proposed mechanism and allow a clear discrimination between agonists and antagonists. In addition, the MD runs confirm that the agonist binding triggers a set of concatenate conformational shifts which induce the approaching of the S3 segment toward the S4 segment and culminate in an extension of the latter. By introducing suitable constraints, the reported MD simulations were rendered as fast as possible in order to achieve a truly productive compromise between reliability and computational costs. The obtained results emphasize that suitably targeted MD runs can be fast enough to be systematically applied to predict the bioactivity of large datasets providing it as an useful tool in rational ligand design process. [Copyright &y& Elsevier]

Accumulating evidences have indicated that disturbances in intracellular free calcium ([Ca2+]i) concentration play an important role in the pathophysiology of prostate cancers. Ca2+ passes cell membrane via different channels such as chemical and voltage gated channels. Apart from the well-known cation channels, there is recently discovered channels namely transient receptor potential (TRP) family. One member of the TRP superfamily is TRP melastatin 8 (TRPM8). The Na+ and Ca2+-permeable TRPM8 channels can be gated by different stimuli including cold and menthol. In etiology of prostate cancer, excessive Ca2+ entry and oxidative stress have important role (Grolez and Gkika, 206). Considering that TRPM8 is activated by menthol, mediated cell death and proliferation, and is highly expressed in the plasmalemma of epithelial cells, androgen-dependent extracapsular prostate cancers and androgen-dependent metastasis (Bidaux et al. 2016). Recently, we found that oxidative stress and ADPRibose (ADPR) treatments could induce the TRPM8 activations resulting in the overload Ca2+ entry, apoptosis, and mitochondrial oxidative stress. More importantly, we found that GSH could protect the Du 145 prostate cancer cells from oxidative stress-induced apoptosis via maintaining the intracellular Ca2+ hemostasis as well as down-regulating mitochondrial oxidative stress pathway (Unpublished data) I concluded that the oxidative dysfunction of TRPM8 causes changes through activation of second messengers, which may lead to the pathology of prostate cancer. It seems to that the exact relationship between TRPM8 channels activation and prostate cancers still remain to be determined. [ABSTRACT FROM AUTHOR]

Various families of ion channels have been characterized in mesenchymal stem cells (MSCs), including some members of transient receptor potential (TRP) channels family. TRP channels are involved in critical cellular processes as differentiation and cell proliferation. Here, we analyzed the expression of TRPM8 channel in human bone marrow MSCs (hBM-MSCs), and its relation with osteogenic differentiation. Patch-clamp recordings showed that hBM-MSCs expressed outwardly rectifying currents which were increased by exposure to 500 μM menthol and were partially inhibited by 10 μM of BCTC, a TRPM8 channels antagonist. Additionally, we have found the expression of TRPM8 by RT-PCR and western blot. We also explored the TRPM8 localization in hBM-MSCs by immunofluorescence using confocal microscopy. Remarkably, hBM-MSCs treatment with 100 μM of menthol or 10 μM of icilin, TRPM8 agonists, increases osteogenic differentiation. Conversely, 20 μM of BCTC, induced a decrease of osteogenic differentiation. These results suggest that TRPM8 channels are functionally active in hBM-MSCs and have a role in cell differentiation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Henao, Grismaldo, Barreto, Rodríguez-Pardo, Mejía-Cruz, Leal-Garcia, Pérez-Núñez, Rojas, Latorre, Carvacho and Torres.)

Search for plant medicines is very old and still an important source for new lead drugs (Harvey et al., 2015). Volatile oils of medicinal plants are traditionally used since antiquity for diseases including pain but their effects on TRP cation channels as a mechanism of action is has not been clarified yet. Borneol is one of the naturally occurring volatile compounds of medicinal plants ethnomedically used against pain at the East Mediterranean countries (Aydin et al. 1996). The involvement of TRP cation channels as the mechanism of action of borneol was reported recently (Wang et al. 2017). The aim of this study was to investigate the analgesic actions of (+)-borneol in mice. (+)-Borneol was commercially obtained and it was diluted in DMSO (100 mg/kg). Mechanical and thermal algesic stimuli were used in experiments. Application of a bulldog clamp on the tail of albino mice of both sex was used for mechanical algesic stimulus and 52oC water for thermal algesia. Cutoff time was 15 sec and the following formula was used to calculate percent analgesia. R programming packages were used for statistical evaluation and plotting. % analgesia=(post drug latency - prodrug latency) /(cutoff time - prodrug latency)*100 Analgesic action of borneol was observed against mechanical algesia but not against thermal algesic stimulus. In conclusion, borneol is a bicyclic oxygenated small compound substituted with dimethyl and hydroxyl groups with actions on TRPM8. The effects on mechanical but not thermal algesia suggest the presence of interactions between borneol and TRP channels and the interactions should be discovered by future studies. [ABSTRACT FROM AUTHOR]