While the involvement of thermosensitive transient receptor potential channels (TRPs) in dry eye disease (DED) has been known for years, their expression in the meibomian gland (MG) has never been investigated. This study aims to show their expression and involvement in the lipogenesis of the MG, providing a possible new drug target in the treatment of DED. Our RT-PCR, Western blot and immunofluorescence analysis showed the expression of TRPV1, TRPV3, TRPV4 and TRPM8 in the MG at the gene and the protein level. RT-PCR also showed gene expression of TRPV2 but not TRPA1. Calcium imaging and planar patch-clamping performed on an immortalized human meibomian gland epithelial cell line (hMGECs) demonstrated increasing whole-cell currents after the application of capsaicin (TRPV1) or icilin (TRPM8). Decreasing whole-cell currents could be registered after the application of AMG9810 (TRPV1) or AMTB (TRPM8). Oil red O staining on hMGECs showed an increase in lipid expression after TRPV1 activation and a decrease after TRPM8 activation. We conclude that thermo-TRPs are expressed at the gene and the protein level in MGs. Moreover, TRPV1 and TRPM8\'s functional expression and their contribution to their lipid expression could be demonstrated. Therefore, TRPs are potential drug targets and their clinical relevance in the therapy of meibomian gland dysfunction requires further investigation.

Temperature-sensitive ion channels, such as those from the TRP family (thermo-TRPs) present in all animal cells, serve to perceive heat and cold sensations. A considerable number of protein structures have been reported for these ion channels, providing a solid basis for revealing their structure-function relationship. Previous functional studies suggest that the thermosensing ability of TRP channels is primarily determined by the properties of their cytosolic domain. Despite their importance in sensing and wide interests in the development of suitable therapeutics, the precise mechanisms underlying acute and steep temperature-mediated channel gating remain enigmatic. Here, we propose a model in which the thermo-TRP channels directly sense external temperature through the formation and dissociation of metastable cytoplasmic domains. An open-close bistable system is described in the framework of equilibrium thermodynamics, and the middle-point temperature T½ similar to the V½ parameter for a voltage-gating channel is defined. Based on the relationship between channel opening probability and temperature, we estimate the change in entropy and enthalpy during the conformational change for a typical thermosensitive channel. Our model is able to accurately reproduce the steep activation phase in experimentally determined thermal-channel opening curves, and thus should greatly facilitate future experimental verification.

Despite the very large number of phytocannabinoids isolated from Cannabis (Cannabis sativa L.), bioactivity studies have long remained focused on the so called \"Big Four\" [Δ9-THC (1), CBD (2), CBG (3) and CBC (4)] because of their earlier characterization and relatively easy availability via isolation and/or synthesis. Bioactivity information on the chemical space associated with the remaining part of the cannabinome, a set of ca 150 compounds traditionally referred to as \"minor phytocannabinoids\", is scarce and patchy, yet promising in terms of pharmacological potential. According to their advancement stage, we sorted the bioactivity data available on these compounds, better referred to as the \"dark cannabinome\", into categories: discovery (in vitro phenotypical and biochemical assays), preclinical (animal models), and clinical. Strategies to overcome the availability issues associated with minor phytocannabinoids are discussed, as well as the still unmet challenges facing their development as mainstream drugs.

Transient receptor potential (TRP) channels, which can sense temperature, pressure and mechanical stimuli, were involved in many physiological and biochemical reactions. Whether thermosensitive TRP channels (Thermo-TRPs) are involved in thermoregulation in small mammals is still not clear. We measured the changes of thermo-TRPs at 4 °C, 23 °C and 30 °C in Brandt\'s voles (Lasiopodomys brandtii) to test the hypothesis that Thermo-TRPs are involved in cold-induced thermogenesis of brown adipose tissue (BAT) in small mammals. Results showed that air temperatures had no effect on body mass and rectal temperature, but the food intake and basal metabolic rate (BMR) in the 4 °C group were significantly higher than in the 30 °C group. Compared with 30 °C group, the protein contents of uncoupling protein 1(UCP1), TRP vanilloid 2 (TRPV2), TRP ankyrin 1 (TRPA1), TRP melastatin 2 (TRPM2), silent Information Regulator T1 (SIRT1), AMP-activated protein kinase (AMPK) and Calcium/calmodulin-dependent protein kinase II (CaMKII) in BAT increased significantly in 4 °C group, but there was no significant difference in the protein content of Thermo-TRPs in the hypothalamus among groups. Further, the expression of PRDM16 (PR domain containing 16) in inguinal white adipose tissue (iWAT) at 4 °C was significantly higher than that at 30 °C, but no difference was observed in the expression of other browning-related genes or TRPV2. In conclusion, TRP channels may participate in BAT thermoregulation through the CaMKII, AMPK, SIRT1 and UCP1 pathway in cold-acclimated Brandt\'s voles.

The ability to sense temperature changes is crucial for mammalian survival. Mammalian thermal sensing is primarily carried out by thermosensitive transient receptor potential channels (Thermo-TRPs). Some mammals hibernate to survive cold winter conditions, during which time their body temperature fluctuates dramatically. However, the underlying mechanisms by which these mammals regulate thermal responses remain unclear. Using quantitative real-time polymerase chain reaction (qRT-PCR) and the Western blotting, we found that Myotis ricketti bats had high levels of heat-activated TRPs (e.g., TRPV1 and TRPV4) during torpor in winter and cold-activated TRPs (e.g., TRPM8 and TRPC5) during active states in summer. We also found that laboratory mice had high mRNA levels of cold-activated TRPs (e.g., Trpm8 and Trpc5) under relatively hot conditions (i.e., 40 °C). These data suggest that small mammals up-regulate the expression of cold-activated TRPs even under warm or hot conditions. Binding site analysis showed that some homeobox (HOX) transcription factors (TFs) regulate the expression of hot- and cold-activated TRP genes and that some TFs of the Pit-Oct-Unc (POU) family regulate warm-sensitive and cold-activated TRP genes. The dual-luciferase reporter assay results demonstrated that TFs HOXA9, POU3F1, and POU5F1 regulate TRPC5 expression, suggesting that Thermo-TRP genes are regulated by multiple TFs of the HOX and POU families at different levels. This study provides insights into the adaptive mechanisms underlying thermal sensing used by bats to survive hibernation.
感知温度变化的能力对哺乳动物的生存至关重要。哺乳动物主要是通过温度敏感型瞬时受体电位通道（Thermosensitive transient receptor potential channels, Thermo-TRPs）感应温度变化。一些哺乳类动物为了度过寒冷的冬季并存活下来会进入冬眠状态，在此期间它们的体温有剧烈波动；然而，这些哺乳动物具有哪些潜在的温度感受（thermal response）调节机制还不清楚。我们运用实时荧光聚合酶链式反应和蛋白质免疫印记等方法，发现大足鼠耳蝠（ Myotis ricketti） 在冬季蛰伏期会高表达热激活通道TRPs（例如TRPV1和TRPV4），而在夏季活跃期则高表达冷激活TRPs（例如，TRPM8和TRPC5）。我们也发现小鼠在温度相对较高的条件（40 oC）下，会高表达冷激活TRPs（例如 Trpm8 和 Trpc5 ）。这些结果提示，小型哺乳动物在温暖或较热的状况下，会上调表达冷激活TRPs。通过结合位点分析，我们发现一些同源异型盒（HOX）转录因子（Transcription factor, TF）可以调节热激活和冷激活TRPs基因的表达，而POU（Pit-Oct-Unc）家族的一些转录因子则调节温热敏感和冷激活TRPs基因的表达。双荧光素酶报告基因检测结果表明，转录因子HOXA9，POU3F1和POU5F1调节 TRPC5 的表达，可见Thermo-TRPs基因是受到HOX和POU家族中多个转录因子在不同水平上的调控。这项研究揭示蝙蝠为了在冬眠中存活下来，而采取的温度感觉适应机制。.

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It is believed that the biological systems perceiving temperature and light daily cycles were subjected to the simultaneous selective pressures, which resulted in their co-evolutionary association. We investigated the influence of 1h 33°C heat shock on the expression of clock and heat shock protein genes, as well as the role of the thermo-TRP channel, TRPV1, in ZEM-2S cells of the teleost Danio rerio, in constant dark (DD) or light-dark cycles (LD). After heat shock, we observed an acute increase of hsp90 aa1 levels in both DD and LD conditions. Interestingly, the expression of hsp90 aa1 was two-fold lower in LD than in DD, what suggests an antagonistic effect of white light on heat shock action. Regarding clock genes, no effect was found in cells subjected to the heat shock in DD. When cells were kept in LD, the expression of per1, per2, cry1a, and cry1b increased in response to heat shock, indicating that heat shock only affects clock core of LD-synchronized ZEM-2S cells. We then evaluated whether TRPV1 played a role in heat-mediated hsp90 aa1 and per2 responses: hsp90 aa1 increase was unaffected whereas per2 increase was partially blocked by TRPV1 inhibitor, demonstrating the channel participation in clock gene regulation by heat shock. Taken together, our results open a novel investigative perspective regarding the relationship between temperature and clock genes, placing a new player in the regulation of this phenomenon: the TRPV1 channel.