Search Results (19)

Background/Objectives: Capsaicin is the principal pungent compound in chili peppers and is increasingly recognized as a multifunctional phytochemical with systemic effects beyond its sensory properties. It has been linked to metabolic regulation, neuroprotection, inflammation control, and cancer modulation. This review aims to provide an integrative synthesis of capsaicin’s metabolism, its interaction with the gut microbiome, and its physiological implications across organ systems. Methods: We conducted a critical literature review of recent in vivo and in vitro studies exploring capsaicin’s metabolic fate, biotransformation by host enzymes and gut microbes, tissue distribution, and molecular pathways. The literature was analyzed thematically to cover gastrointestinal absorption, hepatic metabolism, microbiota interactions, and systemic cellular responses. Results: Capsaicin undergoes extensive hepatic metabolism, producing hydroxylated and dehydrogenated metabolites that differ in transient receptor potential vanilloid type 1 (TRPV1) receptor affinity and tissue-specific bioactivity. It crosses the blood–brain barrier, alters neurotransmitter levels, and accumulates in brain regions involved in cognition. In addition to its systemic effects, capsaicin appears to undergo microbial transformation and influences gut microbial composition, favoring short-chain fatty acid producers and suppressing pro-inflammatory taxa. These changes contribute to anti-obesity, anti-inflammatory, and potentially anticancer effects. Dose-dependent adverse outcomes, such as epithelial damage or tumor promotion, have also been observed. Conclusions: Capsaicin represents a diet-derived bioactive molecule whose systemic impact is shaped by dynamic interactions between host metabolism and the gut microbiota. Clarifying its biotransformation pathways and context-specific effects is essential for its safe and effective use in metabolic and neurological health strategies. Full article

NGF plays important roles in ocular surface homeostasis and different pathological conditions. One effect includes promoting conjunctival epithelial cell differentiation and mucin secretion. This study characterizes the individual roles of TRPV1 and TRPM8 channel activity in mediating the effects of NGF on intracellular Ca²⁺ regulation and its alteration of regulatory cell volume responses to anisosmotic challenges in human conjunctival epithelial cells (IOBA-NHC). With fura-2/AM-loaded cells, the effects of 40 µM capsaicin and 20 µM AMG 9810 on Ca²⁺ regulation confirm functional TRPV1 expression. TRPM8 expression is evident since 500 µM menthol and 20 µM AMTB have opposing effects on [Ca²⁺]_i. AMG 9810 and AMTB (both 20 µM) suppress the responses to NGF (100 ng/mL). With calcein/AM-loaded cells, the effects of these mediators are evaluated on apparent cell volume responses induced by an anisosmotic challenge. NGF decreases the apparent cell volume that AMG 9810 suppresses, whereas AMTB (both 20 µM) augments this response. Therefore, NGF interacts with TRPV1 and TRPM8 to induce opposing effects on cell volume regulatory behavior. These opposing effects suggest that the signaling pathways and effectors that mediate responses to TRPV1 and TRPM8 activation are not the same. Full article

Resiniferatoxin (RTX), a potent capsaicin analog, is being investigated as a therapeutic agent for neurogenic conditions, particularly those affecting bladder control. However, the transcriptomic effects of RTX on the urinary bladder remain largely unexplored. This study aimed to characterize the transcriptomic changes in the porcine urinary bladder trigone region removed seven days post-treatment with intravesical RTX administration (500 nmol per animal in 60 mL of 5% aqueous solution of ethyl alcohol). High-throughput sequencing identified 126 differentially expressed genes (DEGs; 66 downregulated, 60 upregulated), 5 differentially expressed long non-coding RNAs (DELs), and 22 other RNAs, collectively involved in 175 gene ontology (GO) processes. Additionally, differential alternative splicing events (DASes) and single nucleotide variants (SNVs) were detected. RTX significantly modulated signaling pathways related to nerve growth and myelination. Changes in genes associated with synaptic plasticity and neuromodulation were observed, particularly within serotoninergic and cholinergic signaling. RTX altered the expression of immune-related genes, particularly those involved in chemokine signaling and immune regulation. Notably, altered gene expression patterns suggest a potential anti-cancer role for RTX. These findings provide new insights into RTX’s therapeutic effects beyond TRPV1 receptor interactions, filling a critical gap in our understanding of its molecular impact on bladder tissue. Full article

Due to environmental pollution, unhealthy lifestyles, and autoimmunity, many individuals frequently encounter skin problems, such as sensitive skin, caused by the activation of the TRPV1 pathway and immune-inflammatory reactions. This study aims to synthesize compounds with soothing effects using β-chitooligosaccharides (COS) derived from marine Sargassum, which is investigated for its regulating inflammatory responses and activating of TRPV1 pathways. Dopamine is used as the hydroxyl donor in this process. COS-diDA, a compound that binds two dopamine amines, is synthesized using Michael additions and Schiff base reactions under alkaline circumstances, with a pH of 8.5. This work investigates the soothing effects of COS-diDA using a HaCaT cell model activated with capsaicin (CAP). ELISA and immunofluorescence experiments provide evidence that COS-diDA efficiently inhibits the activation of the TRPV1 protein in HaCaT cells by reducing its levels when stimulated with CAP. In addition, ELISA analysis demonstrates that COS-diDA reduces the secretion of IL-1α, IL-6, and IL-8 from HaCaT cells stimulated with CAP, indicating an interaction between the TRPV1 protein and interleukins. Additional research on in vitro pain models generated by CAP confirms the anti-inflammatory and soothing properties of COS-diDA. The study indicates that COS-diDA exhibits favorable adhesion qualities and possesses anti-inflammatory action, making it a viable candidate for inclusion as an anti-inflammatory component of cosmetic formulations. Full article

Cancer is a global health challenge with rising incidence and mortality rates, posing significant concerns. The World Health Organization reports cancer as a leading cause of death worldwide, contributing to nearly one in six deaths. Cancer pathogenesis involves disruptions in cellular signaling pathways, resulting in uncontrolled cell growth and metastasis. Among emerging players in cancer biology, Transient Receptor Potential (TRP) channels, notably TRPV1, have garnered attention due to their altered expression in cancer cells and roles in tumorigenesis and progression. TRPV1, also known as the capsaicin receptor, is pivotal in cancer cell death and pain mediation, offering promise as a therapeutic target. Activation of TRPV1 triggers calcium influx and affects cell signaling linked to growth and death. Additionally, TRPV1 is implicated in cancer-induced pain and chemo-sensitivity, with upregulation observed in sensory neurons innervating oral cancers. Also, when capsaicin, a compound from chili peppers, interacts with TRPV1, it elicits a “hot” sensation and influences cancer processes through calcium influx. Understanding TRPV1’s multifaceted roles in cancer may lead to novel therapeutic strategies for managing cancer-related symptoms and improving patient outcomes. The current review elucidates the comprehensive role of capsaicin in cancer therapy, particularly through the TRPV1 channel, highlighting its effects in various cells via different signaling pathways and discussing its limitations. Full article

Peripheral nerve regeneration depends on close interaction between neurons and Schwann cells (SCs). After nerve injury, SCs produce growth factors and cytokines that are crucial for axon re-growth. Previous studies revealed the supernatant of SCs exposed to nuclear magnetic resonance therapy (NMRT) treatment to increase survival and neurite formation of rat dorsal root ganglion (DRG) neurons in vitro. The aim of this study was to identify factors involved in transferring the observed NMRT-induced effects to SCs and consequently to DRG neurons. Conditioned media of NMRT-treated (CM NMRT) and untreated SCs (CM CTRL) were tested by beta-nerve growth factor (ßNGF) ELISA and multiplex cytokine panels to profile secreted factors. The expression of nociceptive transient receptor potential vanilloid 1 (TRPV1) channels was assessed and the intracellular calcium response in DRG neurons to high-potassium solution, capsaicin or adenosine triphosphate was measured mimicking noxious stimuli. NMRT induced the secretion of ßNGF and pro-regenerative-signaling factors. Blocking antibody experiments confirmed ßNGF as the main factor responsible for neurotrophic/neuritogenic effects of CM NMRT. The TRPV1 expression or sensitivity to specific stimuli was not altered, whereas the viability of cultured DRG neurons was increased. Positive effects of CM NMRT supernatant on DRG neurons are primarily mediated by increased ßNGF levels. Full article

The affinity of specific phenolic compounds (PCs) and capsaicinoids (CAPs) present in three Capsicum annuum varieties (Friariello, Cayenne and Dzuljunska Sipka) to the transient receptor potential vanilloid member 1 (TRPV1) was investigated by integrating an analytic approach for the simultaneous extraction and analysis through high-performance liquid chromatography coupled with ion trap mass spectrometry (HPLC/ITMS) and UV detection (HPLC-UV) of PCs and CAPs and structural bioinformatics based on the protein modelling and molecular simulations of protein–ligand docking. Overall, a total of 35 compounds were identified in the different samples and CAPs were quantified. The highest content of total polyphenols was recorded in the pungent Dzuljunska Sipka variety (8.91 ± 0.05 gGAE/Kg DW) while the lowest was found in the non-pungent variety Friariello (3.58 ± 0.02 gGAE/Kg DW). Protein modelling generated for the first time a complete model of the homotetrameric human TRPV1, and it was used for docking simulations with the compounds detected via the analytic approach, as well as with other compounds, as an inhibitor reference. The simulations indicate that different capsaicinoids can interact with the receptor, providing details on the molecular interaction, with similar predicted binding energy values. These results offer new insights into the interaction of capsaicinoids with TRPV1 and their possible actions. Full article

Based on the advances made by artificial intelligence (AI) technologies in drug discovery, including target identification, hit molecule identification, and lead optimization, this study investigated natural compounds that could act as transient receptor potential vanilloid 1 (TRPV1) channel protein antagonists. Using a molecular transformer drug–target interaction (MT-DTI) model, troxerutin was predicted to be a TRPV1 antagonist at IC₅₀ 582.73 nM. In a TRPV1-overexpressing HEK293T cell line, we found that troxerutin antagonized the calcium influx induced by the TRPV1 agonist capsaicin in vitro. A structural modeling and docking experiment of troxerutin and human TRPV1 confirmed that troxerutin could be a TRPV1 antagonist. A small-scale clinical trial consisting of 29 participants was performed to examine the efficacy of troxerutin in humans. Compared to a vehicle lotion, both 1% and 10% w/v troxerutin lotions reduced skin irritation, as measured by skin redness induced by capsaicin, suggesting that troxerutin could ameliorate skin sensitivity in clinical practice. We concluded that troxerutin is a potential TRPV1 antagonist based on the deep learning MT-DTI model prediction. The present study provides a useful reference for target-based drug discovery using AI technology and may provide useful information for the integrated research field of AI technology and biology. Full article

Nitric oxide is one of the endogenous molecules that play a key role in migraine. However, the interaction between NO and the main players in the nociceptive activity of the meningeal trigeminal afferents—TRPV1 and P2X3 receptors—remains unstudied. In the current project, the effects of acute and chronic NO administration on the activity of TRPV1 and P2X3 receptors in the peripheral afferents were studied using electrophysiological recording of action potentials of the trigeminal nerve in the rat hemiskull preparations. The data obtained indicate that exogenous and endogenous NO increased the activity of the trigeminal nerve independent on the inhibition of the TRPV1 and P2X3 receptors. The activity of the trigeminal nerve triggered by ATP changed neither in acute incubation in the NO donor—sodium nitroprusside (SNP) nor in the chronic nitroglycerine (NG)-induced migraine model. Moreover, the chronic NG administration did not increase in the number of degranulated mast cells in the rat meninges. At the same time, the capsaicin-induced activity of the trigeminal nerve was higher with chronic NO administration or after acute NO application, and these effects were prevented by N-ethylmaleimide. In conclusion, we suggested that NO positively modulates the activity of TRPV1 receptors by S-nitrosylation, which may contribute to the pro-nociceptive action of NO and underlie the sensitization of meningeal afferents in chronic migraine. Full article

Marine cyanobacteria are a rich source of bio-active metabolites that have been utilized as leads for drug discovery and pharmacological tools for basic science research. Here, we describe the re-isolation of a well-known metabolite, barbamide, from Curaçao on three different occasions and the characterization of barbamide’s biological interactions with targets of the mammalian nervous system. Barbamide was originally discovered as a molluscicidal agent from a filamentous marine cyanobacterium. In our hands, we found little evidence of toxicity against mammalian cell cultures. However, barbamide showed several affinities when screened for binding affinity for a panel of 45 receptors and transporters known to be involved in nociception and sensory neuron activity. We found high levels of binding affinity for the dopamine transporter, the kappa opioid receptor, and the sigma receptors (sigma-1 and sigma-2 also known as transmembrane protein 97; TMEM97). We tested barbamide in vitro in isolated sensory neurons from female mice to explore its functional impact on calcium flux in these cells. Barbamide by itself had no observable impact on calcium flux. However, barbamide enhanced the effect of the TRPV1 agonist capsaicin and enhanced store-operated calcium entry (SOCE) responses after depletion of intracellular calcium. Overall, these results demonstrate the biological potential of barbamide at sensory neurons with implications for future drug development projects surrounding this molecule. Full article

Capsaicin is a naturally occurring alkaloid derived from chili pepper which is responsible for its hot, pungent taste. It exerts multiple pharmacological actions, including pain-relieving, anti-cancer, anti-inflammatory, anti-obesity, and antioxidant effects. Previous studies have shown that capsaicin significantly affects the contractility and automaticity of the heart and alters cardiovascular functions. In this study, the effects of capsaicin were investigated on voltage-gated ion currents in rabbit ventricular myocytes. Capsaicin inhibited rapidly activated (I_Kr) and slowly activated (I_Ks) K⁺ currents and transient outward (I_to) K⁺ current with IC₅₀ values of 3.4 µM,14.7 µM, and 9.6 µM, respectively. In addition, capsaicin, at higher concentrations, suppressed voltage-gated Na⁺ and Ca²⁺ currents and inward rectifier I_K1 current with IC₅₀ values of 42.7 µM, 34.9 µM, and 38.8 µM, respectively. Capsaicin inhibitions of I_Na, I_L-Ca, I_Kr, I_Ks, I_to, and I_K1 were not reversed in the presence of capsazepine (3 µM), a TRPV1 antagonist. The inhibitory effects of capsaicin on these currents developed gradually, reaching steady-state levels within 3 to 6 min, and the recoveries were usually incomplete during washout. In concentration-inhibition curves, apparent Hill coefficients higher than unity suggested multiple interaction sites of capsaicin on these channels. Collectively, these findings indicate that capsaicin affects cardiac electrophysiology by acting on a diverse range of ion channels and suggest that caution should be exercised when capsaicin is administered to carriers of cardiac channelopathies or to individuals with arrhythmia-prone conditions, such as ischemic heart diseases. Full article

The skin is a protective organ, able to decode a wide range of tactile, thermal, or noxious stimuli. Some of the sensors belonging to the transient receptor potential (TRP) family, for example, TRPV1, can elicit capsaicin-induced heat pain or histamine-induced itching sensations. The sensory nerve fibers, whose soma is located in the trigeminal or the dorsal root ganglia, are able to carry signals from the skin’s sensory receptors toward the brain via the spinal cord. In some cases, in response to environmental factors, nerve endings might be hyper activated, leading to a sensitive skin syndrome (SSS). SSS affects about 50% of the population and is correlated with small-fiber neuropathies resulting in neuropathic pain. Thus, for cosmetical and pharmaceutical industries developing SSS treatments, the selection of relevant and predictive in vitro models is essential. In this article, we reviewed the different in vitro models developed for the assessment of skin and neuron interactions. In a second part, we presented the advantages of microfluidic devices and organ-on-chip models, with a focus on the first model we developed in this context. Full article

Cinnamaldehyde and capsaicin have been reported to exert effects on the gastric function, mediated by the interaction with transient receptor potential ankyrin channel 1 (TRPA1) and transient receptor potential vanilloid channel 1 (TRPV1), respectively. This study examined whether these compounds could trigger the release of cholecystokinin (CCK) and/or glucagon-like peptide 1 (GLP-1) in the pig’s gut in a porcine ex-vivo intestinal segment model. Furthermore, it was verified whether this response was mediated by TRPA1 or TRPV1 by using the channel’s antagonist. These gut peptides play a key role in the “intestinal brake”, a feedback mechanism that influences the function of proximal parts of the gut. Structural analogues of cinnamaldehyde were screened as well, to explore structure-dependent activation. Results showed a significant effect of capsaicin on GLP-1 release in the proximal small intestine, TRPV1 independent. TRPA1 showed to be strongly activated by cinnamaldehyde, both in proximal and distal small intestine, evidenced by the release of CCK and GLP-1, respectively. Out of all structural derivates, cinnamaldehyde showed the highest affinity for TRPA1, which elucidates the importance of the α,β-unsaturated aldehyde moiety. In conclusion, cinnamaldehyde as a TRPA1 agonist, is a promising candidate to modulate gastric function, by activating intestinal brake mechanisms. Full article

Transient receptor potential channels-vanilloid receptor 1 (TRPV1) regulates thermotaxis in sperm-oriented motility. We investigated the role of membrane cholesterol (Chol) on TRPV1-mediated human sperm migration. Semen samples were obtained from five normozoospemic healthy volunteers. Sperm membrane Chol content, quantified by liquid chromatography-mass spectrometry, was modified by incubating cells with 2-hydroxypropyl-ß-cyclodextrin (CD) or the complex between CD and Chol (CD:Chol). The effect on sperm migration on a 10 μM capsaicin gradient (CPS), a TRPV1 agonist, was then investigated. Motility parameters were evaluated by Sperm Class Analyser. Intracellular calcium concentration and acrosome reaction were measured by staining with calcium orange and FITC-conjugated anti-CD46 antibody, respectively. TRPV1-Chol interaction was modelled by computational molecular-modelling (MM). CD and CD:Chol, respectively, reduced and increased membrane Chol content in a dose-dependent manner, resulting in a dose-dependent increase and reduction of sperm migration in a CPS gradient. MM confirmed a specific interaction of Chol with a TRPV1 domain that appeared precluded to the Chol epimer epicholesterol (Epi-Chol). Accordingly, CD:Epi-Chol was significantly less efficient than CD:Chol, in reducing sperm migration under CPS gradient. Chol inhibits TRPV1-mediated sperm function by directly interacting with a consensus sequence of the receptor. Full article

Chemotherapy-induced neuropathic pain (CINP) is a severe adverse effect of platinum- and taxane-derived anticancer drugs. The pathophysiology of CINP includes damage to neuronal networks and dysregulation of signal transduction due to abnormal Ca²⁺ levels. Therefore, methods that aid the recovery of neuronal networks could represent a potential treatment for CINP. We developed a mouse model of paclitaxel-induced peripheral neuropathy, representing CINP, to examine whether intrathecal injection of decursin could be effective in treating CINP. We found that decursin reduced capsaicin-induced intracellular Ca²⁺ levels in F11 cells and stimulated neurite outgrowth in a concentration-dependent manner. Decursin directly reduced mechanical allodynia, and this improvement was even greater with a higher frequency of injections. Subsequently, we investigated whether decursin interacts with the transient receptor potential vanilloid 1 (TRPV1). The web server SwissTargetPrediction predicted that TRPV1 is one of the target proteins that may enable the effective treatment of CINP. Furthermore, we discovered that decursin acts as a TRPV1 antagonist. Therefore, we demonstrated that decursin may be an important compound for the treatment of paclitaxel-induced neuropathic pain that functions via TRPV1 inhibition and recovery of damaged neuronal networks. Full article