RESUMEN

The influence of extrinsic hand-feel touch cues on consumer experiences in food and beverage consumption is well established. However, their impact on trigeminal perception, particularly the oral irritation caused by capsaicin or spicy foods, is less understood. This study aimed to determine the existence of cross-modal associations between hand-feel touch and capsaicin-induced oral irritation. This study investigated whether these potential associations were driven by the sensory contributions of the hand-feel tactile materials (measured by instrumental physical parameters) or by affective responses (evaluated through hedonic scales and the self-reported emotion questionnaire, EsSense Profile®, by consumers). In our study, 96 participants tasted a capsaicin solution while engaging with nine hand-feel tactile materials, i.e., cardboard, linen, rattan, silicone, stainless steel, sandpaper (fine), sandpaper (rough), sponge, and towel. They subsequently rated their liking and emotional responses, perceived intensity of oral irritation, and the congruency between hand-feel tactile sensation and oral irritation. Instrumental measurements characterized the surface texture of the hand-feel tactile materials, which were correlated with the collected sensory data. The results revealed that unique cross-modal associations between hand-feel touch and capsaicin-induced oral irritation. Specifically, while sandpapers demonstrated high congruence with the sensation of oral irritation, stainless steel was found to be least congruent. These associations were influenced by both the common emotional responses ("active," "aggressive," "daring," "energetic," "guilty," and "worried") evoked by the hand-feel tactile materials and the capsaicin, as well as by participants' liking for the hand-feel tactile materials and the characteristics of the surface textures. This study provides empirical evidence of the cross-modality between hand-feel tactile sensations and capsaicin-induced oral irritation, opening new avenues for future research in this area.

Asunto(s)

Capsaicina , Tacto , Humanos , Capsaicina/efectos adversos , Femenino , Masculino , Adulto , Adulto Joven , Mano , Gusto , Adolescente , Emociones , Percepción del Tacto , Persona de Mediana Edad

RESUMEN

The incidence of liver disease continues to rise, encompassing a spectrum from simple steatosis or non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), cirrhosis and liver cancer. Dietary habits in individuals with liver disease may significantly impact the treatment and prevention of these conditions. This article examines the role of chili peppers, a common dietary component, in this context, focusing on capsaicin, the active ingredient in chili peppers. Capsaicin is an agonist of the transient receptor potential vanilloid subfamily 1 (TRPV1) and has been shown to exert protective effects on liver diseases, including liver injury, NAFLD, liver fibrosis and liver cancer. These protective effects are attributed to capsaicin's anti-oxidant, anti-inflammatory, anti-steatosis and anti-fibrosis effects. This article reviewed the different molecular mechanisms of the protective effect of capsaicin on liver diseases.

RESUMEN

Astringency, commonly described as a drying, roughening, and/or puckering sensation associated with polyphenol-rich foods affects their palatability. While the compounds eliciting astringency are known, its mechanism of action is debated. This study investigated the role of transient receptor potential (TRP) channels A1 and V1 in astringency perception. If TRP A1 or V1 have a functional role in astringency perception, then desensitizing these receptors should decrease perceived astringency. Thirty-seven panelists underwent unilateral lingual desensitization of TRP A1 and V1 channels using mustard oil and capsaicin, respectively. Panelists then evaluated four astringent stimuli: epicatechin (EC), epigallocatechin gallate (EGCG), tannic acid (TA), and potassium alum (Alum), via 2-AFC and intensity ratings. When TRPA1 receptors were desensitized on one half of the tongue via mustard oil, no significant differences were observed between the treated and untreated sides for both 2-AFC and intensity ratings. Similarly, when TRPV1 receptors were desensitized on one half of the tongue via capsaicin, no significant differences were observed between the treated and untreated sides for both 2-AFC and intensity ratings. These findings challenge the notion that TRP channels play a pivotal role in astringency perception.

RESUMEN

Peppers globally renowned for their distinctive spicy flavor, have attracted significant research attention, particularly in understanding spiciness regulation. While the activator MYB's role in spiciness regulation is well-established, the involvement of repressor MYB factors remains unexplored. This study identified the MYB4 transcription factor through RNA-seq and genome-wide analysis as being associated with spiciness. Consequently, CcMYB4-2 and CcMYB4-12 were cloned from Hainan Huangdenglong peppers, both exhibiting nuclear subcellular localization. qRT-PCR analysis revealed that CcMYB4-2/4-12 had high expression levels during the accumulation period of capsaicin, but there were differences in their peak expression levels, which may be related to the formation of pepper spiciness. Heterologous expression in Arabidopsis thaliana resulted in significantly elevated CcMYB4-2/4-12 expression levels and reduced lignin content. In CcMYB4-2 silenced plants, PAL expression remained unchanged, while PAL expression significantly increased in CcMYB4-12 silenced plants, leading to elevated lignin content and reduced capsaicin content. Yeast one-hybrid (Y1H) and dual luciferase reporter assays (DLR) demonstrated that CcMYB4-2/4-12 inhibited the transcription of CcPAL2 by binding to its promoter. Notably, CcMYB4-12 exhibited more pronounced inhibition. Therefore, it is hypothesized that CcMYB4-12 plays a pivotal role in regulating lignin and capsaicin biosynthesis. This study elucidates the molecular mechanism of MYB4 binding to the PAL promoter, providing a foundational understanding for analyzing phenylpropanoid metabolism and its diverse branches. KEY MESSAGE: Through functional verification analysis of the repressor CcMYB4, transcriptional regulation experiments revealed that CcMYB4 can bind to the CcPAL2 promoter, negatively regulating the capsaicin biosynthesis in Capsicum chinense fruits.

RESUMEN

Capsicum oleoresin has potential health benefits, particularly against obesity markers. Due to its high pungency, few studies have been done to explore the intake of this ingredient. The objective of this study was to use the Capsicum oleoresin (CO) microencapsulated into a high-fat diet to evaluate its metabolic effect on mice. Two formulation containing 15 % solids were prepared: the first (F1) with 5% CO and 95% emulsifier, and the second (F2) with 2.5% corn oil, 2.5% CO, and 95% emulsifier. These formulation were atomized in a spray dryer. Ultra-Performance Liquid Chromatography determined the capsaicin content for both formulations. Mice were divided into two groups: lean control (normocaloric AIN diet, n = 10) and high fat (HF diet: hypercaloric, n = 30), which were subdivided into three subgroups: HF control diet (n = 10); diet F1: HF + 20 % CO oleoresin microparticles (n = 10); and diet F2: HF + 20 % CO microparticles containing corn oil (n = 10). The animals treated with the microparticles showed lower glucose levels than the HF control. Mice fed with HF-containing CO microparticles had cholesterol blood levels similar to that of the lean group and lower (<100 mg/dL) than that of the HF control group (150 mg/dL). Capsicum oleoresin microparticles added to high-fat diets promoted lower weight gain and protected the liver against hepatic steatosis. Leptin levels for mice fed with HF diet plus CO microparticles averaged between 2 and 5 ng/ml, whereas the fat control group developed leptin resistance. Capsicum microparticles evidenced a protective effect against dyslipidemia compared to the fat control group, which suggests their use as a potential ingredient for the control of obesity.

Asunto(s)

Capsicum , Dieta Alta en Grasa , Obesidad , Extractos Vegetales , Animales , Capsicum/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones , Capsaicina/farmacología , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/efectos de los fármacos , Enfermedades Metabólicas/prevención & control

RESUMEN

Aging is associated with a decline in oral immune function, marked by reduced levels of antimicrobial peptides such as defensins. Capsaicin, a bioactive component found in chili peppers, has been theorized to modulate immune responses through specific receptor pathways. This study examined the effects of aging on oral defensin levels and the potential mitigating role of capsaicin, mediated by the immune response in oral tissues. We conducted a comparative analysis between young and aged mice, with or without capsaicin supplementation, for 3 months. The effect of capsaicin was also studied in vitro in senescence-induced human oral keratinocytes. We found that aging did not reduce defensin levels uniformly but did so in some instances. Capsaicin treatment increased defensin levels in these cases, potentially through transient receptor potential cation channel subfamily V member 1 (TRPV1)-mediated pathways in the oral cavity. Capsaicin supplementation may counteract age-related declines in oral defensin levels, enabling the maintenance of oral immune function during aging.

RESUMEN

Capsaicin, carotenoids, and phenolic compounds from cumari-do-Pará peppers (Capsicum chinense Jacq.) harvested from two different locations in Pará, Brazil, and at different ripening stages were extracted by employing green methodologies as an alternative to organic solvents. Edible vegetable oils from soybeans (Glycine max), Brazilian nuts (Bertholettia excelsa H.B.), and palm olein were used in combination with ultrasonic-assisted extraction (UAE). The proximate composition of the pepper extracts and vitamin C were determined through AOAC methods, total phenolics and carotenoids were assessed by UV/Vis spectrophotometry, and capsaicin by high-performance liquid chromatography. Antioxidant cumari-do-Pará extract activities were evaluated by the ABTS radical scavenging and ß-carotene/linoleic acid assays. The vegetable oils were suitable for extracting and preserving bioactive pepper compounds, especially mature ones harvested from Igarapé-Açu. Bioactive compound content and antioxidant activity varied with harvesting location and ripening stage. Soybean oil was the most effective in extracting bioactive pepper compounds, particularly carotenoids, with 69% recovery. Soybean oil extracts enriched in capsaicin, carotenoids, and phenolics obtained from cumari-do-Pará can be used as spices in foodstuffs and/or as additives in pharmaceutical and nutraceutical formulations. Edible vegetable oils combined with UAE are promising for bioactive compound extraction, representing an environmentally friendly, safe, low-cost, versatile, and fast alternative.

RESUMEN

BACKGROUND: Ventilator-induced lung injury (VILI) is one of the severe complications in the clinic concerning mechanical ventilation (MV). Capsaicin (CAP) has anti-inflammatory and inhibitory effects on oxidative stress, which is a significant element causing cellular ferroptosis. Nevertheless, the specific role and potential mechanistic pathways through which CAP modulates ferroptosis in VILI remain elusive. METHODS: VILI was established in vivo, and the pulmonary epithelial cell injury model induced by circulation stretching (CS) was established in vitro. Both mice and cells were pretreated with CAP. Transmission electron microscopy, ELISA, Western blot, immunofluorescence, RT-PCR, fluorescent probes, and other experimental methods were used to clarify the relationship between iron death and VILI in alveolar epithelial cells, and whether capsaicin alleviates VILI by inhibiting iron death and its specific mechanism. RESULTS: Ferroptosis was involved in VILI by utilizing in vivo models. CAP inhibited ferroptosis and alleviated VILI's lung damage and inflammation, and this protective effect of CAP was dependent on maintaining mitochondrial redox system through SITR3 signaling. In the CS-caused lung epithelial cell injury models, CAP reduced pathological CS-caused ferroptosis and cell injury. Knockdown SIRT3 reversed the role of CAP on the maintaining mitochondria dysfunction under pathological CS and eliminated its subsequent advantageous impacts for ferroptosis against overstretching cells. CONCLUSION: The outcomes showed that CAP alleviated ferroptosis in VILI via improving the activity of SITR3 to suppressing mitochondrial oxidative damage and maintaining mitochondrial redox homeostasis, illustrating its possibility as a novel therapeutic goal for VILI.

Asunto(s)

Capsaicina , Ferroptosis , Homeostasis , Mitocondrias , Oxidación-Reducción , Sirtuina 3 , Lesión Pulmonar Inducida por Ventilación Mecánica , Ferroptosis/efectos de los fármacos , Animales , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Ratones , Sirtuina 3/metabolismo , Sirtuina 3/genética , Lesión Pulmonar Inducida por Ventilación Mecánica/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/tratamiento farmacológico , Oxidación-Reducción/efectos de los fármacos , Capsaicina/farmacología , Masculino , Modelos Animales de Enfermedad , Humanos , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/efectos de los fármacos , Transducción de Señal/efectos de los fármacos

RESUMEN

Capsaicin is a bioactive compound found prominently in Capsicum annuum L. plants and takes on a pivotal role in their characteristic spiciness. Previous studies have delved into the potential analgesic effect of capsaicin in various oral conditions, such as oral neuropathic pain, trigeminal neuralgia, oral mucositis, temporomandibular joint disorders and burning mouth syndrome. Capsaicin has also demonstrated promise in inhibiting the proliferation of different oral cancer cell lines. Its antimicrobial properties have also been shown to inhibit the growth of oral pathogens associated with dental caries, periodontitis and oral candidiasis. However, to harness its benefits effectively, more studies are required to establish optimal dosages for pain relief while minimizing adverse effects. In addition, investigation of the effect of capsaicin on nonpathogenic oral bacteria and viruses is warranted. Human-based research is crucial for elucidating the biomolecular mechanisms underlying the properties of capsaicin, potentially leading to the development of more effective interventions for oral health problems.

RESUMEN

Capsaicin analogs, whether sourced from natural origins or synthesized de novo, have garnered significant attention across diverse scientific disciplines. This comprehensive investigation explores the expansive domain of medicinal chemistry and pharmacology, focusing on capsaicin and its analogs. Notably, these analogs exhibit a wideranging pharmacological spectrum, with a particular emphasis on their potent antitumor properties. Researchers frequently explore structural modifications, particularly in region C, consistently enhancing their pharmacological activities. A highlighted finding is that analogs with alterations in both regions A and C manifest a diverse array of effects, spanning from anti-obesity to protection against ischemia. They also demonstrate anti- Alzheimer's, anti-fibrotic, anti-inflammatory, anti-diabetic, antimalarial, and anti-epileptic properties. This underscores the potential of structural adaptations in these regions, expanding the therapeutic applications of capsaicin-like compounds. Additionally, manipulations in regions B and C result in compounds that possess antioxidant and anti-obesity properties, providing valuable insights for the development of novel compounds. The therapeutic potential of capsaicin analogs opens innovative avenues for drug design and development, promising to address a broad spectrum of diseases and enhance global quality of life. Moreover, this article meticulously examines various synthetic methodologies for synthesizing capsaicin analogs, complementing the main review. These methodologies distinguish themselves through their simplicity, mild reaction conditions, and reliance on readily available commercial reagents. The accessible synthesis pathways enable researchers from diverse backgrounds to explore these compounds, fostering investigations and potential therapeutic applications.

RESUMEN

Chronic low-grade inflammation (CLGI) is associated with obesity and is one of its pathogenetic mechanisms. Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, is the principal cause of CLGI. Studies have found that capsaicin significantly reduces the relative abundance of LPS-producing bacteria. In the present study, TRPV1-knockout (TRPV1-/-) C57BL/6J mice and the intestinal epithelial cell line Caco-2 (TRPV1-/-) were used as models to determine the effect of capsaicin on CLGI and elucidate the mechanism by which it mediates weight loss in vivo and in vitro. We found that the intragastric administration of capsaicin significantly blunted increases in body weight, food intake, blood lipid, and blood glucose in TRPV1-/- mice fed a high-fat diet, suggesting an anti-obesity effect of capsaicin. Capsaicin reduced LPS levels in the intestine by reducing the relative abundance of Proteobacteria such as Helicobacter, Desulfovibrio, and Sutterella. Toll-like receptor 4 (TLR4) levels decreased following decreases in LPS levels. Then, the local inflammation of the intestine was reduced by reducing the expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 mediated by TLR4. Attenuating local intestinal inflammation led to the increased expression of tight junction proteins zonula occludens 1 (ZO-1) and occludin and the restoration of the intestinal barrier function. Capsaicin increased the expression of ZO-1 and occludin at the transcriptional and translational levels, thereby increasing trans-endothelial electrical resistance and restoring intestinal barrier function. The restoration of intestinal barrier function decreases intestinal permeability, which reduces the concentration of LPS entering the circulation, and reduced endotoxemia leads to decreased serum concentrations of inflammatory cytokines such as TNF-α and IL-6, thereby attenuating CLGI. This study sheds light on the anti-obesity effect of capsaicin and its mechanism by reducing CLGI, increasing our understanding of the anti-obesity effects of capsaicin. It has been confirmed that capsaicin can stimulate the expression of intestinal transmembrane protein ZO-1 and cytoplasmic protein occludin, increase the trans-epithelial electrical resistance value, and repair intestinal barrier function.

Asunto(s)

Capsaicina , Inflamación , Lipopolisacáridos , Ratones Endogámicos C57BL , Obesidad , Canales Catiónicos TRPV , Receptor Toll-Like 4 , Animales , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Capsaicina/farmacología , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Humanos , Ratones , Receptor Toll-Like 4/metabolismo , Células CACO-2 , Ratones Noqueados , Dieta Alta en Grasa/efectos adversos , Masculino , Ocludina/metabolismo , Ocludina/genética , Proteína de la Zonula Occludens-1/metabolismo , Proteína de la Zonula Occludens-1/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos

RESUMEN

Background: Tooth bleaching sensitivity (TBS) after bleaching procedures is a common problem. This study was undertaken to determine the effect of preoperative systemic capsaicin on tooth sensitivity (TS) after in-office bleaching procedures. Materials and Methods: Thirty participants received the treatment in this clinical trial. The subjects were randomly assigned to two groups (n = 15). Placebo and 0.25% capsaicin were administered three times daily for 24 h, with the first dose being administrated 1 h before the bleaching procedure. The subjects underwent two bleaching sessions at a 2-week interval by applying 40% hydrogen peroxide gel on six upper anterior teeth. A visual analog scale (VAS) was used to evaluate TS. Data were analyzed with SPSS 24. Statistical analyses were carried out with the Wilcoxon test and paired t-test. Statistical significance was set at P ≤ 0.05. Results: In the capsaicin group, there was a significant increase in TBS between the immediate and 1-h postoperative intervals and a significant decrease between 1- and 24-h postoperative intervals (P = 0.01 and P = 0.000, respectively). In the placebo group, there was a significant decrease between immediate and 24-h and between 1- and 24-h postoperative intervals (P = 0.007, P = 0.02). Milder TS was detected in the placebo group 24 h after bleaching (P < 0.05). Conclusion: Under the limitations of this study, preoperative use of systemic capsaicin did not significantly affect TS after the in-office bleaching procedure.

RESUMEN

Capsaicin, the most prominent pungent compound of chilli peppers, has been used in traditional medicine systems for centuries; it already has a number of established clinical and industrial applications. Capsaicin is known to act through the TRPV1 receptor, which exists in various tissues; capsaicin is hepatically metabolised, having a half-life correlated with the method of application. Research on various applications of capsaicin in different formulations is still ongoing. Thus, local capsaicin applications have a pronounced anti-inflammatory effect, while systemic applications have a multitude of different effects because their increased lipophilic character ensures their augmented bioavailability. Furthermore, various teams have documented capsaicin's anti-cancer effects, proven both in vivo and in vitro designs. A notable constraint in the therapeutic effects of capsaicin is its increased toxicity, especially in sensitive tissues. Regarding the traditional applications of capsaicin, apart from all the effects recorded as medicinal effects, the application of capsaicin in acupuncture points has been demonstrated to be effective and the combination of acupuncture and capsaicin warrants further research. Finally, capsaicin has demonstrated antimicrobial effects, which can supplement its anti-inflammatory and anti-carcinogenic actions.

RESUMEN

Clodronate (Clod), a first-generation bisphosphonate, acts as a natural analgesic inhibiting vesicular storage of the nociception mediator ATP by vesicular nucleotide transporter (VNUT). Epidermal keratinocytes participate in cutaneous nociception, accumulating ATP within vesicles, which are released following different stimulations. Under stress conditions, keratinocytes produce microvesicles (MVs) by shedding from plasma membrane evagination. MV secretion has been identified as a novel and universal mode of intercellular communication between cells. The aim of this project was to evaluate if two nociceptive stimuli, Capsaicin and Potassium Hydroxide (KOH), could stimulate MV shedding from human keratinocytes, if these MVs could contain ATP, and if Clod could inhibit this phenomenon. In our cellular model, the HaCaT keratinocyte monolayer, both Capsaicin and KOH stimulated MV release after 3 h incubation, and the released MVs contained ATP. Moreover, Clod (5 µM) was able to reduce Caps-induced MV release and abolish the one KOH induced, while the Dansylcadaverine, an endocytosis inhibitor of Clod uptake, partially failed to block the bisphosphonate activity. Based on these new data and given the role of the activation of ATP release by keratinocytes as a vehicle for nociception and pain, the "old" bisphosphonate Clodronate could provide the pharmacological basis to develop new local analgesic drugs.

Asunto(s)

Adenosina Trifosfato , Capsaicina , Ácido Clodrónico , Queratinocitos , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Adenosina Trifosfato/metabolismo , Ácido Clodrónico/farmacología , Capsaicina/farmacología , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/efectos de los fármacos , Nocicepción/efectos de los fármacos , Línea Celular

RESUMEN

BACKGROUND: Assessment of taste and somatosensory perception in clinical practice lacks fast tests that are validated and reliable. Recently, a 12-item identification test for taste and oral trigeminal perception, and its shorter version, the Seven-iTT, was developed. The objectives of this study were to evaluate its test-retest reliability and establish normative data. NEW METHOD: Two-hundred participants (120 women, 80 men) with a good sense of taste performed a whole-mouth identification test using 12 filter-paper strips impregnated with low and high concentrations of sweet, sour, salty, bitter, astringency, and spiciness. Fifty of them repeated the task, with a median interval of 122 days from the first visit. Test-retest reliability was determined using Spearman correlation and the Bland-Altman plot method. RESULTS: There was a significant correlation in identification score between the first and the second session for both versions of the test (r ≥ 0.28; p ≤ 0.048). The Bland-Altman plot reflected a good congruence between the results of the two sessions. Additionally, frequencies of correct identification were consistent between sessions, with women outperforming men (p = 0.005). Hypogeusia was established at Seven-iTT score of 3 of less. COMPARISON WITH EXISTING METHODS: The identification test combines taste and somatosensory perception, thus creating a more detailed diagnosis tool. Scores were correlated with self-rated taste perception. CONCLUSION: The present results confirmed the applicability of Seven-iTT for a reliable, fast evaluation of taste and somatosensory perception in the general population, that can be extended to clinical practice.

Asunto(s)

Percepción del Gusto , Humanos , Femenino , Masculino , Adulto , Reproducibilidad de los Resultados , Adulto Joven , Persona de Mediana Edad , Percepción del Gusto/fisiología , Nervio Trigémino/fisiología , Valores de Referencia , Gusto/fisiología , Anciano , Adolescente

RESUMEN

TRPV1 acts as a unique polymodal ion channel having distinct structure and gating properties. In this context, TRPV1-R575D represents a special mutant located at the inner lipid-water-interface (LWI) region that has less possibility of interaction with membrane cholesterol. In control conditions, this lab-generated mutant of TRPV1 shows no "ligand-sensitivity", reduced surface expression, reduced localization in the lipid rafts, yet induces high cellular lethality. Notably, the cellular lethality induced by TRPV1-R575D expression can be rescued by adding 5'I-RTX (a specific inhibitor of TRPV1) or by introducing another mutation in the next position, i.e. in TRPV1-R575D/D576R. In this work we characterized TRPV1-R575D and TRPV1-R575D/D576R mutants in different cellular conditions and compared with the TRPV1-WT. We report that the "ligand-insensitivity" of TRPV1-R575D can be rescued in certain conditions, such as by chelation of extracellular Ca2+, or by reduction of the membrane cholesterol. Here we show that Ca2+ plays an important role in the channel gating of TRPV1-WT as well as LWI mutants (TRPV1-R575D, TRPV1-R575D/D576R). However, chelation of intracellular Ca2+ or depletion of ER Ca2+ did not have a significant effect on the TRPV1-R575D. Certain properties related to channel gating of mutant TRPV1-R575D/D576R can be rescued partially or fully in a context -dependent manner. Cholesterol depletion also alters these properties. Our data suggests that lower intracellular basal Ca2+ acts as a pre-requisite for further opening of TRPV1-R575D. These findings enable better understanding of the structure-function relationship of TRPV1 and may be critical in comprehending the channelopathies induced by other homologous thermosensitive TRPVs.

Asunto(s)

Calcio , Capsaicina , Colesterol , Canales Catiónicos TRPV , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Colesterol/metabolismo , Capsaicina/farmacología , Calcio/metabolismo , Humanos , Células HEK293 , Mutación , Agua/metabolismo , Agua/química , Quelantes/farmacología , Animales

RESUMEN

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major 21st-century epidemic. T2DM elevates the risk of myocardial infarction and heart failure while also reducinges survival rates. Recently Ferroptosis has been found to be involved in the development of various cardiovascular diseases. TRPV1 is also a potential therapeutic target for cardioprotection. This study explores whether capsaicin, a transient receptor potential vanilloid receptor 1 (TRPV1) agonist, can prevent diabetic myocardial infarction-induced injury by inhibiting ferroptosis. METHODS: T2DM model was induced by high-fat diet (HFD) feeding combined with streptozocin (STZ) injections, and the diabetic mice were treated with capsaicin(0.015 %) in their food. Myocardial infarction model was established as well. Mouse' general characteristics, cardiac function, and morphological histology were observed and analyzed. RNA-seq was used to investigate the possible mechanism of injury in AC16 cardiomyocytes cultured with high glucose and hypoxia. In addition, the potential mechanism of capsaicin against injury was further investigated in AC16 cardiomyocytes cultured with high glucose and hypoxia. RESULTS: The RNA-seq analysis revealed that ferroptosis was associated with cell death induced by high-glucose in combination with hypoxia, and CAP treatment could effectively inhibit ferroptosis to enhance cell survival. In vivo studies demonstrated that CAP treatment significantly improved post-MI cardiac function, attenuated myocardial inflammation and fibrosis. Furthermore, it was observed that CAP reduced ferroptosis levels by activating TRPV1 in the heart, upregulating Nrf2 expression, promoting Nrf2 nuclear translocation and increasing the expression of the Nrf2 downstream molecule Heme oxygenase-1 (HMOX1). CONCLUSIONS: Dietary capsaicin may inhibit cardiomyocyte ferroptosis through activation of myocardial TRPV1 and Nrf2/HMOX1 signaling pathway, which in turn exerts a protective effect on the myocardium after myocardial infarction in type 2 diabetic mice.

Asunto(s)

Capsaicina , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ferroptosis , Hemo-Oxigenasa 1 , Ratones Endogámicos C57BL , Infarto del Miocardio , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Canales Catiónicos TRPV , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Capsaicina/uso terapéutico , Capsaicina/farmacología , Ferroptosis/efectos de los fármacos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ratones , Masculino , Transducción de Señal/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Hemo-Oxigenasa 1/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Dieta Alta en Grasa/efectos adversos , Línea Celular , Humanos , Proteínas de la Membrana

RESUMEN

Capsaicin (CAP) exerts significant anti-tumor effects on a variety of tumors, with low intrinsic toxicity. Cisplatin (DDP) is currently the first-line drug for the treatment of oral cancer; however, its clinical efficacy is impeded by chemoresistance and negligible side effects. Whether the combined use of CAP and DDP has a synergistic antitumor effect on tongue squamous cell carcinoma (TSCC) cells and its underlying mechanisms remains unclear. The present study revealed that CAP reduced the activity of TSCC cells in a dose- and time-dependent manner. We also observed changes in the mitochondrial functional structure of TSCC cells, along with the induction of mitochondrial apoptosis. Moreover, when CAP was combined with DDP, a synergistic cytotoxic effect on TSCC cells was observed, which had a significant impact on inducing apoptosis, inhibiting proliferation, and disrupting the mitochondrial membrane potential in TSCC cells compared to the single-drug treatment and control groups. These effects are associated with TRPV1, a high-affinity CAP receptor. The combined use of CAP and DDP can activate the TRPV1 receptor, resulting in intracellular Ca2+ overload and activation of the calpain pathway, ultimately leading to mitochondrial apoptosis. This potential mechanism was validated in TSCC xenograft models. In conclusion, our findings clearly demonstrate that CAP exerts synergistic pro-apoptotic effects with DDP in TSCC through the calpain pathway mediated by TRPV1. Thus, CAP can be considered an effective adjuvant drug for DDP in the treatment of TSCC.

RESUMEN

Vanilloid analogs, which can activate transient receptor potential vanilloid 1 (TRPV1), have been classified into two types based on susceptibility to forskolin (FSK). Treatment of cells expressing TRPV1 with FSK enhances TRPV1 responses to capsaicin-type ligands while diminishing the responses to eugenol-type ligands. In this study, we determined the effect of FSK on the activation of TRPV1 stimulated with vanilloid ligands, through the influx of Ca2+ in HEK293T cells expressing TRPV1. Our findings suggest that the effects of FSK can be attributed to the phosphorylation of TRPV1, as evidenced by using a protein kinase A (PKA) inhibitor and TRPV1 mutants at potential phosphorylation sites. Furthermore, we examined the structure-activity relationship of 13 vanilloid analogs. Our results indicated that vanilloid compounds could be classified into three types, i.e., the previously reported two types and a novel type of 10-shogaol, by which TRPV1 activation was insusceptible to the FSK treatment.

RESUMEN

Tongue squamous cell carcinoma (TSCC) is one of the most common malignant tumors among oral cancers, and its treatment is based on radio-chemotherapy and surgery, which always produces more serious side effects and sequelae. Traditional medicine can compensate for the shortcomings of modern medical treatments and play a better therapeutic role. Currently, active ingredients derived from plants are attracting the attention of researchers and clinical professionals. We examined capsaicin (CAP), an active ingredient isolated from Capsicum annuum (family Solanaceae), and explored the effect of CAP combined with cisplatin (DDP) on epithelial-mesenchymal transition (EMT) and TSCC cells migration. Our results demonstrated that Transforming growth factor-ß1(TGF-ß1) induced EMT and promoted cell migration in TSCC cells. CAP combined with DDP inhibits non-TGF-ß1-induced or TGF-ß1-induced EMT and migration. Mechanistically, the inhibition of non-TGF-ß1-induced EMT and migration by CAP combined with DDP was mediated by the AMPK/mTOR pathway, whereas TGF-ß1-induced EMT and migration were regulated by the Claudin-1/PI3K/AKT/mTOR pathway. A nude lung metastasis mouse model was established for in vivo validation. These results support our hypothesis that the combination of CAP and DDP inhibits TSCC metastasis. These data set the stage for further studies aimed at validating CAP as an effective active ingredient for enhancing chemotherapy efficacy and reducing the dosage and toxicity of chemotherapeutic drugs, ultimately paving the way for translational research and clinical trials for TSCC eradication.