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

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

The factors that contribute to pain after nerve injury remain incompletely understood. Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are common surgical techniques to correct refractive errors. After LASIK or PRK, a subset of patients suffers intense and persistent pain, of unknown origin, described by patients as feeling like shards of glass in their eye. Here, we evaluated a TRPV1 variant, p.V527M, found in a 49-y-old woman who developed corneal pain after LASIK and subsequent PRK enhancement, reporting an Ocular Surface Disease Index score of 100. Using patch-clamp and Ca2+ imaging, we found that the V527M mutation enhances the response to acidic pH. Increasing proton concentration induced a stronger leftward shift in the activation curve of V527M compared to WT, resulting in channel activity of the mutant in acidic pH at more physiological membrane potentials. Finally, comparing the responses to consecutive applications of different agonists, we found in V527M channels a reduced capsaicin-induced desensitization and increased sensitization by the arachidonic acid metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). We hypothesize that the increased response in V527M channels to protons and enhanced sensitization by 12-HETE, two inflammatory mediators released in the cornea after tissue damage, may contribute to the pathogenesis of corneal neuralgia after refractive surgery.

Asunto(s)

Bradiquinina , Capsaicina , Mutación , Neuralgia , Canales Catiónicos TRPV , Animales , Humanos , Ratas , Bradiquinina/metabolismo , Bradiquinina/farmacología , Capsaicina/farmacología , Córnea/metabolismo , Córnea/patología , Células HEK293 , Concentración de Iones de Hidrógeno , Neuralgia/genética , Neuralgia/metabolismo , Neuralgia/etiología , Queratectomía Fotorrefractiva/efectos adversos , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo

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

Sexual dimorphism among mammals includes variations in the pain threshold. These differences are influenced by hormonal fluctuations in females during the estrous and menstrual cycles of rodents and humans, respectively. These physiological conditions display various phases, including proestrus and diestrus in rodents and follicular and luteal phases in humans, distinctly characterized by varying estrogen levels. In this study, we evaluated the capsaicin responses in male and female mice at different estrous cycle phases, using two murine acute pain models. Our findings indicate that the capsaicin-induced pain threshold was lower in the proestrus phase than in the other three phases in both pain assays. We also found that male mice exhibited a higher pain threshold than females in the proestrus phase, although it was similar to females in the other cycle phases. We also assessed the mRNA and protein levels of TRPV1 in the dorsal root and trigeminal ganglia of mice. Our results showed higher TRPV1 protein levels during proestrus compared to diestrus and male mice. Unexpectedly, we observed that the diestrus phase was associated with higher TRPV1 mRNA levels than those in both proestrus and male mice. These results underscore the hormonal influence on TRPV1 expression regulation and highlight the role of sex steroids in capsaicin-induced pain.

Asunto(s)

Capsaicina , Dolor , Canales Catiónicos TRPV , Animales , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Capsaicina/farmacología , Masculino , Femenino , Ratones , Dolor/metabolismo , Dolor/genética , Hormonas Esteroides Gonadales/metabolismo , Ciclo Estral/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Caracteres Sexuales , ARN Mensajero/metabolismo , ARN Mensajero/genética

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

Acute nociceptive pain in mice caused by subcutaneous (intraplantar) injection of TRPV1 ion channel agonist capsaicin (1.6 µg/mouse) and the effects of protein kinase A inhibitor H-89 (0.05 mg/mouse, intraplantar injection) and NMDA receptor channel antagonists MK-801 (7.5 and 15 µg/mouse, topical application) and hemantane (0.5 mg/mouse, topical application) on the pain were assessed. MK-801 and hemantane were found to reduce the duration of the pain response. H-89 did not significantly affect the pain in animals, but preliminary administration of this drug abolished the antinociceptive effect of MK-801 (7.5 µg/mouse) and weakens the effect of hemantane (0.5 mg/mouse).

Asunto(s)

Analgésicos , Capsaicina , Maleato de Dizocilpina , Receptores de N-Metil-D-Aspartato , Animales , Capsaicina/farmacología , Ratones , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Masculino , Maleato de Dizocilpina/farmacología , Analgésicos/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Dolor Nociceptivo/tratamiento farmacológico , Dolor Nociceptivo/inducido químicamente , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos

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

The objective of this work was to determine whether the addition of phytogenic compounds based on essential oils (carvacrol, eugenol, cinnamaldehyde) and resinous pepper oil (capsaicin) to the diet of Jersey cows at the beginning of lactation affects anti-inflammatory, antioxidant and immunomodulatory responses, as well as whether there are effects of EO on blood metabolites, ruminal fermentation, digestibility and milk production and composition. Six primiparous cows (370.00 ± 17 kg body weight (BW); 13.02 kg dry matter intake (DMI); 21 days of lactation and average milk production of 20 ± 2 L per day) were allocated to crossed experimental design (2 × 2) with two experimental periods of 28 days and two treatments. Blood, milk and rumen fluid were collected and, at the end of each period, feed and feces samples were collected to evaluate the apparent digestibility of nutrients. The groups were control (CLT) without supplementation and treated (BEO) with the addition of 150 mg/kg of dry matter of the phytogenic to the concentrated portion of the diet. Cows in the BEO group had lower numbers of leukocytes (P ≤ 0.05) and lymphocytes (P ≤ 0.02), but total protein and globulin levels were higher on days 21 and 28 (P ≤ 0.01). In the BEO group, the levels of immunoglobulin A, immunoglobulin heavy chain and transferrin were higher (P ≤ 0.05). The levels of ceruloplasmin, haptoglobin and C-reactive protein were lower in the BEO group (P ≤ 0.05). Lipid peroxidation levels and protein carbonyl content were lower in the BEO group. The total antioxidant capacity (P ≤ 0.09) and the activity of glutathione S-transferase (P ≤ 0.03) and glutathione peroxidase (P ≤ 0.05) were higher in the BEO group. Cows in the BEO group had lower pH (P ≤ 0.05), acetic acid concentrations (P ≤ 0.01) and higher protozoa counts (P ≤ 0.01). Our results suggest that phytogenic supplementation has positive effects on the health of Jersey cows in early lactation, characterized by immunostimulant, antioxidant and anti-inflammatory effects.

Asunto(s)

Alimentación Animal , Antioxidantes , Capsaicina , Dieta , Lactancia , Aceites Volátiles , Animales , Bovinos , Femenino , Lactancia/efectos de los fármacos , Dieta/veterinaria , Aceites Volátiles/administración & dosificación , Aceites Volátiles/farmacología , Alimentación Animal/análisis , Capsaicina/administración & dosificación , Capsaicina/farmacología , Leche/química , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Suplementos Dietéticos/análisis , Rumen/metabolismo

RESUMEN

Diabetic neuropathic pain (DNP) is a diabetic complication that causes severe pain and deeply impacts the quality of the sufferer's daily life. Currently, contemporary clinical treatments for DNP generally exhibit a deficiency in effectiveness. Electroacupuncture (EA) is recognized as a highly effective and safe treatment for DNP with few side effects. Regrettably, the processes via which EA alleviates DNP are still poorly characterized. Transient receptor potential vanilloid 1 (TRPV1) and phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) are overexpressed on spinal cord dorsal horn (SCDH) in DNP rats, and co-localization is observed between them. Capsazepine, a TRPV1 antagonist, effectively reduced nociceptive hypersensitivity and downregulated the overexpression of phosphorylated CaMKIIα in rats with DNP. Conversely, the CaMKII inhibitor KN-93 did not have any impact on TRPV1. EA alleviated heightened sensitivity to pain caused by nociceptive stimuli and downregulated the level of TRPV1, p-CaMKIIα, and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in DNP rats. Intrathecal injection of capsaicin, on the other hand, reversed the above effects of EA. These findings indicated that the CaMKII/CREB pathway on SCDH is located downstream of TRPV1 and is affected by TRPV1. EA alleviates DNP through the TRPV1-mediated CaMKII/CREB pathway.

Asunto(s)

Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Neuropatías Diabéticas , Electroacupuntura , Ratas Sprague-Dawley , Canales Catiónicos TRPV , Animales , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/antagonistas & inhibidores , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Electroacupuntura/métodos , Ratas , Masculino , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Neuropatías Diabéticas/terapia , Neuropatías Diabéticas/metabolismo , Capsaicina/farmacología , Capsaicina/análogos & derivados , Transducción de Señal , Asta Dorsal de la Médula Espinal/metabolismo , Bencenosulfonamidas , Bencilaminas

RESUMEN

Rosacea patients show facial hypersensitivity to stimulus factors (such as heat and capsaicin); however, the underlying mechanism of this hyperresponsiveness remains poorly defined. Here, we show capsaicin stimulation in mice induces exacerbated rosacea-like dermatitis but has no apparent effect on normal skin. Nociceptor ablation substantially reduces the hyperresponsiveness of rosacea-like dermatitis. Subsequently, we find that γδ T cells express Ramp1, the receptor of the neuropeptide CGRP, and are in close contact with these nociceptors in the skin. γδ T cells are significantly increased in rosacea skin lesions and can be further recruited and activated by neuron-secreted CGRP. Rosacea-like dermatitis is reduced in T cell receptor δ-deficient (Tcrd-/-) mice, and the nociceptor-mediated aggravation of rosacea-like dermatitis is also reduced in these mice. In vitro experiments show that CGRP induces IL17A secretion from γδ T cells by regulating inflammation-related and metabolism-related pathways. Finally, rimegepant, a CGRP receptor antagonist, shows efficacy in the treatment of rosacea-like dermatitis. In conclusion, our findings demonstrate a neuron-CGRP-γδT cell axis that contributes to the hyperresponsiveness of rosacea, thereby showing that targeting CGRP is a potentially effective therapeutic strategy for rosacea.

Asunto(s)

Péptido Relacionado con Gen de Calcitonina , Capsaicina , Receptores de Antígenos de Linfocitos T gamma-delta , Rosácea , Células Receptoras Sensoriales , Animales , Rosácea/inmunología , Ratones , Péptido Relacionado con Gen de Calcitonina/metabolismo , Células Receptoras Sensoriales/metabolismo , Capsaicina/farmacología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Piel/patología , Piel/inmunología , Piel/metabolismo , Interleucina-17/metabolismo , Interleucina-17/inmunología , Ratones Noqueados , Ratones Endogámicos C57BL , Dermatitis/inmunología , Dermatitis/metabolismo , Dermatitis/patología , Modelos Animales de Enfermedad , Masculino , Nociceptores/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Humanos , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo

RESUMEN

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Asunto(s)

Monoterpenos Acíclicos , Analgésicos , Capsaicina , Codeína , Dolor Facial , Dimensión del Dolor , Terpenos , Animales , Codeína/farmacología , Dolor Facial/inducido químicamente , Dolor Facial/tratamiento farmacológico , Monoterpenos Acíclicos/farmacología , Masculino , Dimensión del Dolor/efectos de los fármacos , Capsaicina/farmacología , Terpenos/farmacología , Analgésicos/farmacología , Ratones , Factores de Tiempo , Modelos Animales de Enfermedad , Reproducibilidad de los Resultados , Formaldehído , Ácido Glutámico , Resultado del Tratamiento , Nocicepción/efectos de los fármacos , Análisis de Varianza , Estadísticas no Paramétricas , Conducta Animal/efectos de los fármacos

RESUMEN

The immune and sensory nervous systems communicate to maintain homeostasis. Wu et al. recently demonstrated that sensory neurons innervate the mouse spleen. These neurons promote calcitonin gene-related peptide (CGRP)-dependent responses in splenic B cell germinal centers (GCs) and antigen-specific antibody production. Dietary capsaicin activates these neurons to enhance humoral immunity against influenza virus infection.

Asunto(s)

Linfocitos B , Centro Germinal , Inmunidad Humoral , Bazo , Animales , Bazo/inmunología , Bazo/inervación , Humanos , Centro Germinal/inmunología , Ratones , Linfocitos B/inmunología , Células Receptoras Sensoriales/inmunología , Células Receptoras Sensoriales/fisiología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Péptido Relacionado con Gen de Calcitonina/inmunología , Capsaicina/farmacología

RESUMEN

Capsaicin (CAP), the active ingredient in hot chilli peppers, has anti-inflammatory and hepatoprotection effects. Acute alcoholic liver injury (AALI) is liver damage caused by acute alcohol abuse, which can lead to severe liver lesions and even be life-threatening. Pyroptosis is inflammation-related programmed cell death characterized by membrane rupture and plays a key role in AALI. The endosomal sorting complexes required for transport (ESCRT) proteins can gather at damaged areas of the membrane to facilitate the process of sealing the membrane. In this study, we found that CAP could relieve acute alcohol-induced pyroptosis of hepatocytes in vitro and in vivo. Mechanically, we found that CAP could alleviate acute alcohol-induced pyroptosis by activating the ESCRT-III-dependent membrane repair machinery. Furthermore, the data showed that CAP induced ESCRT-III protein expression by activating transient receptor potential vanilloid member 1 (TRPV1) on the cell membrane and Ca2+ influx. TRPV1 inhibitor capsazepine (CPZ) inhibited the relief effect of CAP on acute alcohol-induced pyroptosis. Overall, these results showed that CAP might activate ESCRT-III-dependent membrane repair machinery through Ca2+ influx, which is regulated by TRPV1 calcium channels, therefore mitigating acute alcohol-induced pyroptosis. Our research provides a new perspective on a naturally active food product to promote cell repair and relieve AALI.

Asunto(s)

Capsaicina , Membrana Celular , Complejos de Clasificación Endosomal Requeridos para el Transporte , Hepatocitos , Piroptosis , Canales Catiónicos TRPV , Piroptosis/efectos de los fármacos , Capsaicina/farmacología , Capsaicina/análogos & derivados , Animales , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Ratones , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Canales Catiónicos TRPV/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Etanol , Hepatopatías Alcohólicas/tratamiento farmacológico , Hepatopatías Alcohólicas/metabolismo

RESUMEN

Capsaicinoids are the pungent compounds in chili peppers. The present study investigated the effect of capsaicinoids on obesity in mice induced by a high-fat-high-fructose diet. Thirty-two male C57BL/6J mice were randomly divided into four groups (n = 8) and fed one of the following diets, namely, a low-fat diet (LFD), a high-fat-high-fructose diet (HFF), an HFF + 0.015% capsaicinoids (LCP), and an HFF + 0.045% capsaicinoids (HCP), for 12 weeks. Results showed that capsaicinoids significantly reversed HFF-induced obesity. Supplementation with capsaicinoids improved glucose tolerance, reduced plasma lipids, and attenuated inflammation. Capsaicinoids also reduced hepatic lipid accumulation by upregulating the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In addition, capsaicinoids enhanced the production of fecal short-chain fatty acids (SCFAs) and increased the fecal excretion of lipids. Gut microbiota analysis revealed that capsaicinoids decreased the Firmicutes/Bacteroidetes ratio and beneficially reconstructed the microbial community. However, the effects of capsaicinoids on intestinal villus length and lipid tolerance were negligible. In conclusion, capsaicinoids effectively attenuated HFF-induced obesity and metabolic syndrome by favorably modulating lipid metabolism, improving SCFA production, and reshaping gut microbial structure.

Asunto(s)

Capsaicina , Dieta Alta en Grasa , Suplementos Dietéticos , Fructosa , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Obesidad , Animales , Masculino , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Ratones , Dieta Alta en Grasa/efectos adversos , Capsaicina/farmacología , Fructosa/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Capsicum/química , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Ácidos Grasos Volátiles/metabolismo

RESUMEN

Transient receptor potential vanilloid 1 (TRPV1) is a calcium-permeable ion channel that is gated by the pungent constituent of red chili pepper, capsaicin, and by related chemicals from the group of vanilloids, in addition to noxious heat. It is expressed mostly in sensory neurons to act as a detector of painful stimuli produced by pungent chemicals and high temperatures. Although TRPV1 is also found outside the sensory nervous system, its expression and function in the bladder detrusor smooth muscle (DSM) remain controversial. Here, by using Ca2+ imaging and patch clamp on isolated rat DSM cells, in addition to tensiometry on multicellular DSM strips, we show that TRPV1 is expressed functionally in only a fraction of DSM cells, in which it acts as an endoplasmic reticulum Ca2+-release channel responsible for the capsaicin-activated [Ca2+]i rise. Carbachol-stimulated contractions of multicellular DSM strips contain a TRPV1-dependent component, which is negligible in the circular DSM but reaches ≤50% in the longitudinal DSM. Activation of TRPV1 in rat DSM during muscarinic cholinergic stimulation is ensured by phospholipase A2-catalysed derivation of arachidonic acid and its conversion by lipoxygenases to eicosanoids, which act as endogenous TRPV1 agonists. Immunofluorescence detection of TRPV1 protein in bladder sections and isolated DSM cells confirmed both its preferential expression in the longitudinal DSM sublayer and its targeting to the endoplasmic reticulum. We conclude that TRPV1 is an essential contributor to the cholinergic contraction of bladder longitudinal DSM, which might be important for producing spatial and/or temporal anisotropy of bladder wall deformation in different regions during parasympathetic stimulation. KEY POINTS: The transient receptor potential vanilloid 1 (TRPV1) heat/capsaicin receptor/channel is localized in the endoplasmic reticulum membrane of detrusor smooth muscle (DSM) cells of the rat bladder, operating as a calcium-release channel. Isolated DSM cells are separated into two nearly equal groups, within which the cells either show or do not show TRPV1-dependent [Ca2+]i rise. Carbachol-stimulated, muscarinic ACh receptor-mediated contractions of multicellular DSM strips contain a TRPV1-dependent component. This component is negligible in the circular DSM but reaches ≤50% in longitudinal DSM. Activation of TRPV1 in rat DSM during cholinergic stimulation involves phospholipase A2-catalysed derivation of arachidonic acid and its conversion by lipoxygenases to eicosanoids, which act as endogenous TRPV1 agonists.

Asunto(s)

Contracción Muscular , Músculo Liso , Canales Catiónicos TRPV , Vejiga Urinaria , Animales , Canales Catiónicos TRPV/metabolismo , Vejiga Urinaria/fisiología , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/metabolismo , Contracción Muscular/fisiología , Músculo Liso/fisiología , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Ratas , Masculino , Carbacol/farmacología , Capsaicina/farmacología , Calcio/metabolismo , Ratas Sprague-Dawley , Ratas Wistar

RESUMEN

Stimulation of the calcium-sensing receptor (CaSR) regulates vascular contractility, but cellular mechanisms involved remain unclear. This study investigated the role of perivascular sensory nerves in CaSR-induced relaxations of male rat mesenteric arteries. In fluorescence studies, colocalisation between synaptophysin, a synaptic vesicle marker, and the CaSR was present in the adventitial layer of arterial segments. Using wire myography, increasing external Ca2+ concentration ([Ca2+]o) from 1 to 10 mM induced vasorelaxations, previously shown to involve the CaSR, which were inhibited by pretreatment with capsaicin. [Ca2+]o-induced vasorelaxations were partially reduced by the calcitonin gene-related peptide (CGRP) receptor blockers, CGRP 8-37 and BIBN 4096, and the neurokinin 1 (NK1) receptor blocker L733,060. The inhibitory effect of CGRP 8-37 required a functional endothelium whereas the inhibitory action of L733,060 did not. Complete inhibition of [Ca2+]o-induced vasorelaxations occurred when CGRP 8-37 and L733,060 were applied together. [Ca2+]o-induced vasorelaxations in the presence of capsaicin were abolished by the ATP-dependent K+ channel (KATP) blocker PNU 37883, but unaffected by the endothelium nitric oxide synthase (eNOS) inhibitor L-NAME. We suggest that the CaSR on perivascular sensory nerves mediate relaxations in rat mesenteric arteries via endothelium-dependent and -independent mechanisms involving CGRP and NK1 receptor-activated NO production and KATP channels, respectively.

Asunto(s)

Péptido Relacionado con Gen de Calcitonina , Arterias Mesentéricas , Receptores Sensibles al Calcio , Receptores de Neuroquinina-1 , Vasodilatación , Animales , Masculino , Receptores Sensibles al Calcio/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Péptido Relacionado con Gen de Calcitonina/farmacología , Receptores de Neuroquinina-1/metabolismo , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Arterias Mesentéricas/metabolismo , Ratas , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Ratas Wistar , Antagonistas del Receptor de Neuroquinina-1/farmacología , Calcio/metabolismo , Capsaicina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Transducción de Señal/fisiología

RESUMEN

The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is unknown but likely multifactorial. IC/BPS symptoms can be exacerbated by psychological stress, but underlying mechanisms remain to be defined. Transient receptor potential vanilloid 1 (TRPV1) channels, expressed on nerve fibers, have been implicated in bladder dysfunction and colonic hypersensitivity with stress in rodents. Histamine/H1R activation of TRPV1+ nerves increases bladder afferent fiber sensitivity to distension. TRPV1 channels are also expressed on mast cells, previously implicated in contributing to IC/BPS etiology and symptoms. We have examined the contribution of TRPV1 and mast cells to bladder dysfunction after repeated variate stress (RVS). RVS increased (P ≤ 0.05) serum and fecal corticosterone expression and induced anxiety-like behavior in wild-type (WT) mice. Intravesical instillation of the selective TRPV1 antagonist capsazepine (CPZ) rescued RVS-induced bladder dysfunction in WT mice. Trpv1 knockout (KO) mice did not increase voiding frequency with RVS and did not exhibit increased serum corticosterone expression despite exhibiting anxiety-like behavior. Mast cell-deficient mice (B6.Cg-Kitw-sh) failed to demonstrate RVS-induced increased voiding frequency or serum corticosterone expression, whereas control (no stress) mast cell-deficient mice had similar functional bladder capacity to WT mice. TRPV1 protein expression was significantly increased in the rostral lumbar (L1-L2) spinal cord and dorsal root ganglia (DRG) in WT mice exposed to RVS, but no changes were observed in lumbosacral (L6-S1) spinal segments or DRG. These studies demonstrated TRPV1 and mast cell involvement in RVS-induced increased voiding frequency and suggest that TRPV1 and mast cells may be useful targets to mitigate stress-induced urinary bladder dysfunction.NEW & NOTEWORTHY Using pharmacological tools and transgenic mice in a repeated variate stress (RVS) model in female mice, we demonstrate that transient receptor potential vanilloid 1 (TRPV1) and mast cells contribute to the increased voiding frequency observed following RVS. TRPV1 and mast cells should continue to be considered as targets to improve bladder function in stress-induced bladder dysfunction.

Asunto(s)

Corticosterona , Mastocitos , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Psicológico , Canales Catiónicos TRPV , Vejiga Urinaria , Animales , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Mastocitos/metabolismo , Femenino , Vejiga Urinaria/metabolismo , Vejiga Urinaria/inervación , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Corticosterona/sangre , Modelos Animales de Enfermedad , Cistitis Intersticial/metabolismo , Cistitis Intersticial/fisiopatología , Cistitis Intersticial/patología , Cistitis Intersticial/genética , Ratones , Micción , Capsaicina/farmacología , Capsaicina/análogos & derivados , Conducta Animal , Ansiedad/metabolismo

RESUMEN

Although anesthesia provides favorable conditions for surgical procedures, recent studies have revealed that the brain remains active in processing noxious signals even during anesthesia. However, whether and how these responses affect the anesthesia effect remains unclear. The ventrolateral periaqueductal gray (vlPAG), a crucial hub for pain regulation, also plays an essential role in controlling general anesthesia. Hence, it was hypothesized that the vlPAG may be involved in the regulation of general anesthesia by noxious stimuli. Here, we found that acute noxious stimuli, including capsaicin-induced inflammatory pain, acetic acid-induced visceral pain, and incision-induced surgical pain, significantly delayed recovery from sevoflurane anesthesia in male mice, whereas this effect was absent in the spared nerve injury-induced chronic pain. Pretreatment with peripheral analgesics could prevent the delayed recovery induced by acute nociception. Furthermore, we found that acute noxious stimuli, induced by the injection of capsaicin under sevoflurane anesthesia, increased c-Fos expression and activity in the GABAergic neurons of the ventrolateral periaqueductal gray. Specific reactivation of capsaicin-activated vlPAGGABA neurons mimicked the effect of capsaicin and its chemogenetic inhibition prevented the delayed recovery from anesthesia induced by capsaicin. Finally, we revealed that the vlPAGGABA neurons regulated the recovery from anesthesia through the inhibition of ventral tegmental area dopaminergic neuronal activity, thus decreasing dopamine (DA) release and activation of DA D1-like receptors in the brain. These findings reveal a novel, cell- and circuit-based mechanism for regulating anesthesia recovery by nociception, and it is important to provide new insights for guiding the management of the anesthesia recovery period.

Asunto(s)

Anestésicos por Inhalación , Ratones Endogámicos C57BL , Nocicepción , Sustancia Gris Periacueductal , Sevoflurano , Sevoflurano/farmacología , Animales , Masculino , Ratones , Anestésicos por Inhalación/farmacología , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Mesencéfalo/efectos de los fármacos , Estado de Conciencia/efectos de los fármacos , Estado de Conciencia/fisiología , Periodo de Recuperación de la Anestesia , Capsaicina/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/fisiología