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.

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.

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.

As a fruit and vegetable crop, the ornamental pepper is not just highly ornamental but also rich in nutritional value. The quality of ornamental pepper fruits is given in their contents of capsaicin, vitamin C (VC), flavonoids and total phenols. The study concentrated on the accumulation of capsaicin and dihydrocapsaicin in different tissues of 18 peppers during fruit growth and development. The results showed that the pericarp and placenta contained significantly higher levels of capsaicin than dihydrocapsaicin. Additionally, the placenta contained significantly higher levels of both capsaicin and dihydrocapsaicin compared to the pericarp. The content of capsaicin was in the range of 0-6.7915 mg·g-1, the range of dihydrocapsaicin content was 0-5.329 mg·g-1. Interestingly, we found that the pericarp is rich in VC (5.4506 mg·g-1) and the placenta is high in flavonoids (4.8203 mg·g-1) and total phenols (119.63 mg·g-1). The capsaicin is the most important component using the correlation analysis and principal component analysis. The qPCR results substantiated that the expression of genes in the placenta was significantly higher than that in the pericarp and that the expression of genes in green ripening stage was higher than that in red ripening stage. This study could be utilized to select the best ripening stages and tissues to harvest peppers according to the use of the pepper and to the needs of producers. It not only provides a reference for quality improvement and processing for consumers and market but also provides a theoretical basis for high-quality pepper breeding.

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.
METHODS: 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.
METHODS: The identification test combines taste and somatosensory perception, thus creating a more detailed diagnosis tool. Scores were correlated with self-rated taste perception.
CONCLUSIONS: 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.

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 possibilities 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.

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.

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.

Obesity is a widespread prevailing health concern with multifactorial causes. Among the various defined molecular targets associated with obesity, peroxisome proliferator activated receptor gamma, leptin, ghrelin, and adiponectin play crucial roles in fundamental processes including energy balance, adipose tissue biology, and metabolic health, making them particularly significant in the study of obesity.Capsaicin and orange peel exhibit promising anti-obesity properties through their thermogenic, metabolic, and anti-inflammatory effects. Potential pathways for therapeutic approaches in the management of obesity are provided by these targets. The lipid-lowering and anti-obesity benefits of specific plant species have been highlighted in Asian medicine. Due to the potential anti-obesity qualities, capsaicin, which is derived from chilli peppers, and orange peel extract has been focused in this review. Capsaicin causes apoptosis in preadipocytes and adipocytes and suppresses adipogenesis. Citrus fruits are a significant source of bioactive substances, primarily flavonoids. Due to their ability to reduce adipocyte development and cellular lipid content, citrus polyphenols are helpful in the control of obesity. This extensive analysis offers insights into new treatment approaches for the prevention and management of obesity and metabolic syndrome by examining the interactions of molecular variables in obesity as well as the possible anti-obesity advantages of capsaicin and orange peel extract.

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).