Interrelated involvement of the endocannabinoid/endovanilloid (TRPV1) systems and epigenetic processes in anxiety- and working memory impairment-related behavioural effects of nicotine as a stressor.

The addictive use of nicotine contained in tobacco is associated with stressor-like emotional and cognitive effects such as anxiety and working memory impairment, and the involvement of epigenetic mechanisms such as histone acetylation has recently been reported. Although the precise nature of behavioural plasticity remains unclear, both anxiogenic- and working memory impairment-like effects were observed in the present experimental model of mice treated with repeated subcutaneous nicotine and/or immobilization stress, and these effects were commonly attenuated by the histone deacetylase (HDAC) inhibitors that induce histone acetylation. Such HDAC inhibitor-induced resilience was mimicked by ligands for the endocannabinoid (ECB) system, a neurotransmitter system that is closely associated with nicotine-induced addiction-related behaviours: the anxiogenic-like effects were mitigated by the cannabinoid type 1 (CB1) agonist arachidonylcyclopropylamide (ACPA), whereas the working memory impairment-like effects were mitigated by the CB1 antagonist SR 141716A. Moreover, the effects of the HDAC inhibitors were also mimicked by ligands for the endovanilloid (transient receptor potential vanilloid 1 [TRPV1]) system, a system that shares common characteristics with the ECB system: the anxiogenic-like effects were mitigated by the TRPV1 antagonist capsazepine, whereas the working memory impairment-like effects were mitigated by the TRPV1 agonist olvanil. Notably, the HDAC inhibitor-induced anxiolytic-like effects were attenuated by SR 141716A, which were further counteracted by capsazepine, whereas the working memory improvement-like effects were attenuated by capsazepine, which were further counteracted by SR 141716A. These results suggest the contribution of interrelated control of the ECB/TRPV1 systems and epigenetic processes such as histone acetylation to novel therapeutic approaches.

The difference analysis of physicochemical indexes and volatile flavor compounds of chili oil prepared from different varieties of chili pepper.

Because of its peculiar flavor, chili oil is widely used in all kinds of food and is welcomed by people. Chili pepper is an important raw material affecting its quality, and commercial chili oil needs to meet various production needs, so it needs to be made with different chili peppers. However, the current compounding method mainly relies on the experience of professionals and lacks the basis of objective numerical analysis. In this study, the chroma and capsaicinoids of different chili oils were analyzed, and then the volatile components were determined by gas chromatography-mass spectrometry (GC-MS) and gas chromatography-ion migration spectrometer (GC-IMS) and electronic nose (E-nose). The results showed that Zidantou chili oil had the highest L*, b*, and color intensity (ΔE) (52.76 ± 0.52, 88.72 ± 0.89, and 118.84 ± 1.14), but the color was tended to be greenyellow. Xinyidai chili oil had the highest a* (65.04 ± 0.2). But its b* and L* were relatively low (76.17 ± 0.29 and 45.41 ± 0.16), and the oil was dark red. For capsaicinoids, Xiaomila chili oil had the highest content of capsaicinoids was 2.68 ± 0.07 g/kg, Tianjiao chili oil had the lowest content of capsaicinoids was 0.0044 ± 0.0044 g/kg. Besides, 96 and 54 volatile flavor substances were identified by GC-MS and GC-IMS respectively. And the main volatile flavor substances of chili oil were aldehydes, alcohols, ketones, and esters. A total of 11 key flavor compounds were screened by the relative odor activity value (ROAV). Moguijiao chili oil and Zidantou chili oil had a prominent grass aroma because of hexanal, while Shizhuhong chili oil, Denglongjiao chili oil, Erjingtiao chili oil, and Zhoujiao chili oil had a prominent floral aroma because of 2, 3-butanediol. Chili oils could be well divided into 3 groups by the partial least squares discriminant analysis (PLS-DA). According to the above results, the 10 kinds of chili oil had their own characteristics in color, capsaicinoids and flavor. Based on quantitative physicochemical indicators and flavor substances, the theoretical basis for the compounding of chili oil could be provided to meet the production demand more scientifically and accurately.

Galacturonic acid-capsaicin prodrug for prolonged nociceptive-selective nerve blockade.

There is an urgent clinical need to develop nerve-blocking agents capable of inducing long duration sensory block without muscle weakness or paralysis to treat post-operative and chronic pain conditions. Here, we report a galacturonic acid-capsaicin (GalA-CAP) prodrug as an effective nociceptive-selective axon blocking agent. Capsaicin selectively acts on nociceptive signaling without motor nerve blockade or disruption of proprioception and touch sensation, and the galacturonic acid moiety enhance prodrug permeability across the restrictive peripheral nerve barriers (PNBs) via carrier-mediated transport by the facilitative glucose transporters (GLUTs). In addition, following prodrug transport across PNBs, the inactive prodrug is converted to active capsaicin through linker hydrolysis, leading to sustained drug release. A single injection of GalA-CAP prodrug at the sciatic nerves of rats led to nociceptive-selective nerve blockade lasting for 234 ± 37 h, which is a sufficient duration to address the most intense period of postsurgical pain. Furthermore, the prodrug markedly mitigated capsaicin-associated side effects, leading to a notable decrease in systemic toxicity, benign local tissue reactions, and diminished burning and irritant effects.

Roles of Thermosensitive Transient Receptor Channels TRPV1 and TRPM8 in Paclitaxel-Induced Peripheral Neuropathic Pain.

Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this study, Western blotting, immunofluorescence staining, and calcium imaging revealed that the expression and functional activity of TRPV1 were upregulated in rat dorsal root ganglion (DRG) neurons in PIPNP. Behavioral assessments using the von Frey and brush tests demonstrated that mechanical hyperalgesia in PIPNP was significantly inhibited by intraperitoneal or intrathecal administration of the TRPV1 antagonist capsazepine, indicating that TRPV1 played a key role in PIPNP. Conversely, the expression of TRPM8 protein decreased and its channel activity was reduced in DRG neurons. Furthermore, activation of TRPM8 via topical application of menthol or intrathecal injection of WS-12 attenuated the mechanical pain. Mechanistically, the TRPV1 activity triggered by capsaicin (a TRPV1 agonist) was reduced after menthol application in cultured DRG neurons, especially in the paclitaxel-treated group. These findings showed that upregulation of TRPV1 and inhibition of TRPM8 are involved in the generation of PIPNP, and they suggested that inhibition of TRPV1 function in DRG neurons via activation of TRPM8 might underlie the analgesic effects of menthol.

Randomized Placebo-Controlled Trial of Topical Capsaicin for Delayed Chemotherapy-Induced Nausea and Vomiting.

PURPOSE: We examined the efficacy of topical capsaicin in reducing delayed chemotherapy-induced nausea and vomiting (CINV). METHODS: Adults on highly emetogenic chemotherapy regimens applied 2 g of capsaicin ointment (0.075%) or matching placebo four times a day to the abdomen for 5 days in addition to standard antiemetic regimen in this blinded randomized controlled trial. Patients were monitored for nausea and vomiting in the immediate (day 1), delayed (days 2-5), and extended phases (days 2-15). Self-reported incidence and daily episodes of CINV were compared between the groups. Onset, severity, need for rescue antiemetics, cumulative vomiting episodes, and safety were also compared. RESULTS: In total, 160 patients were enrolled. The final modified intention-to-treat population included 75 patients each in the capsaicin and placebo groups. Fewer patients experienced nausea (36.0% [n = 27] v 53.3% [n = 40]; P = .033) and vomiting (28.0% [n = 21] v 42.7% [n = 32]; P = .060) in the capsaicin arm during the delayed phase. During the extended phase, there was a significantly lower incidence of nausea (44% v 64.0%; P = .014) in the capsaicin arm. No difference in nausea (26.7% v 25.3%) or vomiting (22.7% v 18.7%) was evident in the immediate phase. The average daily episodes of nausea and vomiting were significantly fewer in the capsaicin arm during the delayed and extended phases. With capsaicin, no grade 3 nausea (9.3% v 0.0%; P = .007) was observed, and the time to first nausea and vomiting was significantly prolonged. There were no differences between the groups with respect to rescue antiemetics, unscheduled hospital visits, and adverse events. CONCLUSION: Topical capsaicin reduced the incidence of nausea and the average number of vomiting episodes during delayed and extended phases without increasing adverse effects.

Development of an RP-HPLC Method for Quantifying Diclofenac Diethylamine, Methyl Salicylate, and Capsaicin in Pharmaceutical Formulation and Skin Samples.

An RP-HPLC method with a UV detector was developed for the simultaneous quantification of diclofenac diethylamine, methyl salicylate, and capsaicin in a pharmaceutical formulation and rabbit skin samples. The separation was achieved using a Thermo Scientific ACCLAIMTM 120 C18 column (Waltham, MA, USA, 4.6 mm × 150 mm, 5 µm). The optimized elution phase consisted of deionized water adjusted to pH = 3 using phosphoric acid mixed with acetonitrile in a 35:65% (v/v) ratio with isocratic elution. The flow rate was set at 0.7 mL/min, and the detection was performed at 205 nm and 25 °C. The method exhibits good linearity for capsaicin (0.05-70.0 µg/mL), methyl salicylate (0.05-100.0 µg/mL), and diclofenac diethylamine (0.05-100.0 µg/mL), with low LOD values (0.0249, 0.0271, and 0.0038 for capsaicin, methyl salicylate, and diclofenac diethylamine, respectively). The RSD% values were below 3.0%, indicating good precision. The overall greenness score of the method was 0.61, reflecting its environmentally friendly nature. The developed RP-HPLC method was successfully applied to analyze Omni Hot Gel® pharmaceutical formulation and rabbit skin permeation samples.

Effective suppression of Ih and INa caused by capsazepine, known to be a blocker of TRPV1 receptor.

A synthetic inhibitor of capsaicin-induced TRPV1 channel activation is called capsazepine (CPZ). In this study, we aimed to explore the effects of CPZ on hyperpolarization-activated cationic current (Ih) and voltage-gated Na + current (INa) in pituitary tumor (GH3) cells. Through patch-clamp recordings, we found that CPZ concentration-dependently inhibited Ih amplitude and slowed its activation time course. The IC50 and KD values were 3.1 and 3.16 µM, respectively. CPZ also shifted the steady-state activation curve of Ih towards a more hyperpolarized potential. However, there was no change in the gating charge of the curve. A modified Markovian model predicted the CPZ-induced decrease in the voltage-dependent hysteresis of Ih. CPZ suppressed INa in GH3 cells, without altering its activation or inactivation time course. Additionally, exposure to CPZ reduced spontaneous firing. These findings suggest that CPZ's inhibitory effects on Ih and INa are direct and not dependent on vanilloid receptor binding. This could provide light on an unidentified ionic mechanism influencing the membrane excitability of neurons and endocrine or neuroendocrine cells in vivo.

Genetic Influence on Capsaicin Tolerance: Precision Nutrition Implications for Obesity Handling.

INTRODUCTION: It has been suggested that capsaicin (CAP), a major pungent component in chili peppers, can be used as an anti-obesity ingredient due to effects on energy metabolism, but evidence is not consistent. Genetics may account for differences in CAP tolerance and its impact on adiposity status. The aim of this study was to systematically review current evidence concerning the role of genetic polymorphisms influencing CAP tolerance. METHODS: The present systematic review analyzed and synthesized available evidence concerning associations between genetic polymorphisms and CAP tolerance following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. Databases such as PubMed/MEDLINE, Cochrane, Scopus, Google Scholar, SciELO, and LILACS were screened. Out of 228 publications identified, only 6 meet inclusion criteria and were finally included in the final report. RESULTS: Overall, a total of 28 single nucleotide polymorphisms were associated with several CAP tolerance traits including sensitivity to burning/stinging, heat pain, and cough reactions, and detection of bitter taste thresholds. These genetic variants were located within 6 genes involved in key physiological processes such synthesis of tetrahydrobiopterin and nitric oxide production (GCH1), CAP uptake and transduction of thermal stimuli (TRPV1), and bitter taste perception (TAS2R38, TAS2R3, TAS2R4, and TAS2R5). CONCLUSION: There is evidence about the influence of genetic polymorphisms on CAP tolerance by affecting nociceptive signaling, CAP binding, and bitter tasting. This knowledge may facilitate the design and implementation of innovative CAP-based nutrigenetic strategies for a more precise clinical management of obesity.

The effects of simulated gastroesophageal reflux on infant pig oropharyngeal feeding physiology.

The neural connectivity among the oral cavity, pharynx, and esophagus is a critical component of infant feeding physiology. Central integration of oral and pharyngeal afferents alters motor outputs to structures that power swallowing, but the potential effects of esophageal afferents on preesophageal feeding physiology are unclear. These effects may explain the prevalence of oropharyngeal dysphagia in infants suffering from gastroesophageal reflux (GER), though the mechanism underlying this relationship remains unknown. Here we use the validated infant pig model to assess the impacts of simulated GER on preesophageal feeding parameters. We used high-speed videofluoroscopy and electromyography to record bottle-feeding before and following the infusion of a capsaicin-containing solution into the lower esophagus. Sucking parameters were minimally affected by capsaicin exposure, such that genioglossus activity was unchanged and tongue kinematics were largely unaffected. Aspects of the pharyngeal swallow were altered with simulated GER, including increased thyrohyoid muscle activity, increased excursions of the hyoid and thyroid per swallow, decreased swallow frequency, and increased bolus sizes. These results suggest that esophageal afferents can elicit changes in pharyngeal swallowing. In addition, decreased swallowing frequency may be the mechanism by which esophageal pathologies induce oropharyngeal dysphagia. Although recent work indicates that oral or pharyngeal capsaicin may improve dysphagia symptoms, the decreased performance following esophageal capsaicin exposure highlights the importance of designing sensory interventions based upon neurophysiology and the mechanisms underlying disordered feeding. This mechanistic approach requires comprehensive data collection across the entirety of the feeding process, which can be achieved using models such as the infant pig.NEW & NOTEWORTHY Simulated gastroesophageal reflux (GER) in an infant pig model resulted in significant changes in pharyngeal swallowing, which suggests that esophageal afferents are centrally integrated to alter motor outputs to the pharynx. In addition, decreased swallow frequency and increased bolus sizes may be underlying mechanisms by which esophageal pathologies induce oropharyngeal dysphagia. The infant pig model used here allows for a mechanistic approach, which can facilitate the design of intervention strategies based on neurophysiology.

Capsaicin combined with stem cells improved mitochondrial dysfunction in PIG3V cells, an immortalized human vitiligo melanocyte cell line, by inhibiting the HSP70/TLR4/mTOR/FAK signaling axis.

BACKGROUND: Vitiligo is a common autoimmune skin disease. Capsaicin has been found to exert a positive effect on vitiligo treatment, and mesenchymal stem cells (MSCs) are also confirmed to be an ideal cell type. This study aimed to explore the influence of capsaicin combined with stem cells on the treatment of vitiligo and to confirm the molecular mechanism of capsaicin combined with stem cells in treating vitiligo. METHODS AND RESULTS: PIG3V cell proliferation and apoptosis were detected using CCK-8 and TUNEL assays, MitoSOX Red fluorescence staining was used to measure the mitochondrial ROS level, and JC-1 staining was used to detect the mitochondrial membrane potential. The expression of related genes and proteins was detected using RT‒qPCR and Western blotting. Coimmunoprecipitation was used to analyze the protein interactions between HSP70 and TLR4 or between TLR4 and mTOR. The results showed higher expression of HSP70 in PIG3V cells than in PIG1 cells. The overexpression of HSP70 reduced the proliferation of PIG3V cells, promoted apoptosis, and aggravated mitochondrial dysfunction and autophagy abnormalities. The expression of HSP70 could be inhibited by capsaicin combined with MSCs, which increased the levels of Tyr, Tyrp1 and DCT, promoted the proliferation of PIG3V cells, inhibited apoptosis, activated autophagy, and improved mitochondrial dysfunction. In addition, capsaicin combined with MSCs regulated the expression of TLR4 through HSP70 and subsequently affected the mTOR/FAK signaling pathway CONCLUSIONS: Capsaicin combined with MSCs inhibits TLR4 through HSP70, and the mTOR/FAK signaling pathway is inhibited to alleviate mitochondrial dysfunction and autophagy abnormalities in PIG3V cells.

Innervation of nociceptor neurons in the spleen promotes germinal center responses and humoral immunity.

Peripheral sensory neurons widely innervate various tissues to continuously monitor and respond to environmental stimuli. Whether peripheral sensory neurons innervate the spleen and modulate splenic immune response remains poorly defined. Here, we demonstrate that nociceptive sensory nerve fibers extensively innervate the spleen along blood vessels and reach B cell zones. The spleen-innervating nociceptors predominantly originate from left T8-T13 dorsal root ganglia (DRGs), promoting the splenic germinal center (GC) response and humoral immunity. Nociceptors can be activated by antigen-induced accumulation of splenic prostaglandin E2 (PGE2) and then release calcitonin gene-related peptide (CGRP), which further promotes the splenic GC response at the early stage. Mechanistically, CGRP directly acts on B cells through its receptor CALCRL-RAMP1 via the cyclic AMP (cAMP) signaling pathway. Activating nociceptors by ingesting capsaicin enhances the splenic GC response and anti-influenza immunity. Collectively, our study establishes a specific DRG-spleen sensory neural connection that promotes humoral immunity, suggesting a promising approach for improving host defense by targeting the nociceptive nervous system.

High humidity and NO2 co-exposure exacerbates allergic asthma by increasing oxidative stress, inflammatory and TRP protein expressions in lung tissue.

Allergic asthma is a chronic inflammatory airway disease with a high mortality rate and a rapidly increasing prevalence in recent decades that is closely linked to environmental change. Previous research found that high humidity (HH) and the traffic-related air pollutant NO2 both aggregated allergic asthma. Their combined effect and mechanisms on asthma exacerbation, however, are unknown. Our study aims to toxicologically clarify the role of HH (90%) and NO2 (5 ppm) on allergic asthma. Ninety male Balb/c mice were randomly assigned to one of six groups (n = 15 in each): saline control, ovalbumin (OVA)-sensitized, OVA + HH, OVA + NO2, OVA + HH + NO2, and OVA + HH + NO2+Capsazepine (CZP). After 38 days of treatment, the airway function, pathological changes in lung tissue, blood inflammatory cells, and oxidative stress and inflammatory biomarkers were comprehensively assessed. Co-exposure to HH and NO2 exacerbated histopathological changes and airway hyperresponsiveness, increased IgE, oxidative stress markers malonaldehyde (MDA) and allergic asthma-related inflammation markers (IL-1ß, TNF-α and IL-17), and upregulated the expressions of the transient receptor potential (TRP) ion channels (TRPA1, TRPV1 and TRPV4). Our findings show that co-exposure to HH and NO2 disrupted the Th1/Th2 immune balance, promoting allergic airway inflammation and asthma susceptibility, and increasing TRPV1 expression, whereas CZP reduced TRPV1 expression and alleviated allergic asthma symptoms. Thus, therapeutic treatments that target the TRPV1 ion channel have the potential to effectively manage allergic asthma.

Alcohol inducing macrophage M2b polarization in colitis by modulating the TRPV1-MAPK/NF-κB pathways.

BACKGROUND: Macrophages exhibit different phenotypes in inflammatory bowel disease (IBD) and promote inflammation or tissue repair depending on their polarization state. Alcohol is a widely used solvent in pharmaceutical formulations, and its consumption is associated with an increased risk of colitis; however, its effects on macrophages in IBD remain poorly understood. PURPOSE: This study aimed to investigate the effect of alcohol on macrophages in dextran sodium sulfate (DSS)-induced colitis and understand the underlying mechanisms. METHODS: DSS-treated C57BL/6 mice were exposed to varying concentrations of alcohol, transient receptor potential vanilloid 1 (TRPV1) antagonist, and 5-aminosalicylic acid. The distal colon was resected, fixed, stained, and histologically analyzed, through hematoxylin and eosin (H&E) staining and immunofluorescence staining. Ratio [Ca2+]i measurements, western blotting, quantitative polymerase chain reaction, cytokine measurements, and RNA sequencing analyses were also performed. Peritoneal macrophages and RAW264.7 cells were used for in vitro experiments, and various assays were performed to evaluate cellular responses, gene expression, and signaling pathways. RESULTS: Alcohol exacerbated DSS-treated mice colitis and promoted the secretion of various inflammatory cytokines from colonic macrophages. Alcohol enhances the calcium ion influx induced by lipopolysaccharide (LPS) in peritoneal macrophages, while the TRPV1 antagonist capsazepine (CPZ) inhibits LPS- and/or alcohol- induced calcium influx in macrophages. Alcohol and LPS activate the MAPK/P38, MAPK/ERK, and NF-κB signaling pathways and induce the macrophage M2b polarization, resulting in the increased expression level of inflammatory cytokines such as Tnf, Il1b, and Il10. Additionally, CPZ can inhibit the facilitatory effects of alcohol or LPS on the abovementioned pathways and inflammatory factors, reversing macrophage M2b polarization and promoting alcohol-induced colitis. The inhibition of nucleotide binding oligomerization domain containing 2 (NOD2) partially suppressed the alcohol and LPS effects on macrophages. CONCLUSION: Alcohol exacerbates experimental colitis and induces M2b polarization of macrophage via TRPV1-MAPK/NF-κB. Our study provides new insights into the potential therapeutic targets for IBD treatment by elucidating the role of TRPV1 in alcohol-exacerbated colitis, using CPZ as a potential therapeutic option. The identification of transient receptor potential ankyrin subtype 1 (TRPA1) as a therapeutic target expands the scope of future research.

Comparative effectiveness of nitro dihydrocapsaicin, new synthetic derivative capsaicinoid, and capsaicin in alleviating oxidative stress and inflammation on lipopolysaccharide-stimulated corneal epithelial cells.

Loss of tear homeostasis, characterized by hyperosmolarity of the ocular surface, induces cell damage through inflammation and oxidation. Transient receptor potential vanilloid 1 (TRPV1), a sensor for osmotic changes, plays a crucial role as a calcium ion channel in the pathogenesis of hypertonic-related eye diseases. Capsaicin (CAP), a potent phytochemical, alleviates inflammation during oxidative stress events by activating TRPV1. However, the pharmacological use of CAP for eye treatment is limited by its pungency. Nitro dihydrocapsaicin (NDHC) was synthesized with aromatic ring modification of CAP structure to overcome the pungent effect. We compared the molecular features of NDHC and CAP, along with their biological activities in human corneal epithelial (HCE) cells, focusing on antioxidant and anti-inflammatory activities. The results demonstrated that NDHC maintained cell viability, cell shape, and exhibited lower cytotoxicity compared to CAP-treated cells. Moreover, NDHC prevented oxidative stress and inflammation in HCE cells following lipopolysaccharide (LPS) administration. These findings underscore the beneficial effect of NDHC in alleviating ocular surface inflammation, suggesting that NDHC may serve as an alternative anti-inflammatory agent targeting TRPV1 for improving hyperosmotic stress-induced ocular surface damage.

Novel Immunosensor Based on Metal Single-Atom Nanozymes with Enhanced Oxidase-Like Activity for Capsaicin Analysis in Spicy Food.

Capsaicin (CAP) is a primary indicator for assessing the level of pungency. Herein, iron-based single-atom nanozymes (SAzymes) (Fe/NC) with exceptional oxidase-like activity were used to construct an immunosensor for CAP analysis. Fe/NC could imitate oxidase actions by transforming O2 to •O2- radicals in the absence of hydrogen peroxide (H2O2), which could avoid complex operations and unstable results. By regulating the Fe atom loads, an optimal Fe0.7/NC atom usage rate could improve the catalytic activity (Michaelis-Menten constant (Km) = 0.09 mM). Fe0.7/NC was integrated with goat antimouse IgG by facile mix incubation to develop a competitive enzyme-linked immunosorbent assay (ELISA). Our Fe0.7/NC immunosensing platform is anticipated to outperform the conventional ELISA in terms of stability and shelf life. The proposed immunosensor provided color responses across 0.01-1000 ng/mL CAP concentrations, with a detection limit of 0.046 ng/mL. Fe/NC may have potential as nanozymes for CAP detection in spicy foods, with promising applications in food biosensing.

Enhanced Bone Healing Through Systemic Capsaicin Administration: An Experimental Study on Wistar Rats.

BACKGROUND The healing of bone defects is a serious challenge worldwide. One branch of dentistry deals with bone defects. Capsaicin has anti-inflammatory, anti-oxidative, and cholesterol-reducing effects. The aim of this study was to evaluate the effects of systemic capsaicin administered at different doses on bone healing. MATERIAL AND METHODS A total of 32 male wistar rats was used, their weight varying between 250 and 300 g. The rats were randomly divided into 4 groups of 8 rats each. The analyses served to evaluate the effect on healing of different doses of capsaicin and grafts. A significant increase was observed in the number of osteoblasts in the capsaicin-applied groups, compared with the control group. RESULTS The analyses served to evaluate the effect on healing of different doses of capsaicin and grafts. A significant increase was observed in the number of osteoblasts in the capsaicin-applied groups, compared with that of the control group. The inflammation scores showed a significant difference only in the control group and in the group administered with 50 mg/kg capsaicin (P=0.010). The osteoclast counts were significantly different between all groups. CONCLUSIONS As a result of the analyses, positive effects on bone healing were observed when capsaicin 0.25 mg/kg and 0.50 mg/kg was administered intraperitoneally. However, more studies are needed for more accurate information.

A Comprehensive Review of Capsaicin and Its Role in Cancer Prevention and Treatment.

This study examines the fundamental chemical mechanisms responsible for capsaicin's advantageous impact on cancer, specifically investigating its influence on several biological processes such as inflammation in cancer metastasis, apoptosis, angiogenesis, and cellular proliferation. This entity's connections with other signaling pathways, including PI3K/AKT, NF-B, and TRPV channels, which have been linked to tumor growth, are thoroughly examined in this work. This study presents a thorough analysis of preclinical studies and clinical trials investigating the efficacy of capsaicin in treating many forms of cancer, such as breast, prostate, colorectal, pancreatic, and others. Through tests conducted in both live organisms and laboratory settings, it has been determined that capsaicin has the ability to inhibit tumor growth and induce apoptosis in cancer cells. (in vitro and in vivo). Researchers have also looked at the results of combining capsaicin with chemotherapy medications in traditional treatment. The efficacy and bioavailability of capsaicin as a viable medicinal drug are being studied, along with ways to improve its clinical value. The present investigation carefully assesses the challenges and potential options for maximizing the therapeutic benefits of capsaicin, including customized drug delivery and personalized therapeutic strategies. In finalization, this comprehensive investigation brings together the evidence currently obtainable on the anticancer properties of capsaicin, underscoring its potential as an autonomous treatment option in the struggle against cancer. Capsaicin is a compound of significant relevance for continuing research and clinical exploration in the field of cancer treatment due to its diverse mechanisms of action and ability for boosting prevailing therapy approaches.

Theoretical exploration of the phenolic compounds' inhibition mechanism of heterocyclic aromatic amines in roasted beef patties by density functional theory.

The ability of spices (bay leaf, star anise, and red pepper) and their characteristic phenolic compounds (quercetin, kaempferol, and capsaicin) to inhibit Heterocyclic aromatic amines (HAAs) in roasted beef patties were compared. Density functional theory (DFT) was used to reveal phenolic compounds interacting with HAAs-related intermediates and free radicals to explore possible inhibitory mechanisms for HAAs. 3 % red chili and 0.03 % capsaicin reduced the total HAAs content by 57.09 % and 68.79 %, respectively. DFT demonstrated that this was due to the stronger interaction between capsaicin and the ß-carboline HAAs intermediate (Ebind = -32.95 kcal/mol). The interaction between quercetin and phenylacetaldehyde was found to be the strongest (Ebind = -17.47 kcal/mol). Additionally, DFT indicated that capsaicin reduced the carbonyl content by transferring hydrogen atoms (HAT) to eliminate HO·, HOO·, and carbon-centered alkyl radicals. This study provided a reference for the development of DFT in the control of HAAs.

Identification of compounds that cause axonal dieback without cytotoxicity in dorsal root ganglia explants and intervertebral disc cells with potential to treat pain via denervation.

Low back pain, knee osteoarthritis, and cancer patients suffer from chronic pain. Aberrant nerve growth into intervertebral disc, knee, and tumors, are common pathologies that lead to these chronic pain conditions. Axonal dieback induced by capsaicin (Caps) denervation has been FDA-approved to treat painful neuropathies and knee osteoarthritis but with short-term efficacy and discomfort. Herein, we propose to evaluate pyridoxine (Pyr), vincristine sulfate (Vcr) and ionomycin (Imy) as axonal dieback compounds for denervation with potential to alleviate pain. Previous literature suggests Pyr, Vcr, and Imy can cause undesired axonal degeneration, but no previous work has evaluated axonal dieback and cytotoxicity on adult rat dorsal root ganglia (DRG) explants. Thus, we performed axonal dieback screening using adult rat DRG explants in vitro with Caps as a positive control and assessed cytotoxicity. Imy inhibited axonal outgrowth and slowed axonal dieback, while Pyr and Vcr at high concentrations produced significant reduction in axon length and robust axonal dieback within three days. DRGs treated with Caps, Vcr, or Imy had increased DRG cytotoxicity compared to matched controls, but overall cytotoxicity was minimal and at least 88% lower compared to lysed DRGs. Pyr did not lead to any DRG cytotoxicity. Further, neither Pyr nor Vcr triggered intervertebral disc cell death or affected cellular metabolic activity after three days of incubation in vitro. Overall, our findings suggest Pyr and Vcr are not toxic to DRGs and intervertebral disc cells, and there is potential for repurposing these compounds for axonal dieback compounds to cause local denervation and alleviate pain.

Astrocytes in preoptic area regulate acute nociception-induced hypothermia through adenosine receptors.

AIMS: The preoptic area (POA) of the hypothalamus, crucial in thermoregulation, has long been implicated in the pain process. However, whether nociceptive stimulation affects body temperature and its mechanism remains poorly studied. METHODS: We used capsaicin, formalin, and surgery to induce acute nociceptive stimulation and monitored rectal temperature. Optical fiber recording, chemical genetics, confocal imaging, and pharmacology assays were employed to confirm the role and interaction of POA astrocytes and extracellular adenosine. Immunofluorescence was utilized for further validation. RESULTS: Acute nociception could activate POA astrocytes and induce a decrease in body temperature. Manipulation of astrocytes allowed bidirectional control of body temperature. Furthermore, acute nociception and astrocyte activation led to increased extracellular adenosine concentration within the POA. Activation of adenosine A1 or A2A receptors contributed to decreased body temperature, while inhibition of these receptors mitigated the thermo-lowering effect of astrocytes. CONCLUSION: Our results elucidate the interplay between acute nociception and thermoregulation, specifically highlighting POA astrocyte activation. This enriches our understanding of physiological responses to painful stimuli and contributes to the analysis of the anatomical basis involved in the process.