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Purpose: Capsiate (cap) is a metabolite that affects a number of biological processes, and diabetic retinopathy (DR) is now known to be the primary cause of end-stage eye illness. Methods: In order to examine the effects of the cap intervention on body weight, nutritional intake, changes in body weight composition, glucose metabolism levels, retinopathy, and oxidative stress levels, we proposed using a mouse model of diabetic retinopathy caused by STZ. Results: Our findings demonstrated that, in addition to increasing lean body mass and lowering fat body mass content, cap intervention significantly improved body weight and dietary consumption in STZ mice. Additionally, our results on glucose metabolism revealed that cap had a significant impact on insulin resistance and the stabilization of OGTT levels. In conclusion, we examined the levels of oxidative stress and retinopathy. We discovered that the cap intervention greatly reduced the levels of MDA and significantly improved the levels of VEGF and retinopathy. In contrast, the STZ group's levels of SOD, CAT, and GSH were significantly higher. Conclusions: According to our research, the Cap intervention improved the damage caused by diabetic retinopathy by reversing the levels of oxidative stress and the disrupted state of glucose metabolism, which in turn decreased the levels of VEGF. [ABSTRACT FROM AUTHOR]

Capsaicinoids and capsinoids are bioactive compounds mostly found in peppers. Although preclinical studies have reported that these compounds can improve exercise performance due to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated thermogenesis, sympathetic modulation, and releasing calcium, it is still unclear how they affect exercise performance in humans as ergogenic supplements. Conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guide 2020, this systematic review examined the ergogenic effect of capsaicinoids and capsinoids on exercise performance in healthy adults. A total of 19 randomized placebo-controlled trials were included in the study. Studies were accessed by searching five databases (PubMed, Scopus, SPORTDiscus, Web of Science, and Cochrane Library). The quality of the studies was evaluated using the Cochrane risk-of-bias assessment tool. According to the study results, 10 studies examining the effect of capsaicinoid and capsinoid supplements on exercise performance reported positive effects. Also, the effect of capsaicinoids and capsinoids on exercise performance is more pronounced in resistance training. This difference, which varies according to the type of exercise, may be due to the correlation between capsaicin transient receptor potential vanilloid subtype 1 and insulin-like growth factor-1. [ABSTRACT FROM AUTHOR]

Understanding the effect of main extracts of capsicum, a general name of a series of capsaicinoids and capsinoids substances, on exercise performance can provide a basis for the application of this substance in sports. This article provides a comprehensive and critical review of the research on main extracts of capsicum and exercise performance based on selected articles published in peer-reviewed journal over the past 20 years. The results show that: The main extracts of capsicum are effective for improving aerobic endurance, anaerobic, muscle strength and high intensity intermittent exercise performance. The mechanism by which the main extracts of capsaicum enhancing muscle explosive strength, maximum strength, anaerobic performance is related to the increase of sarcoplasmic reticulum Ca2+ concentration and neuromuscular junction acetylcholine release and improving aerobic endurance, muscle endurance, high-intensity intermittent exercise performance is related to its antioxidant, anti-inflammatory, analgesic, vasodilator, and increasing energy contribution from fat. Future research needs to focus on more exercise types and subject groups, special environment, chronic intervention, dose-effect relationship, mechanism confirmation, and application of capsiate. In summary, the main extracts of capsicum can improve the exercise performance, and it may have a wide application prospect in sports.

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The requirement for good parental lines of pepper (Capsicum annuum L.) with high phytochemicals, especially for capsinoids (CATs) and capsaicinoids (CAPs), is rapidly increasing, and plant breeders are encouraged to develop new pepper varieties. The objective of this study was to estimate the general combining ability (GCA) and specific combining ability (SCA) for the contents of CATs and CAPs in pepper in two different environments. The mean performances for fresh yield, dry yield and phytochemical contents in C. annuum L. were significantly affected by the environment. The effect of additive gene action was significant in determining the traits of CAT, Sum CATs, CAT yield and Sum CAPs. Conversely, non-additive gene action played a crucial role in the accumulation of DI-CAT in this population. The parental lines 203, 201, 101 and 202 were identified as the best parents for fruit yield, sum CAPs, sum CATs and CAT yield, respectively, based on their high positive GCA values and mean actual values. The SCA estimates for fruit yield, sum CAPs and sum CATs were positive and high for the hybrids 102/203, 101/201 and 102/202, indicating that they hold promise for use in commercial hybrids. [ABSTRACT FROM AUTHOR]

Capsiate is a non-pungent analogue of capsaicin. It belongs to the family of capsinoids which are esters of vanillyl alcohol with fatty acids while capsaicin belongs to the family of capsaicinoids that are amides of vanillylamine with a variety of branched-chain fatty acids. While capsaicin is extensively reported for plethora of pharmacological actions, capsiate remains much less explored. Extracted from various species of Capsicum plant, the molecule has also been chemically synthesized via a number of synthetic and enzymatic routes. Based on its action on transient receptor potential vanilloid subfamily member 1 receptors, recent research has focused on its potential roles in treatment of obesity, metabolic disorders, cancer, cardiovascular disorders and gastro-intestinal disorders. Its toxicity profile has been reported to be much safe. The molecule, however, faces the challenge of low aqueous solubility and stability. It has been commercialized for its use as a weight loss supplement. However, the therapeutic potential of the compound which is much beyond boosting metabolism remains unexplored hitherto. This comprehensive review summarizes the studies demonstrating the therapeutic potential of capsiate in various pathological conditions. Discussed also are potential future directions for formulation strategies to develop efficient, safe and cost-effective dosage forms of capsiate to explore its role in various disease conditions. The databases investigated include Cochrane library, Medline, Embase, Pubmed and in-house databases. The search terms were "capsiate," "capsinoids," "thermogenesis," and their combinations. The articles were screened for relevance by going through their abstract. All the articles pertaining to physicochemical, physiological, pharmacological and therapeutic effects of capsiate have been included in the manuscript. [ABSTRACT FROM AUTHOR]

The requirement for good parental lines of pepper (Capsicum annuum L.) with high phytochemicals, especially for capsinoids (CATs) and capsaicinoids (CAPs), is rapidly increasing, and plant breeders are encouraged to develop new pepper varieties. The objective of this study was to estimate the general combining ability (GCA) and specific combining ability (SCA) for the contents of CATs and CAPs in pepper in two different environments. The mean performances for fresh yield, dry yield and phytochemical contents in C. annuum L. were significantly affected by the environment. The effect of additive gene action was significant in determining the traits of CAT, Sum CATs, CAT yield and Sum CAPs. Conversely, non-additive gene action played a crucial role in the accumulation of DI-CAT in this population. The parental lines 203, 201, 101 and 202 were identified as the best parents for fruit yield, sum CAPs, sum CATs and CAT yield, respectively, based on their high positive GCA values and mean actual values. The SCA estimates for fruit yield, sum CAPs and sum CATs were positive and high for the hybrids 102/203, 101/201 and 102/202, indicating that they hold promise for use in commercial hybrids.

Medical management of obesity represents a large unmet clinical need. Animal experiments suggest a therapeutic potential for dietary capsaicin, the pungent ingredient in hot chili peppers, to lose weight. This is an attractive theory since capsaicin has been a culinary staple for thousands of years and is generally deemed safe when consumed in hedonically acceptable, restaurant-like doses. This review critically evaluates the available experimental and clinical evidence for and against capsaicin as a weight control agent and comes to the conclusion that capsaicin is not a magic "exercise in a pill", although there is emerging evidence that it may help restore a healthy gut microbiota. [ABSTRACT FROM AUTHOR]

Capsiate is a non-pungent analogue of capsaicin. Consumed worldwide, capsiate hitherto remains unexplored despite its proven track record as a food ingredient and recent use for its therapeutic profile. Though possessing a much better safety profile and an equivalent therapeutic potential, the molecule has not been extensively explored in scientific research pertaining to either food or therapeutic sciences. This comprehensive review summarizes the studies demonstrating the therapeutic potential of capsiate in various pathological conditions. The mechanistic pathways for these pharmacological activities are also deliberated upon. Discussed also are various patents that have been filed for various innovative uses of capsiate. The molecule has been successfully explored in treatment of obesity, metabolic disorders, cancer, cardiovascular disorders and gastro-intestinal disorders. It, however, faces the challenge of low aqueous solubility and stability. The lack of popularity of this immensely useful therapeutic nutraceutical probably accrues from these two factors. Designing an effective dosage form with complete absence of water is a challenge in itself. The capsules available in the market for its anti-obesity effect are also oily in nature. The challenge further intensifies when topical delivery across the mucous membrane of skin is targeted. The approaches that may be used for exploration of this drug in conditions like weight management, cancer, pain, diabetes, dysphagia, skin diseases and muscle atrophy include solid lipid nanoparticles, polymer nanoparticles, dendrimers, non-aqueous nanoemulsions and even liquid/solid self-nanoemulsifying drug delivery systems that may be reconstituted at the time of injection. • Conventional and modern methods for isolation of capsiate. • Chemical and enzymatic strategies for synthesis of capsiate. • Therapeutic benefits of capsiate due to activation of TRPV1 receptors. • Patents on the isolation, formulation development and pharmacological actions of capsiate. [ABSTRACT FROM AUTHOR]

Ferroptosis, a new type of cell death has been found to aggravate intestinal ischemia/reperfusion (I/R) injury. However, little is known about the changes of gut microbiota and metabolites in intestinal I/R and the role of gut microbiota metabolites on ferroptosis-induced intestinal I/R injury. This study aimed to establish a mouse intestinal I/R model and ileum organoid hypoxia/reoxygenation (H/R) model to explore the changes of the gut microbiota and metabolites during intestinal I/R and protective ability of capsiate (CAT) against ferroptosis-dependent intestinal I/R injury. Intestinal I/R induced disturbance of gut microbiota and significant changes in metabolites. We found that CAT is a metabolite of the gut microbiota and that CAT levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with intestinal I/R injury. Furthermore, CAT reduced ferroptosis-dependent intestinal I/R injury in vivo and in vitro. However, the protective effects of CAT against ferroptosis-dependent intestinal I/R injury were abolished by RSL3, an inhibitor of glutathione peroxidase 4 (Gpx4), which is a negative regulator of ferroptosis. We also found that the ability of CAT to promote Gpx4 expression and inhibit ferroptosis-dependent intestinal I/R injury was abrogated by JNJ-17203212, an antagonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). This study suggests that the gut microbiota metabolite CAT enhances Gpx4 expression and inhibits ferroptosis by activating TRPV1 in intestinal I/R injury, providing a potential avenue for the management of intestinal I/R injury.

Peppers are fruits with wide genetic variability and multiple ways of being consumed that hold a relevant position in the human diet. Nowadays, consumers are interested in new gastronomic experiences provided by pepper cultivars that present new shapes, colors, and flavors while preserving their bioactive compounds, such as their capsaicinoids and capsinoids. However, numerous changes take place during their development that may alter their biological properties. Therefore, this work evaluates the capsaicinoid and capsiate contents in two traditional varieties of ornamental peppers (“Filius Blue” and “Filius Green’”) during fruit maturation. The aim is to determine the ideal harvesting moment depending on the farmer’s objective (e.g., achieving a specific color, shape, or flavor; achieving the maximum concentrations of bioactive compounds). The capsaicinoid contents followed different patterns in the two varieties analyzed. The “Filius Blue” variety exhibited increasing concentrations of capsaicinoids up to the 41st day post-anthesis (dpa), from which point on this trend was reversed. The concentrations in the “Filius Green” variety increased and decreased several times, reaching maximum concentrations on the 69th dpa. Regarding capsiate contents, both varieties varied in the same way, reaching maximum concentrations on the 34th dpa and then decreasing.

Highlights • The serum concentrations of anthocyanin were increased by capsaicin or capsiate. • The intestinal absorption of black chokeberry was lower than that of haskap. • The capsaicin and capsiate may open tight junctions in the rat small intestine. Abstract Recent studies have shown that aronia (black chokeberry) and haskap fruits (contain anthocyanins) have beneficial health effects in animals and humans. However, some reports have shown that anthocyanin is poorly absorbed in the small intestine. In this study, we compared the intestinal absorption of aronia and haskap anthocyanins by using rats with a ligated small intestinal loop and cannulated portal vein. Our results clearly showed that the intestinal absorption of aronia anthocyanins was significantly lower than that of haskap anthocyanins, suggesting that the intestinal absorption of anthocyanins is influenced by the glycoside type (galactoside or glucoside). In addition, we also examined the effects of capsaicin and capsiate on intestinal anthocyanin absorption. The amount of aronia anthocyanins in portal blood was much higher when they were co-administered with capsaicin or capsiate. Our study is the first to show that the intestinal absorption of aronia anthocyanins is promoted by capsaicin and capsiate. [ABSTRACT FROM AUTHOR]

Highlights • The HPLC-ESI-MS(QTOF) method has been validated for capsinoid determination. • The method developed provided higher sensitivity than the methods used routinely. • The method was used to identify capsiate and dihydrocapsiate in 8 pepper cultivars. • Capsiate was the major capsinoid in all pepper fruits. • Isomers of nornorcapsiate and nordihydrocapsiate were detected for the first time. Abstract A highly sensitive, selective method has been developed and validated for determination of capsiate and dihydrocapsiate for the first time using HPLC-ESI/MS(QTOF). For both capsinoids, LODs and LOQs were 0.02 and 0.05 µmol/l, respectively. The intra- and interday repeatability values (RSD %) were 0.26–0.41% for retention time, and 2.25–2.11% for peak area. Recoveries were up to 98% and 97% for capsiate and dihydrocapsiate, respectively. This method was successfully applied to quantify capsiate and dihydrocapsiate in eight pepper fruit accessions. Capsinoids were found in the range of 1.21–544.59 μg/g DW for capsiate and of 0.61–81.95 μg/g DW for dihydrocapsiate. In the ‘Tabasco’ accession, capsiate and dihydrocapsiate were quantified for the first time, ranging from 3.09 to 58.76 and 1.80 to 6.94 μg/g DW, respectively. Additionally, the ESI-MS/MS(QTOF) analysis has allowed the tentative identification of two other minor capsinoids by exact mass and fragmentation pattern, in the ‘Bhut Jolokia’ accession. [ABSTRACT FROM AUTHOR]

“Naga Jolokia” (Capsicum chinense Jacq.) is a hot pepper variety native to India which has received the attention of the global scientific community due to its high capsaicinoid concentration. The present study evaluated the influence of fruit ripening on the total and individual capsaicinoids, as well as capsiate content. The aim was to determine the optimal moment to harvest the peppers depending on their pungent properties. Ultrasound-assisted extraction (UAE) using methanol as the extraction solvent and reverse-phase ultra-high-performance liquid chromatography (UHPLC-photodiode array (PDA)) were employed. Capsaicinoids gradually accumulated in the peppers from the moment they started growing until they reached a maximum concentration (7.99 ± 0.11 mg g−1 of fresh weight (FW)) at 33 days postanthesis (dpa). For this reason, based on its content of pungent compounds, as it is one of the main attributes of this variety, the optimal time for collection would be on day 33. From then on, there was a sharp decrease (96.35% of the total concentration) due to the peroxidase enzymes. The evolution of the principal capsaicinoids in “Naga Jolokia” peppers had a different behavior with respect to literature reports. After this investigation, these changes in content can be attributed to each pepper genotype. Capsiate content reached it maximum value at 19 dpa (0.27 ± 0.01 mg g−1 of FW). Then, there was a gradual drop due to the activities of different peroxidases. Given the important biological activity of capsaicinoids and capsinoids, the information described here allows for determining the ideal time to harvest “Naga Jolokia” peppers.

With raising prevalence of obesity, the regulation of human body fat is increasingly relevant. The modulation of fatty acid uptake by enterocytes represents a promising target for body weight maintenance. Recent results demonstrated that the trigeminal active compounds capsaicin, nonivamide, and trans-pellitorine dose-dependently reduce fatty acid uptake in differentiated Caco-2 cells as a model for the intestinal barrier. However, non-pungent alternatives have not been investigated and structural determinants for the modulation of intestinal fatty acid uptake have not been identified so far. Thus, based on the previous results, we synthesized 23 homovanillic acid esters in addition to the naturally occurring capsiate and screened them for their potential to reduce intestinal fatty acid uptake using the fluorescent fatty acid analog Bodipy-C12 in differentiated Caco‑2 cells as an enterocyte model. Whereas pre-incubation with 100 µM capsiate did not change fatty acid uptake by Caco-2 enterocytes, a maximum inhibition of −47% was reached using 100 µM 1‑methylpentyl-2-(4-hydroxy-3-methoxy-phenyl)acetate. Structural analysis of the 24 structural analogues tested in the present study revealed that a branched fatty acid side chain, independent of the chain length, is one of the most important structural motifs associated with inhibition of fatty acid uptake in Caco-2 enterocytes. The results of the present study may serve as an important basis for designing potent dietary inhibitors of fatty acid uptake.

Background: Certain food ingredients promote thermogenesis and fat loss. Similarly, whey protein improves body composition. Due to this potential synergistic effect, a blend of thermogenic food ingredients containing African mango, citrus fruit extract, Coleus forskohlii, dihydrocapsiate and red pepper was tested alone and in combination with a whey protein supplement for its effects on body composition in sedentary mice during high-fat diet. Objective: The objective of this study was to evaluate the interaction of thermogenic foods on improving body composition during consumption of an unhealthy diet. Materials and Methods: C57BL/6J young adult male mice (n = 12) were placed on a 60% high-fat diet for 4 weeks and subsequently randomly assigned to receive daily dosing by oral gavage of vehicle, the novel blend alone or with whey protein supplement for another 4 weeks. Body composition, thermal imaging of brown adipose tissue (BAT), mitochondrial BAT uncoupling protein 1 (UCP1) and plasma levels of leptin were assessed. Results: Novel blend alone and in combination with protein supplement attenuated body weight gain, fat, and increased surface BAT temperature in comparison to vehicle control and to baseline (P < 0.5). The combination of novel blend and whey protein supplement also significantly increased UCP1 protein expression in BAT mitochondria in comparison to vehicle control and novel blend alone (P < 0.5). Conclusions: These data indicate that this novel blend stimulates thermogenesis and attenuates the gain in body weight and fat in response to high-fat diet in mice and these effects were improved when administered in combination with whey protein supplement. [ABSTRACT FROM AUTHOR]

Capsiate is a key ingredient in the fruits of a nonpungent cultivar of Capsicum annuum . We investigated the effects of a C. annuum extract (CE) and a capsiate-rich fraction of CE (CR) on nuclear receptors involved in multiple signaling pathways, glucose uptake, and adipogenesis in comparison to pure capsiate (Ca). Similar to the effect of Ca (100 μM), CE (500 μg/mL) and CR (100 μg/mL) caused the activation of PPARα and PPARγ (>3-fold), while CR also activated LXR and NRF2 (>2 fold). CR (200 μg/mL) and Ca (100 μM) decreased lipid accumulation (22.6 ± 14.1 and 49.7 ± 7.3%, respectively) in adipocytes and increased glucose uptake (44.7 ± 6.2 and 30.1 ± 12.2%, respectively) in muscle cells and inhibited the adipogenic effect induced by rosiglitazone by 41.2 ± 5.6 and 13.9 ± 4.3%, respectively. This is the first report to reveal the agonistic action of CR and Ca on multiple nuclear receptors along with their enhanced glucose uptake and antiadipogenic effects. The results indicate the potential utility of the capsiate-rich fraction of C. annuum in alleviating the symptoms of metabolic syndrome and in preventing the undesired adipogenic effects of full PPARγ agonists such as rosiglitazone.

(1) Background: Capsaicin, a chief ingredient of natural chili peppers, enhances metabolism and energy expenditure and stimulates the browning of white adipose tissue (WAT) and brown fat activation to counter diet-induced obesity. Although capsaicin and its nonpungent analogs are shown to enhance energy expenditure, their efficiency to bind to and activate their receptor—transient receptor potential vanilloid subfamily 1 (TRPV1)—to mediate thermogenic effects remains unclear. (2) Methods: We analyzed the binding efficiency of capsaicin analogs by molecular docking. We fed wild type mice a normal chow or high fat diet (± 0.01% pungent or nonpungent capsaicin analog) and isolated inguinal WAT to analyze the expression of thermogenic genes and proteins. (3) Results: Capsaicin, but not its nonpungent analogs, efficiently binds to TRPV1, prevents high fat diet-induced weight gain, and upregulates thermogenic protein expression in WAT. Molecular docking studies indicate that capsaicin exhibits the highest binding efficacy to TRPV1 because it has a hydrogen bond that anchors it to TRPV1. Capsiate, which lacks the hydrogen bond, and therefore, does not anchor to TRPV1. (4) Conclusions: Long-term activation of TRPV1 is imminent for the anti-obesity effect of capsaicin. Efforts to decrease the pungency of capsaicin will help in advancing it to mitigate obesity and metabolic dysfunction in humans.

18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDGPET/ CT) is widely used as a standard method for evaluating human brown adipose tissue (BAT), a recognized therapeutic target of obesity. However, a longitudinal BAT study using FDG-PET/CT is lacking owing to limitations of the method. Near-infrared time-resolved spectroscopy (NIRTRS) is a technique for evaluating human BAT density noninvasively. This study aimed to test whether NIRTRS could detect changes in BAT density during or after long-term intervention. First, using FDG-PET/CT, we confirmed a significant increase (+48.8%, P < 0.05) in BAT activity in the supraclavicular region after 6-week treatment with thermogenic capsaicin analogs, capsinoids. Next, 20 volunteers were administered either capsinoids or placebo daily for 8 weeks in a double-blind design, and BAT density was measured using NIRTRS every 2 weeks during the 8-week treatment period and an 8-week period after stopping treatment. Consistent with FDG-PET/CT results, NIRTRS successfully detected an increase in BAT density during the 8-week treatment (+46.4%, P < 0.05), and a decrease in the 8-week follow-up period (−12.5%, P = 0.07), only in the capsinoid-treated, but not the placebo, group. Thus, NIRTRS can be applied for quantitative assessment of BAT in longitudinal intervention studies in humans. [ABSTRACT FROM AUTHOR]

Capsaicin and capsiate, which is an analogue of capsaicin, are agonists of capsaicin-binding transient potential vanilloid 1 ( TRPV1) receptors. However, their physiological effects are different. Capsaicin induces thermogenesis and nociception, while the different kinetics of capsiate result in thermogenesis without nociception in the oral cavity. In the present study, using functional magnetic resonance imaging, we compared the brain activation after intragastric infusion of non-nociceptive levels of capsaicin and capsiate in wild-type and TRPV1-knockout ( KO) mice. Capsaicin activated several brain regions, such as the periaqueductal grey ( PAG), thalamic nuclei and hypothalamus, including the medial preoptic area ( mPOA) and ventromedial hypothalamus ( VMH). Most of these areas were not activated in TRPV1-KO mice. Capsiate activated several regions, including the thalamic nuclei, mPOA and VMH but not PAG in wild-type mice. Most of the activated areas were not activated by intragastric capsiate infusion in TRPV1-KO mice. These results demonstrate that TRPV1 is critical for the induction of activation in the hypothalamus by capsaicin and capsiate, and these distinct brain activations could help to explain the individual physiological reactions of capsaicin and capsiate. [ABSTRACT FROM AUTHOR]

Abstract: Red peppers and red pepper paste are reported to have anti-obesity, analgesic and anti-inflammatory effects in animals and humans due to the capsaicin in red pepper. We investigated whether consuming capsaicin and capsiate, a nonpungent capsaicin analogue, modifies glucose-stimulated insulin secretion, pancreatic β-cell survival and insulin sensitivity in 90% pancreatectomized (Px) diabetic rats, a moderate and non-obese type 2 diabetic animal model. Px diabetic rats were divided into 3 treatment groups: 1) capsaicin (Px-CPA), 2) capsiate (Px-CPI) or 3) dextrose (Px-CON) and provided high fat diets (40 energy % fat) containing assigned components (0.025% capsaicin, capsiate, or dextrose) for 8 weeks. Both capsaicin and capsiate reduced body weight gain, visceral fat accumulation, serum leptin levels and improved glucose tolerance without modulating energy intake in diabetic rats. In comparison to the control, both capsaicin and capsiate potentiated first and second and phase insulin secretion during hyperglycemic clamp. Both also increased β-cell mass by increasing proliferation and decreasing apoptosis of β-cells by potentiating insulin/IGF-1 signaling. However, only capsiate enhanced hepatic insulin sensitivity during euglycemic hyperinuslinemic clamp. Capsiate reduced hepatic glucose output and increased triglyceride accumulation in the hyperinsulinemic state and capsiate alone significantly increased glycogen storage. This was related to enhanced pAkt→PEPCK and pAMPK signaling. Capsaicin and capsiate reduced triglyceride storage through activating pAMPK. In conclusion, capsaicin and capsiate improve glucose homeostasis but they differently enhance insulin sensitivity in the liver, insulin secretion patterns, and islet morphometry in diabetic rats. Capsiate has better anti-diabetic actions than capsaicin. [Copyright &y& Elsevier]

Calcitonin gene-related peptide (CGRP) is a predominant neurotransmitter from capsaicin-sensitive sensory nerves, which are widely distributed in the gastrointestinal system. These sensory nerves are reported to be involved in the protection of gastric mucosa against damage by various stimuli, and CGRP is a potential mediator in this process. In addition to increase in gastric mucosal blood flow, the beneficial effects of CGRP on gastric mucosa include inhibition of gastric acid secretion, prevention of cellular apoptosis and oxidative injury. The synthesis and release of CGRP is regulated by the capsaicin receptor which is known as transient receptor potential vanilloid subfamily member 1 (TRPV1) and the agonists of TRPV1 have the potential for gastric mucosal protection. So far, multiple TRPV1 agonists, including capsaicin, capsiate, anandamide and rutaecarpine are reported to exert beneficial effects on gastric mucosal injury induced by various stimuli. Therefore, the TRPV1/CGRP pathway represents a novel target for therapeutic intervention in human gastric mucosal injury. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies have demonstrated that capsaicin-sensitive sensory nerves are involved in the protection of gastric mucosa against damage by various stimuli and calcitoin gene-related peptide (CGRP) is a potential mediator in this process. This study was performed to explore the effect of vanillyl nonanoate, a capsaicin analog, on ethanol-induced gastric mucosal injury and the possible underlying mechanisms. A rat model of gastric mucosal injury was induced by oral administration of acidified ethanol and gastric tissues were collected for analysis of gastric ulcer index, cellular apoptosis, the activities of caspase-3, catalase and superoxide dismutase (SOD), levels of CGRP, TNF-α and malondialdehyde (MDA). The results showed that acute administration of ethanol significantly increased gastric ulcer index concomitantly with increased cellular apoptosis, caspase-3 activity, TNF-α and MDA levels as well as decreased activities of catalase and SOD. Pretreatment with 1mg/kg vanillyl nonanoate significantly attenuated ethanol-induced gastric mucosal injury and cellular apoptosis accompanied by increase of CGRP expression, and SOD activity and decrease of caspase-3 activity, TNF-α and MDA levels. The effects of vanillyl nonanoate were inhibited by capsazepine, an antagonist of capsaicin receptor. Our results suggested that vanillyl nonanoate was able to protect the gastric mucosa against ethanol-induced gastric mucosal injury. The underlying mechanism is related to stimulation of CGRP release and subsequent suppression of ethanol-induced inflammatory reaction, cellular apoptosis and oxidative stress. [Copyright &y& Elsevier]

Abstract: Chili peppers are the major source of nature capsaicinoids, which consist of capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin, etc. Capsaicinoids are found to exert multiple pharmacological and physiological effects including the activities of analgesia, anticancer, anti-inflammation, antioxidant and anti-obesity. Therefore, capsaicinoids may have the potential value in clinic for pain relief, cancer prevention and weight loss. In addition, capsaicinoids also display the benefits on cardiovascular and gastrointestinal system. It has been shown that capsaicinoids are potential agonists of capsaicin receptor or transient receptor potential vanilloid subfamily member 1 (TRPV1). They could exert the effects not only through the receptor-dependent pathway but also through the receptor-independent one. CH-19 Sweet peppers are the source of nature capsinoids, which share similar structure with capsaicinoids and consist of capsiate, dihydrocapsiate, and nordihydrocapsiate, etc, Comparing with capsaicinoids, capsinoids are less pungent and easily broken down in the normal aqueous conditions. So far, it has been found that capsinoids possess the biological properties of antitumor, antioxidant and anti-obesity. Since capsinoids are less toxic than capsaicinoids, therefore, capsinoids may have the advantages over capsaicinoids in clinical applications such as cancer prevention and weight loss. [ABSTRACT FROM AUTHOR]

The article focuses on the body fat accumulation which can be reduced by capsinoids, non-pungent capsaicin analogs without weight rebound not like dietary restriction in mice. It mentions that capsinoids are famous in suppressing body fat accumulation and decrease body weight through improving energy expenditure in both humans and mice. According to experiment, capsinoid is more beneficial than restricted diet for maintaining body weight.

Capsiate has a structure similar to capsaicin but no oral pungency. Furthermore, capsiate displayed antioxidant activity and inhibited angiogenesis and vascular permeability, and therefore, showed potential as a medicine and food supplement. Capsaicin is now commercially available, however capsiate is scarcely present in natural foods. We investigated the direct enzymatic conversion of a capsaicinoid to a capsinoid. It was observed that the rate of lipase-catalyzed acylation of vanillyl alcohol with nonanoic acid was faster than that of hydrolysis of N-vanillylnonanamide to vanillyl amide and nonanoic acid in n-hexane at 70°C. As a result, we performed a one-procedure synthesis of capsiate from capsaicin via lipase-catalyzed transacylation. [ABSTRACT FROM AUTHOR]

Abstract: Capsiate, one of the major capsaicinoids, is nonpungent and present in sweet pepper. We investigated the effects of capsiate on the ultraviolet B (UVB)-induced inflammatory response in skin and its molecular mechanisms. Capsiate-pretreated human keratinocytes inhibited intracellular reactive oxygen species (ROS), which activate the mitogen-activated protein kinase and nuclear factor-κB (NF-κB) pathways. Therefore, we determined the effects of capsiate on these pathways. Capsiate inhibited UVB-induced cyclooxygenase-2 (COX-2) expression, extracellular signal-related kinase 1/2 phosphorylation, nuclear translocation of NF-κB, and the expression of proinflammatory cytokines and potent angiogenic factors, including vascular endothelial cell growth factor and matrix metalloproteinase-2 (MMP-2) and MMP-9. In addition, capsiate inhibited UVB-induced epidermal growth factor receptor (EGFR) activation, which reduces the levels of proinflammatory cytokines and angiogenic factors. We also investigated the photoprotective effects of capsiate in vivo. Topical treatment with capsiate significantly decreased UVB-induced skin damage and inhibited the expression of COX-2, proinflammatory cytokines, and angiogenic factors, including platelet/endothelial cell adhesion molecule-1 and intercellular adhesion molecule-1. Inhibition of Src kinase activity and ROS may inhibit the EGFR activation. Therefore, capsiate may protect the skin from UVB-induced adverse effects and these results provide a molecular basis for understanding its effects on inflammation and angiogenesis. [Copyright &y& Elsevier]

To further evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate, CAS No. 205687-03-2), a 26-week gavage toxicity study was conducted in Sprague-Dawley rats (20/sex/group). Test animals received either dihydrocapsiate, 100, 300, or 1000 mg/kg/day, or vehicle (medium-chain triglyceride) by gavage and were observed for antemortem and postmortem signs of toxicity including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. After the end of the dosing period, reversibility was assessed (10/sex/group for the control and 1000 mg/kg groups) following a 4-week recovery period. There were no adverse or toxicological changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, blood chemistry, organ weights, or histopathology. It was concluded that the no observable adverse effect level (NOAEL) of dihydrocapsiate was 1000 mg/kg/day for both sexes in this 26-week gavage study. [ABSTRACT FROM AUTHOR]

The article presents a study which assesses the biological similarity of three capsinoids found in non-pungent chili pepper (CH-19 Sweet) fruits. It states that the capsinoids at the same concentration induced virtually no nociceptive responses when applied to the eyes or the oral cavities of mice. Moreover, it mentions that capsinoids and capsaicin must have the same bio-potency as based on present results, though capsinoids do not generate pungency or sensory irritation.

Objectives:The involvement of skeletal muscle mitochondrial uncoupling protein-3 (UCP3) in the control of energy expenditure in skeletal muscle and at the whole-body level is still a matter of debate. We previously reported that UCP3 downregulation is linked to an enhanced mitochondrial energy metabolism in rat skeletal muscle as a result of acute capsiate treatment. Here, we aimed at investigating noninvasively the effects of chronic capsiate ingestion on metabolic changes occurring in exercising gastrocnemius muscle and at the whole-body level.Methods:We used an original experimental setup allowing a complete noninvasive investigation of gastrocnemius muscle function in situ using 31-phosphorus magnetic resonance spectroscopy. Whole-body fat composition was determined using magnetic resonance imaging and UCP3 gene expression was measured by quantitative real-time RT-PCR analysis.Results:We found that a 14-day daily administration of capsiate (100 mg kg−1 body weight) reduced UCP3 gene expression and increased phosphocreatine level at baseline and during the stimulation period in gastrocnemius muscle. During muscle stimulation, pHi showed a larger alkalosis in the capsiate group suggesting a lower glycolysis and a compensatory higher aerobic contribution to ATP production. Although the capsiate-treated rats were hyperphagic as compared to control animals, they showed a lower weight gain coupled to a decreased abdominal fat content.Conclusion:Overall, our data indicated that capsiate administration contributes to the enhancement of aerobic ATP production and the reduction of body fat content coupled to a UCP3 gene downregulation. [ABSTRACT FROM AUTHOR]

The article presents which investigates the effect of capsinoids on the metabolic rate and thermogenesis in mice through gastrointestinal transient receptor potential vanilloid 1 (TRPV1). The study conducted an respiratory gas analysis of male adult C57BL/6 strain wild-type (WT) mice and TRPV1 knockout (KO) mice to measure the energy expenditure and fat oxidation using TRPV1. The results show that capsinoids increase the energy expenditure and enhance thermogenesis through TRPV1.

A series of studies was performed to evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS no. 205687-03-2). This study evaluated the potential genotoxicity of this compound using a variety of in vitro and in vivo test systems, including bacterial reverse mutation test, chromosomal aberration test, micronucleus test, gene mutation assay with transgenic rats, and single-cell gel (SCG) assay (Comet assay). In vitro tests (bacterial reverse mutation test and chromosomal aberration test) produced positive results in the absence of metabolic activation, but negative results in the presence of metabolic activation. The in vivo gene mutation assay (with transgenic rats) produced negative results, as did the in vivo mouse micronucleus assay, which failed to induce micronucleated polychromatic erythrocytes. Although the rat SCG assay produced statistically significant increases in the Olive tail moment and % tail DNA of the liver and intestine in the 2000 mg/kg group (compared with the negative-control group), a number of factors caused the authors to question the validity of these findings. Taken together, these results suggest that dihydrocapsiate has a low or extremely low likelihood of inducing genotoxicity. [ABSTRACT FROM AUTHOR]

Dihydrocapsiate, (4-hydroxy-3-methoxybenzyl 8-methylnona- noate; CAS No. 205687-03-2) is a naturally occurring capsinoid compound found in nonpungent chili peppers. Although the safety of synthetically produced dihydrocapsiate has been previously evaluated, the purpose of this 13-week gavage toxicity study is to evaluate dihydrocapsiate produced with a slightly modified manufacturing process. Sprague-Dawley rats, 10 rats/sex/group, 6 weeks of age at study initiation, were administered the dihydrocapsiate daily by gavage at dose levels of 0 (vehicle), 100, 300, or 1000 mg/kg/day. The rats were observed for antimortem and postmortem signs of toxicity, including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. There were no changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, or blood chemistry that were attributable to the administration of dihydrocapsiate. The only change observed attributable to the dihydrocapsiate administration involved the liver and that change occurred only at the high dose (1000 mg/kg). Both sexes had an increase in organ weights, but this increase correlated with a change in histopathology (i.e., hepatocyte hypertrophy) only in the males. No dihydrocapsiate-related histopathological changes were observed in males at doses ≤ 300 mg/kg or in females at any of the doses tested (≤ 1000 mg/kg). It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 300 mg/kg/day for male rats and 1000 mg/kg/day for female rats in this 13 week gavage study. [ABSTRACT FROM AUTHOR]

In order to determine the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS no. 205687-03-2), teratology studies were conducted in pregnant Sprague-Dawley rats (18 to 20 animals per group) and pregnant New Zealand white rabbits (20 to 21 animals per group). The test substance was administered by gavage for 11 days, from days 7 to 17 of gestation in rats, and for 13 days from days 6 to 18 of gestation in rabbits, at dose levels of 0 (vehicle), 100, 300, or 1000 mg/kg/day. In the rat study, no deaths occurred in any group and there were no test substance-related changes or abnormalities in clinical signs, body weight, food consumption, or gross pathological findings. There were no test substance-related changes in the number of corpora lutea, number of implantations, index of implantations, index of embryofetal deaths, and number, sex ratio, or body weight of live fetuses at the end of the gestation period and there were no abnormalities in the placentae of live fetuses. There were no test substance-related abnormalities or variations in the external, skeletal, or visceral examinations of live fetuses. There were no abnormalities in ossification. En toto, it was concluded there were no teratogenic effects in the rat study. In the rabbit study, there were no test substance-related effects on clinical signs, body weight, food consumption, or necropsy findings in any group. There were neither test substance-related abortions nor test substance-related effects on the number of corpora lutea, number of implantations, or implantation index in any group. There were no test substance-related effects on the number of dead embryos/fetuses, the number, sex ratio, or body weight of live fetuses, or gross pathological finding of placentae. There were no test substance-related external abnormalities, or incidence of visceral or skeletal abnormalities or variations, and there were no test substance-related effects on the progress of ossification in any group. Based upon these data, the no observed adverse effect level (NOAEL) of dihydrocapsiate for general toxicity in dams, reproductive functions of dams, and embryofetal development was judged to be 1000 mg/kg/day both in rats and rabbits. [ABSTRACT FROM AUTHOR]

To evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2), a 13-week gavage toxicity study was conducted in Sprague-Dawley rats (10/sex/group). Test subjects received either dihydrocapsiate, 100, 300, or 1000 mg/kg/day, or vehicle by gavage and were observed for antemortem and postmortem signs of toxicity, which included changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. No changes attributable to the test article were observed in clinical signs, body weights, food consumption, water intake, ophthalmology, urinalysis, hematology, or histopathology. A number of sporadic blood chemistry differences were observed at the high dose between treated and controls, but were not of toxicological significance and were not attributable to the test article. These included increased alanine aminotransferase (ALT) activity in males; increased total protein in males and females; increased calcium, percentage of albumin fraction, and A/G (albumin/globulin) ratio and decreased percentage of γ-globulin fraction in female rats. An effect, which was attributable to the test article, was increases in both absolute and relative liver weights in the high dose (both sexes). In the absence of histopathological changes attributable to the test article, the liver weight changes were considered adaptive (physiological) in nature and not of toxicological significance. It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 1000 mg/kg/day for both male and female rats in this 13-week gavage study. [ABSTRACT FROM AUTHOR]

Abstract: Capsaicin increases calcitonin gene-related peptide (CGRP) release from sensory neurons by stimulating vanilloid receptor-1 (VR-1). Since CGRP increases production of insulin-like growth factor-I (IGF-I) in fetal osteoblasts in vitro, it is possible that sensory neuron activation by capsaicin increases production of IGF-I. In the present study, we attempted to determine whether topical application of capsaicin and related compounds increases dermal IGF-I level in mice and whether it increases facial skin elasticity in humans. Topical application of 0.01% capsaicin significantly increased dermal IGF-I levels from 30 to 180min (p <0.01), but not at 360min, after application in mice. Topical application of 0.01% capsaicinoids (dihydrocapsaicin and nordihydrocapsaicin), 0.01% capsinoids (capsiate, dihydrocapsiate and nordihydrocapsiate), 0.01% anandamide (an endogenous agonist of VR-1), and 0.01% nonylic acid vanillylamide (a synthetic capsaicin) significantly increased dermal IGF-I levels at 30min after topical application in mice (p <0.01). Topical application of 0.01% capsaicin to faces of 17 healthy female volunteers for seven days significantly increased cheek skin elasticity (p <0.01). These observations suggest that topical application of capsaicin and related compounds might be useful in the treatment of detrimental morphological changes of the skin in patients with growth hormone deficiency and those in the elderly by increasing dermal IGF-I levels. [Copyright &y& Elsevier]

The article examines the changes in autonomic nervous activity, body temperature, blood pressure and heart rate after intake of the non-pungent pepper CH-19 Sweet and of hot red pepper in humans to know the mechanisms of diet-induced thermogenesis due to CH-19 Sweet. According to the authors, the CH-19 Sweet activates the sympathetic nervous system and enhances thermogenesis as effectively as hot red pepper and that the heat loss effect due to CH-19 Sweet is weaker compared to hot red pepper.

The article focuses on the possibility of a repeated intake of CH-19 sweet, a non-pungent red pepper, in the body weight and fats in humans. The methods were used to show that the repeated intake of CH-19 sweet reduced the body weight and suppressed body fat accumulation. It further discussed that body weight loss due to repeated intake and was significantly correlated with the sympathetic nervous response after its ingestion.

The article discusses a study which examined the effect of capsiate on the endurance swimming capacity of mice in an adjustable-current water pool. Capsiate is a nonpungent natural analog of capsaicin. After 30 minutes of swimming, the residual glycogen in the gastrocnemius muscle was found to be high. The serum free fatty acid concentration tended to be high and the serum lactic acid level was low. The study suggests that the oral administration of capsiate enhanced fat oxidation and spared carbohydrate utilization.

Abstract: A mild and operationally simple method for the chemoselective esterification of phenolic alcohols is described. The reaction overcomes the tyranny of protection, and capitalizes on the activation of acyl halides with cerium(III) chloride to selectively esterify alcohol hydroxyls in the presence of phenolic ones. The generality of the reaction was demonstrated with a series of phenolic alcohols of dietary relevance (vanillol, hydroxytyrosol, epicatechin), providing an expeditious entry into a series of compounds of relevance for biomedical research, some of which previously available only by enzymatic methods. [Copyright &y& Elsevier]

Some varieties of sweet pepper accumulate non-pungent isosters of capsaicin, a type of compounds exemplified by capsiate. The only structural difference between capsaicin and capsiate is the link between the vanillyl and the acyl moieties, via an amide bond in the former and via an ester bond in the latter. By flow cytometry analyses we have determined that nor -dihydrocapsiate, a simplified analogue of capsiate, is a pro-oxidant compound that induces apoptosis in the Jurkat tumor cell line. The nuclear DNA fragmentation induced by nor -dihydrocapsiate is preceded by an increase in the production of reactive oxygen species and by a subsequent disruption of mitochondria transmembrane potential. Capsiate-induced apoptosis is initiated at the S phase of the cell cycle and is mediated by a caspase-3-dependent pathway. The accumulation of intracellular reactive oxygen species in capsiate-treated cells is greatly prevented by the presence of ferricyanide, suggesting that capsiates target a cellular redox system distinct from the one involved in the mitochondrial electron-chain transport. Methylation of the phenolic hydroxyl of nor-dihydrocapsiate completely abrogated the ability to induce reactive oxygen species and apoptosis, highlighting the relevance of the presence of a free phenolic hydroxyl for the pro-oxidant properties of capsaicinoids. [ABSTRACT FROM AUTHOR]