Avaliação farmacológica de Capsicum baccatum var. pendulum L. em um protocolo experimental patronizado de síndrome metabólica in vivo

O gênero Capsicum compreende mais de 200 espécies de pimentas e pimentões e diversas atividades farmacológicas são descritas na literatura. Estudos prévios do nosso grupo de pesquisa têm explorado diferentes atividades biológicas de Capsicum baccatum var. Pendulum (Solanaceae), como antioxidante, antiinflamatória, hipoglicemiante e antidislipidêmica. A prevalência da síndrome metabólica, caracterizada por fatores como obesidade, resistência à insulina, dislipidemia e hipertensão, tem atingido proporções epidêmicas e acomete cerca de 20% da população mundial. Muitas vezes, apenas a mudança no estilo de vida não é eficaz para impedir a progressão da doença, sendo necessário aderir ao tratamento farmacológico. No entanto, não existem fármacos específicos para o tratamento da síndrome, levando à utilização de polifarmácia, que gera dificuldades de adesão ao tratamento e risco de interações medicamentosas. O principal objetivo desse estudo foi avaliar o efeito do extrato butanólico (BUT) e da fração ativa (AF) dos frutos de C. baccatum em um modelo de síndrome metabólica induzido por dieta em camundongos C57BL/6. Inicialmente apresentamos uma revisão de estudos publicados, que utilizam diferentes tipos de dietas hipercalóricas para induzir a síndrome metabólica em roedores. Ao compararmos esses estudos, observamos a forte tendência à utilização de camundongos da linhagem C57BL/6 machos e jovens, respondendo de forma satisfatória à indução da síndrome metabólica. Após, apresentamos o efeito do BUT e AF, nas doses de 200 e 50 mg/kg, respectivamente, sobre os parâmetros glicídicos e lipídicos em modelo de síndrome metabólica em camundongos C57BL/6 submetidos a uma dieta hiperpalatável (HPD) durante 120 dias. Nesse estudo foi visto que o tratamento com C. baccatum via oral, preveniu o ganho de peso, o desenvolvimento de um perfil de intolerância à glicose, o acúmulo de gordura na região abdominal e a elevação nos níveis de insulina e leptina plasmáticas quando comparados ao grupo HPD. Além disso, também preveniu o acúmulo de colesterol e triglicerídeos no fígado e preservou a morfologia do tecido hepático. Assim, C. baccatum se mostrou promissor, prevenindo alterações dos diversos componentes importantes da síndrome metabólica.The genus Capsicum comprises more than 200 species of peppers and a range of pharmacological activities are described in the literature. Previous studies of our research group have explored several activities for Capsicum baccatum var. pendulum (Solanaceae) species, as antioxidant, anti-inflammatory, hypoglycemic and antidyslipidemic, since the studies with this species are scarce. The prevalence of metabolic syndrome, characterized by the association of factors such as obesity, insulin resistance, dyslipidemia and hypertension, is reaching epidemic proportions worldwide, affecting approximately 20% of world's population. Often, only lifestyle change is not effective in preventing the progression of the disease, being necessary adherence to pharmacological treatment. However, there are no specific drugs for the treatment of the syndrome, leading to the use of polypharmacy, which generates an increase in public spending, difficulties of adherence to treatment, and enhanced risk to drug interactions. The main objective of this study was to evaluate the effect of butanolic extract (BUT) and the active fraction (AF) of C. baccatum on a model of diet-induced metabolic syndrome in C57BL/6 mice. We first present a review of published studies, which use different types of hypercaloric diets to induce metabolic syndrome in rodents. When comparing these studies, we observed a strong trend towards the use of male and young C57BL/6 mice, responding satisfactorily to the metabolic syndrome induction through hypercaloric diets. After, we present the effect of BUT and AF, on glucose and lipid parameters in a model of metabolic syndrome in C57BL/6 mice submitted to a hyperpalatable diet (HPD) for 120 days. In this study, it was seen that oral C. baccatum treatment prevented weight gain, development of a glucose intolerance profile, accumulation of fat in the abdominal area and the increase in plasma insulin and leptin levels when compared to group HPD. Also, it prevented the accumulation of cholesterol and triglycerides in the liver, and preserved the liver tissue morphology. Thus, these results showed the effects of C. baccatum, especially AF, preventing changes in several important components of the metabolic syndrome

Capsicum baccatum red pepper prevents cardiometabolic risk in rats fed with an ultra-processed diet

Metabolic syndrome is a serious health condition reaching epidemic proportions worldwide and is closely linked to an increased risk of cardiovascular problems. The lack of appropriate treatment paves the way for developing new therapeutic agents as a high priority in the current research. In this study, we evaluated the protective effects of Capsicum baccatum red pepper on metabolic syndrome scenarios induced by an ultra-processed diet in rats. After four months, the ultra-processed diet increased central obesity, triglycerides, total cholesterol, LDL-cholesterol plasma levels, and impaired glucose tolerance. The oral administration of C. baccatum concomitantly with the ultra-processed diet avoided the accumulation of adipose tissue in the visceral region, reduced the total cholesterol and LDL fraction, and improved glucose homeostasis, factors commonly associated with metabolic syndrome. The data presented herein reveal an important preventive action of C. baccatum in developing metabolic disorders among animals fed a hypercaloric diet, significantly reducing their cardiometabolic risk. Allied with the absence of toxic effects after chronic use, our study suggests C. baccatum red pepper as a secure and enriched source of bioactive compounds promising to protect against pathological processes associated with metabolic syndrome

Prospecting bioactive compounds from natural sources for the management of multifactorial chronic metabolic diseases

Les maladies métaboliques chroniques, comprenant l'obésité, le diabète et les maladies cardio-vasculaires et hépatiques, sont devenues une menace pour la santé mondiale en raison de leur incidence croissante. Ce sont des maladies complexes causées par une combinaison de facteurs. Dans les pays occidentaux industrialisés, la stéatose hépatique non alcoolique (NAFLD) est la maladie hépatique la plus courante et aucun traitement pharmacologique spécifique n'a été approuvé à ce jour. Cette maladie a un spectre clinique commençant par la stéatose hépatique (NAFL), qui peut évoluer vers une stéatohépatite non alcoolique (NASH), une fibrose avancée, une cirrhose et même un carcinome hépatocellulaire. Parmi les facteurs de risque associés figurent la résistance à l'insuline, l'obésité, l'hyperlipidémie et d'autres composantes du syndrome métabolique (MetS). Des études antérieures de notre groupe de recherche ont montré des résultats prometteurs de l'extrait butanolique (BUT) de Capsicum baccatum var. pendulum et de sa fraction enrichie (EF) dans la prévention des changements métaboliques liés au MetS dans un modèle murin de la maladie, y compris l'amélioration de la santé du foie. Dans ce contexte, cette étude consiste en la prospection et l'évaluation de produits purifiés de C. baccatum à l'aide de modèles NAFLD in vitro et in vivo. La première partie de la thèse a été dédiée à une revue de la littérature étudiant les modèles employés pour développer le MetS chez les rongeurs soumis à des régimes hypercaloriques. A travers cette étude, qui a corrélé les conditions expérimentales de plusieurs investigations avec leurs résultats métaboliques respectifs, il a été possible de proposer des conditions expérimentales optimisées pour induire le MetS chez les rongeurs. La deuxième partie du travail se concentre sur l'obtention des extraits BUT, EF des et composés purifiés, et leur caractérisation par des techniques analytiques telles que HPLC, RMN et MS/MS. Les résultats obtenus jusqu'à présent indiquent la présence de capsianosides, de flavonoïdes, d'anthocyanes et de leurs glycosides, et certains de ces composés n'ont jamais été décrits auparavant pour l'espèce. Les composés purifiés ont ensuite été testés dans un modèle d'accumulation de lipides in vitro induite dans des cellules HepG2 par des acides gras libres qui simulent une stéatose hépatique. Les composés ont inhibé de manière significative l'accumulation de gouttelettes lipidiques dans le cytoplasme des hépatocytes en modulant les voies de signalisation liées à l'oxydation des lipides et à la lipogenèse. Concernant les études in vivo, deux modèles murins induisant la NAFLD ont été employés. La NASH induite par un régime pauvre en choline, défini en acides aminés L (faible teneur en méthionine), et riche en graisses (CDAHFD) a été utilisée pour tester les effets de l'administration orale des extraits BUT et EF. Après 12 semaines d'alimentation par CDAHFD et un traitement concomitant par les extraits BUT ou EF, aucun effet thérapeutique significatif n'a été observé aux doses testées. Dans le deuxième modèle, une étude pilote a été réalisée pour déterminer les effets de l'extrait EF dans un modèle de NASH induite par le régime occidental et des stimuli toxiques à faible dose (CCl4, 0,2 µl/g de poids corporel, une fois par semaine). Après 8 semaines de traitement, on peut voir que l'extrait EF a réduit l'accumulation de graisse épididymaire et l'indice d'adiposité des animaux, et a montré une tendance à la réduction des tissus adipeux inguinaux et rétropéritonéaux, mais les effets sur le foie sont faibles. En conclusion, les résultats obtenus ici indiquent que les composés isolés lors du fractionnement bioguidé des extraits de Capsicum baccatum sont nouveaux pour l'espèce et contribuent aux effets bénéfiques observés dans le modèle NAFL in vitro, représentant une nouvelle classe thérapeutique à explorer dans la gestion des maladies métaboliques chroniques.Chronic metabolic disorders including obesity, diabetes, cardiovascular, and liver diseases have become a threat to global health due to their increasing incidence. They are complex diseases caused by a combination of lifestyle, dietary, genetic, and environment-related factors. In industrialized western countries, non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder, and no specific pharmacological treatment has been approved to date. This disease has a clinical spectrum beginning as hepatic steatosis (NAFL), which can progress to non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and even hepatocellular carcinoma. Among the associated risk factors are insulin resistance, obesity, hyperlipidemia, and other components of metabolic syndrome (MetS). Previous studies by our research group have shown promising results of the butanol extract (BUT) of Capsicum baccatum var. pendulum and its enriched fraction (EF) in the prevention of metabolic changes related to MetS in a murine model of the disease, including improved liver health. In this context, this study consists of the prospection and evaluation of purified products from C. baccatum using in vitro and in vivo NAFLD models. The first part of the thesis was dedicated to a literature review investigating the models used to develop MetS in rodents using high-calorie diets. Through this study, which correlated the experimental conditions of several investigations with their respective metabolic outcomes, it was possible to suggest optimized experimental conditions for inducing MetS in rodents. The second part of the work focuses on obtaining BUT, EF, and purified compounds and their characterization through analytical techniques such as HPLC, NMR, and MS/MS. The results obtained so far indicated the presence of capsianosides, flavonoids, anthocyanins, and their glycosides, and some of these compounds were never described before for the species. The purified compounds were then tested in an in vitro fat accumulation model induced by free fatty acids in HepG2 cells that simulate hepatic steatosis. The compounds significantly inhibited the lipid droplets accumulation in the hepatocyte cytoplasm by modulating signaling pathways related to fatty oxidation and lipogenesis. Concerning the in vivo studies, two murine models that induce the NAFLD were conducted. NASH induced by a choline-deficient, L-amino acid-defined (low methionine) high-fat diet (CDAHFD) was used to test the effects of oral administration of BUT and EF. After 12 weeks of CDAHFD feeding and concomitant treatment with BUT or EF, no significant therapeutic effects were observed at the tested doses. In the second model, a pilot study was performed to investigate the EF effects in a NASH model induced by Western Diet and toxic stimuli in a shallow dose (CCl4, 0.2 µl/g of body weight, once a week). After 8 weeks of treatment, EF reduced epididymal fat accumulation and adiposity index of animals and showed a tendency to reduce the inguinal and retroperitoneal adipose tissues, but the effects on the liver were mild. In conclusion, the results obtained herein indicated that compounds isolated during the bioguided fractionation of C. baccatum are novel for the species and contribute to the beneficial effects observed in the NAFL in vitro model, representing a new therapeutic class to be explored in the management of chronic metabolic diseases

Capsicum baccatum: potencial agente redutor de risco cardiovascular

1

Prospection de composés bioactifs à partir de sources naturelles pour la gestion des maladies métaboliques chroniques multifactorielles

Chronic metabolic disorders including obesity, diabetes, cardiovascular, and liver diseases have become a threat to global health due to their increasing incidence. They are complex diseases caused by a combination of lifestyle, dietary, genetic, and environment-related factors. In industrialized western countries, non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder, and no specific pharmacological treatment has been approved to date. This disease has a clinical spectrum beginning as hepatic steatosis (NAFL), which can progress to non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and even hepatocellular carcinoma. Among the associated risk factors are insulin resistance, obesity, hyperlipidemia, and other components of metabolic syndrome (MetS). Previous studies by our research group have shown promising results of the butanol extract (BUT) of Capsicum baccatum var. pendulum and its enriched fraction (EF) in the prevention of metabolic changes related to MetS in a murine model of the disease, including improved liver health. In this context, this study consists of the prospection and evaluation of purified products from C. baccatum using in vitro and in vivo NAFLD models. The first part of the thesis was dedicated to a literature review investigating the models used to develop MetS in rodents using high-calorie diets. Through this study, which correlated the experimental conditions of several investigations with their respective metabolic outcomes, it was possible to suggest optimized experimental conditions for inducing MetS in rodents. The second part of the work focuses on obtaining BUT, EF, and purified compounds and their characterization through analytical techniques such as HPLC, NMR, and MS/MS. The results obtained so far indicated the presence of capsianosides, flavonoids, anthocyanins, and their glycosides, and some of these compounds were never described before for the species. The purified compounds were then tested in an in vitro fat accumulation model induced by free fatty acids in HepG2 cells that simulate hepatic steatosis. The compounds significantly inhibited the lipid droplets accumulation in the hepatocyte cytoplasm by modulating signaling pathways related to fatty oxidation and lipogenesis. Concerning the in vivo studies, two murine models that induce the NAFLD were conducted. NASH induced by a choline-deficient, L-amino acid-defined (low methionine) high-fat diet (CDAHFD) was used to test the effects of oral administration of BUT and EF. After 12 weeks of CDAHFD feeding and concomitant treatment with BUT or EF, no significant therapeutic effects were observed at the tested doses. In the second model, a pilot study was performed to investigate the EF effects in a NASH model induced by Western Diet and toxic stimuli in a shallow dose (CCl4, 0.2 µl/g of body weight, once a week). After 8 weeks of treatment, EF reduced epididymal fat accumulation and adiposity index of animals and showed a tendency to reduce the inguinal and retroperitoneal adipose tissues, but the effects on the liver were mild. In conclusion, the results obtained herein indicated that compounds isolated during the bioguided fractionation of C. baccatum are novel for the species and contribute to the beneficial effects observed in the NAFL in vitro model, representing a new therapeutic class to be explored in the management of chronic metabolic diseases.Les maladies métaboliques chroniques, comprenant l'obésité, le diabète et les maladies cardio-vasculaires et hépatiques, sont devenues une menace pour la santé mondiale en raison de leur incidence croissante. Ce sont des maladies complexes causées par une combinaison de facteurs. Dans les pays occidentaux industrialisés, la stéatose hépatique non alcoolique (NAFLD) est la maladie hépatique la plus courante et aucun traitement pharmacologique spécifique n'a été approuvé à ce jour. Cette maladie a un spectre clinique commençant par la stéatose hépatique (NAFL), qui peut évoluer vers une stéatohépatite non alcoolique (NASH), une fibrose avancée, une cirrhose et même un carcinome hépatocellulaire. Parmi les facteurs de risque associés figurent la résistance à l'insuline, l'obésité, l'hyperlipidémie et d'autres composantes du syndrome métabolique (MetS). Des études antérieures de notre groupe de recherche ont montré des résultats prometteurs de l'extrait butanolique (BUT) de Capsicum baccatum var. pendulum et de sa fraction enrichie (EF) dans la prévention des changements métaboliques liés au MetS dans un modèle murin de la maladie, y compris l'amélioration de la santé du foie. Dans ce contexte, cette étude consiste en la prospection et l'évaluation de produits purifiés de C. baccatum à l'aide de modèles NAFLD in vitro et in vivo. La première partie de la thèse a été dédiée à une revue de la littérature étudiant les modèles employés pour développer le MetS chez les rongeurs soumis à des régimes hypercaloriques. A travers cette étude, qui a corrélé les conditions expérimentales de plusieurs investigations avec leurs résultats métaboliques respectifs, il a été possible de proposer des conditions expérimentales optimisées pour induire le MetS chez les rongeurs. La deuxième partie du travail se concentre sur l'obtention des extraits BUT, EF des et composés purifiés, et leur caractérisation par des techniques analytiques telles que HPLC, RMN et MS/MS. Les résultats obtenus jusqu'à présent indiquent la présence de capsianosides, de flavonoïdes, d'anthocyanes et de leurs glycosides, et certains de ces composés n'ont jamais été décrits auparavant pour l'espèce. Les composés purifiés ont ensuite été testés dans un modèle d'accumulation de lipides in vitro induite dans des cellules HepG2 par des acides gras libres qui simulent une stéatose hépatique. Les composés ont inhibé de manière significative l'accumulation de gouttelettes lipidiques dans le cytoplasme des hépatocytes en modulant les voies de signalisation liées à l'oxydation des lipides et à la lipogenèse. Concernant les études in vivo, deux modèles murins induisant la NAFLD ont été employés. La NASH induite par un régime pauvre en choline, défini en acides aminés L (faible teneur en méthionine), et riche en graisses (CDAHFD) a été utilisée pour tester les effets de l'administration orale des extraits BUT et EF. Après 12 semaines d'alimentation par CDAHFD et un traitement concomitant par les extraits BUT ou EF, aucun effet thérapeutique significatif n'a été observé aux doses testées. Dans le deuxième modèle, une étude pilote a été réalisée pour déterminer les effets de l'extrait EF dans un modèle de NASH induite par le régime occidental et des stimuli toxiques à faible dose (CCl4, 0,2 µl/g de poids corporel, une fois par semaine). Après 8 semaines de traitement, on peut voir que l'extrait EF a réduit l'accumulation de graisse épididymaire et l'indice d'adiposité des animaux, et a montré une tendance à la réduction des tissus adipeux inguinaux et rétropéritonéaux, mais les effets sur le foie sont faibles. En conclusion, les résultats obtenus ici indiquent que les composés isolés lors du fractionnement bioguidé des extraits de Capsicum baccatum sont nouveaux pour l'espèce et contribuent aux effets bénéfiques observés dans le modèle NAFL in vitro, représentant une nouvelle classe thérapeutique à explorer dans la gestion des maladies métaboliques chroniques

Avaliação farmacológica de Capsicum baccatum var. pendulum L. em um protocolo experimental patronizado de síndrome metabólica in vivo

O gênero Capsicum compreende mais de 200 espécies de pimentas e pimentões e diversas atividades farmacológicas são descritas na literatura. Estudos prévios do nosso grupo de pesquisa têm explorado diferentes atividades biológicas de Capsicum baccatum var. Pendulum (Solanaceae), como antioxidante, antiinflamatória, hipoglicemiante e antidislipidêmica. A prevalência da síndrome metabólica, caracterizada por fatores como obesidade, resistência à insulina, dislipidemia e hipertensão, tem atingido proporções epidêmicas e acomete cerca de 20% da população mundial. Muitas vezes, apenas a mudança no estilo de vida não é eficaz para impedir a progressão da doença, sendo necessário aderir ao tratamento farmacológico. No entanto, não existem fármacos específicos para o tratamento da síndrome, levando à utilização de polifarmácia, que gera dificuldades de adesão ao tratamento e risco de interações medicamentosas. O principal objetivo desse estudo foi avaliar o efeito do extrato butanólico (BUT) e da fração ativa (AF) dos frutos de C. baccatum em um modelo de síndrome metabólica induzido por dieta em camundongos C57BL/6. Inicialmente apresentamos uma revisão de estudos publicados, que utilizam diferentes tipos de dietas hipercalóricas para induzir a síndrome metabólica em roedores. Ao compararmos esses estudos, observamos a forte tendência à utilização de camundongos da linhagem C57BL/6 machos e jovens, respondendo de forma satisfatória à indução da síndrome metabólica. Após, apresentamos o efeito do BUT e AF, nas doses de 200 e 50 mg/kg, respectivamente, sobre os parâmetros glicídicos e lipídicos em modelo de síndrome metabólica em camundongos C57BL/6 submetidos a uma dieta hiperpalatável (HPD) durante 120 dias. Nesse estudo foi visto que o tratamento com C. baccatum via oral, preveniu o ganho de peso, o desenvolvimento de um perfil de intolerância à glicose, o acúmulo de gordura na região abdominal e a elevação nos níveis de insulina e leptina plasmáticas quando comparados ao grupo HPD. Além disso, também preveniu o acúmulo de colesterol e triglicerídeos no fígado e preservou a morfologia do tecido hepático. Assim, C. baccatum se mostrou promissor, prevenindo alterações dos diversos componentes importantes da síndrome metabólica.The genus Capsicum comprises more than 200 species of peppers and a range of pharmacological activities are described in the literature. Previous studies of our research group have explored several activities for Capsicum baccatum var. pendulum (Solanaceae) species, as antioxidant, anti-inflammatory, hypoglycemic and antidyslipidemic, since the studies with this species are scarce. The prevalence of metabolic syndrome, characterized by the association of factors such as obesity, insulin resistance, dyslipidemia and hypertension, is reaching epidemic proportions worldwide, affecting approximately 20% of world's population. Often, only lifestyle change is not effective in preventing the progression of the disease, being necessary adherence to pharmacological treatment. However, there are no specific drugs for the treatment of the syndrome, leading to the use of polypharmacy, which generates an increase in public spending, difficulties of adherence to treatment, and enhanced risk to drug interactions. The main objective of this study was to evaluate the effect of butanolic extract (BUT) and the active fraction (AF) of C. baccatum on a model of diet-induced metabolic syndrome in C57BL/6 mice. We first present a review of published studies, which use different types of hypercaloric diets to induce metabolic syndrome in rodents. When comparing these studies, we observed a strong trend towards the use of male and young C57BL/6 mice, responding satisfactorily to the metabolic syndrome induction through hypercaloric diets. After, we present the effect of BUT and AF, on glucose and lipid parameters in a model of metabolic syndrome in C57BL/6 mice submitted to a hyperpalatable diet (HPD) for 120 days. In this study, it was seen that oral C. baccatum treatment prevented weight gain, development of a glucose intolerance profile, accumulation of fat in the abdominal area and the increase in plasma insulin and leptin levels when compared to group HPD. Also, it prevented the accumulation of cholesterol and triglycerides in the liver, and preserved the liver tissue morphology. Thus, these results showed the effects of C. baccatum, especially AF, preventing changes in several important components of the metabolic syndrome

Capsicum baccatum: potencial agente redutor de risco cardiovascular

1