BR102017005462A2 - composition comprising jabuticaba bark extract, and uses thereof - Google Patents

Abstract

The present invention relates to a composition comprising jabuticaba bark alcohol extract for use in the treatment of metabolic processes such as weight loss and / or weight gain reduction, as well as prostate lesions in aging. The phenolic profile of the composition of jabuticaba bark extract gives the present invention potent anti-cholesterol, anti-angiogenic, anti-inflammatory, anti-proliferative effect, as well as the ability to modulate hormone and glucose metabolism.

Description

(54) Title: COMPOSITION

UNDERSTANDING JABUTICABA SHELL EXTRACT, AND USES OF THE SAME (51) Int. Cl .: A61K 36/61; A61K 129/00; A61P 3/00; A61P 3/06; A61P 3/08; (...) (73) Holder (s): UNIVERSIDADE ESTADUAL DE CAMPINAS - UNICAMP (72) Inventor (s): MÁRIO ROBERTO MAROSTICA JUNIOR; VALÉRIA H. ALVES CAGNON QUITETE; CELINA DE ALMEIDA LAMAS; SABRINA ALVES LENQUISTE; FELIX GUILLERMO REYES REYES; PATRÍCIA APARECIDA DE CAMPOS BRAGA; ANDRESSA MARA BASEGGIO (85) National Phase Start Date:

17/03/2017 (57) Abstract: The present invention relates to a composition comprising alcoholic extract of jabuticaba bark for use in the treatment of metabolic processes, such as weight loss and / or reduction of weight gain, as well as injuries prostatic diseases in aging. The phenolic profile of the composition of the extract of jabuticaba bark, gives the present invention a potent anti-cholesterolemic, anti-angiogenic, anti-inflammatory, antiproliferative effect, in addition to the ability to modulate the hormonal and glucose metabolism.

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COMPOSITION UNDERSTANDING JABUTICABA SHELL EXTRACT, AND USES OF THE SAME

FIELD OF THE INVENTION [001] The present invention falls within the field of Biology, more precisely in the area of Food and Health, and describes a composition comprising hydroalcoholic extract of the bark of jabuticaba with chemical composition defined for use as an anti-inflammatory, in the treatment of metabolic processes, weight loss and / or reduced weight gain, as well as prostatic lesions resulting from aging.

BACKGROUND OF THE INVENTION

Senescence and prostate [002] Increasing age is closely related to prostate problems (KONETY et al., 2008). It is known that, for every two men over 50, one presents alterations in this gland. Already considering the male population over 70 years old, 95% are affected (BERRY et al., 1984). In the state of São Paulo (Brazil), in 2005, a study with 1915 patients revealed that the median age for the diagnosis of prostate cancer was 67.9 years (RODRIGUES NETTO, 2008).

[003] The development of prostatic changes during aging is related to several endocrine changes. Among these changes is the reduction in the levels of free testosterone and GH (UNTERGASSER et al., 1999). Senility is believed to have a progressive decline in circulating testosterone levels, as well as an increase in androgen

2/55 estrogen, leading to an imbalance between them (MORALES, 2002). Wu and Gore (2010) suggested that with advancing age there may be an alteration in the interaction of testosterone with its receptor in the brain regions, involved in the control of male sexual characteristics and the hypothalamic hypophysis-gonadal axis. It has also been reported that advancing age can lead to changes in the activity of 5a-reductase and aromatase enzymes. Inflammatory prostatic stromal cells in senile animals increased plasma estrogen levels. Thus, cytokines secreted by these cells contribute to a positive regulation in the expression of the aromatase enzyme (ELLEM and RISBRIDGER, 2009). In addition, it is possible to verify changes in the number and function of androgen receptors at the tissue level and differentiation of tissues to testosterone sensitivity (KAUFMAN et al., 2005). The change in the expression pattern of prostate hormone receptors was reported by Cândido et al. (2012), who found low levels of testosterone and estrogen, as well as a predominant moderate to weak expression of androgenic and estrogenic receptors (Εα / β) in the ventral and dorsolateral lobes of the prostate of senile animals. In addition, with aging there is a change in IGF-1 levels, in addition to an increase in LH, FSH and prolactin (UNTERGASSER et al., 1999). High levels of IGF-1 have been related to increased cell proliferation and reduced apoptosis, being an important agent in the development of prostatic disorders (MONTICO et al., 2013).

[004] Also, involution of prostatic epithelial cells has been reported, due to the reduction of androgens, in

3/55 elderly animals (CAVAZOS, 1975). In addition, Cordeiro et al. (2008) found a reduction in the expression of genes related to protein synthesis and checking, as well as inhibition of cell growth, in addition to increased transcription of genes for cell survival and apoptotic evasion in senescence. Thus, there is the accumulation of senescent cells, which secrete factors that compromise tissue structure and function. Regarding prostate morphology during aging, Kido et al. (2014) describe the presence of epithelial atrophy, with reduction of secretory epithelial cells and stromal hypertrophy. In addition, these authors observed regions of prostatic intraepithelial neoplasia, proliferative epithelial atrophy and micro-cells.

[005] The development of prostatic functions depends on the epithelium-stroma interaction that involves both structural and hormonal elements, in addition to stimulatory and inhibitory growth factors, such as: IGFs (growth factors linked to insulin), FGFs (fibroblast growth factors ), TGF @ (growth factors β) and IGFBPs (IGF binding proteins).

[006] It is known that, after puberty, prostatic homeostasis is maintained through a balance between inhibitory and stimulatory growth factors. It is believed that with advancing age there is a disturbance in this process that leads to abnormal and possible BPH growth (LEE et al., 2001). Hetzl et al. (2014) demonstrated moderate expression of FGF2 and 8, as well as intense FGF7. In addition, weak expression of AR and ER was seen

4/55 α / β in the prostate of elderly rats.

[007] Due to the alteration of the transcriptional program in aging, enzymes involved in the processes of tissue remodeling and angiogenesis are regulated positively (SPRENGER et al., 2008). Montico et al. (2013) observed an increase in VEGF levels and a reduction in endostatins in elderly animals. Other studies have shown that the positive regulation of VEGF is related to high levels of estrogen, also present in the elderly (GARVIN et al., 2005).

[008] In addition, Montico et al. (2015) found that the prostate of senile animals also presents the reactive stroma that is characteristic of the beginning of tumorigenesis. These authors suggest that the attempt to modulate the pro-angiogenic and pro-inflammatory microenvironment, existing in the prostate of senile organisms, would be the main mechanism that triggers this reactive stroma picture.

[009] In addition to these factors, aging has been related to a higher incidence of oxidative stress (DESAI et al., 2010). This stress is nothing more than an imbalance in the generation of reactive oxygen species (ROS) and free radicals. At low levels, these ROS processes in metabolism, differentiation, apoptosis and senescence), however they can be toxic when at high levels (GUPTA et al., 2004). The organism has two important antioxidant groups in the defense against these ROS, these being the non-enzymatic (glutathione, vitamin E and C) and the enzymatic (catalase, superoxide dismutase, participate in several (cell proliferation,

5/55 glutathione peroxidase) (Kefer et al., 2009). In addition to the increase in oxidative stress with age, studies have reported that in aging there is also a decrease in the body's antioxidant defense activity, leading to damage (DESAI et al., 2010). In an experiment carried out by Alvarez et al. (2004), oxidative stress in this gland led to an increase in the lumen of the acini and a loss of epithelial cell invaginations. Riánsares et al. (2005) found an increase in cell proliferation due to this stress.

Obesity and Prostate [010] Western countries have a higher consumption of saturated fats, milk and calcium derivatives, red meat, and at the same time have a higher incidence of prostate cancer (RODRIGUES NETTO, 2008). This fact demonstrated the important relationship between prostatic disorders and eating habits. This occurs, among other factors, due to the complex correlation between metabolic disorders caused by poor eating habits and changes in circulating androgen levels, affecting the physiology of the gland in different ways (ARAÚJO and WITTERT, 2011).

[011] Obesity is currently considered a public health problem, being associated with serious disorders throughout the body, such as the development of diabetes (MICHALAKIS et al., 2013). In addition, it has also been linked to the development of prostate cancer, but this issue is still controversial. It is believed that, while reducing the risk of non-aggressive cancer, it increases the risk of a more aggressive one (SU et al., 2011). Adiposity has been associated with lower PSA values

6/55 (prostate specific antigen) and enlargement of the gland, leading to greater surgical challenges also related to the different physiology of these tumors (GROSSMANN and WITTERT, 2012). In addition, this increase in visceral adiposity in the metabolic syndrome causes a reduction in testosterone levels, which predisposes to greater fat gain, consequently promoting insulin resistance (GROSSMANN et al., 2010; ARAÚJO and WITTERT, 2011) . Furthermore, testosterone in the body can be converted into estradiol, which, in general, promotes greater activation of ER-α than ER-β, stimulating increased cell proliferation, inflammatory process, and prostate cancer (ELLEM and RISBRIDGER, 2007; WILLIAMS, 2012). In addition, Prins and Korach (2008) found a reduction in ER-β expression in cases of prostate cancer.

[012] It is understood that diabetes also has a protective effect against prostate cancer, reducing its risk by 16% (KASPER and GIOVANNUCCI 2006). However, this effect occurs only when this diagnosis is early, occurring between 1-15 years, which is related to exhaustion of the β cells of the pancreas, reduction of insulin, testosterone and IGF1 (GROSSMANN and WITTERT, 2012). Prolonged diabetes is associated with insulin resistance. This hormone is a potent mitogenic and anti-apoptotic agent, thus stimulating prostate growth and consequently increasing the risk of changes in this gland (HSING et al., 2007). In addition, it is believed that insulin stimulates the release of IGF-1, which stimulates prostate cell growth.

7/55 [013] In addition, the secretion of pro-inflammatory adipokines and cytokines secreted with increased visceral fat · contributes to prostatic disorders. Lenquiste et al. (2012) found that the increase in adiposity was able to increase the levels of adipokines, leptin, ghrelin and adiponectin (LENQUISTE et al., 2012). Leptin, for example, acts in the body as a signal for satiety (HAVEL, 2011). Changes in their levels can promote proliferation of prostate cancer cells, as well as inhibit apoptosis in vitro, in addition to changing the pattern of body fat distribution (ONUMA et al., 2003; HAVEL, 2011). In a recent study, Habib et al. (2015), using malignant prostate cancer cells and benign prostatic hyperplasia cells, observed that leptin was able to reduce ER3 expression and, at the same time, stimulate ERa expression. Adiponectin (insulin sensitive adipokine) is inversely correlated with the amount of visceral fat. Thus, it has a protective role in cancer, inhibiting tumor-induced angiogenesis and cell growth in vitro (BRAKENHIELM et al., 2004; BUB et al., 2006). Currently, the polymorphism of the gene for this adiponectin has been associated with an increased risk of prostate cancer and expression of the insulin receptor and IGF-1 in tumors in this gland (MICHALAKIS et al., 2007; DHILLON et al., 2011). In addition, it is known that adiponectin concentrations are reduced in case of insulin resistance (SAVOPOULOS et al., 2011).

[014] Thus, the pro-inflammatory state,

8/55 associated with metabolic syndrome, contributes to the development and progression of prostate cancer. Cytokines, known to be at high levels in the metabolic syndrome, as tumor necrosis factor α (TNFa) and interleukins 6 and 8 (IL-6, IL-8) are associated with the risk of this tumor (HSING et al., 2007; SHANKAR et al., 2012). Dragano et al. (2013) found changes in the levels of IL-6 and IL-Ιβ in adult animals that consumed a high-fat diet. In addition, these pro-inflammatory factors stimulate the NF-k £ pathway, related to carcinogenesis. The activation of this pathway is constitutive in prostate cancer and is related to the progression of the androgen-independent tumor (GORBACHINSKY et al., 2010; GROSSMANN and WITTERT, 2012).

[015] The oxidative stress caused by obesity is also related to the expression of NF-k8 (FURUKAWA et al., 2004; SHANKAR et al., 2012). It was seen by Carlsen et al. (2009) that the consumption of a high-fat diet is related to the expression of NF-kp in obese rodents. According to Vykhovanets et al. (2009), oxidative stress, caused by a high-fat diet in the prostate, is responsible for activating NF-k £, which contributes to the increase of the entire inflammatory process.

Prostate Morphology and Physiology [016] The prostate is considered the largest accessory gland in the male genital system. It presents a set of 30 to 50 branched tubular alveolar glands, surrounded by a capsule. The duets of these glands flow into a portion of the urethra that passes through the organ,

9/55 known as prostatic urethra (KIERSZENBAUM, 2008; JUNQUEIRA and CARNEIRO, 2012). These glandular structures are surrounded by a dense stroma, interspersed with smooth muscle fibers and blood vessels (HAM and CORMACK, 1991). The main prostatic function is the production and storage of a thin, milky liquid that contains calcium, citrate ions, phosphate ions, coagulation enzyme and profibrolysin, among other proteins, sugars, ions, enzymes, structural membrane lipids, immunosuppressive substances and anti-inflammatory (GUYTON and HALL, 2006; LACORTE, 2008), which will be part of the semen, which is essential for the reproductive process.

[017] Regarding the rodent prostate, it is located caudally to the bladder and incompletely around the urethra (ROYBURMAN et al., 2004). In addition, it is known that it is lobulated, being anatomically and morphologically divided into ventral, lateral, dorsal and anterior prostate, the latter being also called the coagulation gland (HAYASHI et al., 1991). These lobes are composed of a complex system of ductal and tubular-alveolar structures (ROYBURMAN et al., 2004). Between the epithelium and the stroma there is the presence of a basement membrane, rich in type IV collagen and laminin (KNOX et al., 1994).

[018] The ventral lobe has a set of tubuloalveolar structures, in which the epithelium is surrounded by a thin stroma (AUMULLER et al., 1990). This lobe is divided into lobes, the guais have eight sets of duets, coming from the urethra, which branch off distally. According to the position of these duets in relation

10/55 to the urethra, they can be divided into three segments: proximal, intermediate and distal (SHABISIGH et al., 1999). These regions have several differences in terms of cell type, duet pattern, type of secretion, response to hormones, gene expression and protein synthesis (HAYASHI et al., 1991). The epithelium, in these regions, is characterized from low cubic in the proximal to high cylindrical in the distal region. In the segment closest to the urethra, the epithelium is surrounded by a thick layer of smooth muscle, which is thin and continuous in the intermediate region, being sparse and discontinuous in the most distal region. The proliferative capacity of cells also differs between regions, being greater in the distal region, in contrast to the proximal region, which often has apoptotic cells. Thus, these phenotypic differences in epithelial cells must be related to the different distribution of fibrous and smooth muscle tissue (LEE et al., 1990; NEMETH and LEE, 1996).

[019] The prostatic stroma supports the epithelium, being composed of cells and an extracellular matrix. Among these cells are mainly smooth muscle cells and fibroblasts, but mast cells, macrophages are also present, alongside nerves and blood vessels. The main function of these cells is to synthesize the structural and regulatory components in the matrix. The extracellular matrix is made up of collagen fibers, reticular fibers, elastic fibers, proteoglycans, among other glycoproteins (NEMETH and LEE, 1996; MARKER et al., 2003). This matrix is associated with growth factors, molecules

11/55 regulatory and remodeling enzymes, which act as biological signals, acting on epithelial cells. Components of this matrix, such as collagen and elastic fibers, provide mechanical rigidity and flexibility to the prostatic tissue (CUNHA and MATRISIAN, 2002). This association between stroma and extracellular matrix allows the formation of a microenvironment that enables the growth and differentiation of nearby cells, which contributes to the maintenance of the shape and function of the prostatic tissue (CORNELL et al., 2003).

[020] In addition, the interaction between epitheliostroma is essential for regulation and maintenance of the functional activity of the prostate. This process is regulated by the action of hormones, which participate in the differentiation and maintenance of the active state of the gland (CUNHA et al., 2002). The basement membrane of the epithelium works as a point of union of this interaction, guaranteeing mechanical and physiological support, being composed of collagen IV, heparan sulfate and laminin (HAYWARD and CUNHA, 2000).

[021] Androgens, such as testosterone and dihydrotestosterone (DHT), are fundamental hormones in this process of prostate regulation. However, there is also the action of somatotrophic hormones (insulin, prolactin and growth hormone), retinoic acid and estrogens.

[022] Testosterone that acts on the male organism is produced mainly in the testicles (95%), part of which is produced by the adrenal glands (5%) (AUMULLER and SEITZ, 1990). Androgen can be converted to DHT by means of the enzyme 5a-reductase, present mainly in prostatic stromal cells (KIERSZENBAUM, 2008).

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Although both interact with the same receptor, DHT has 5-10 times more affinity to these than testosterone (PRINS et al., 1991). This hormonal action occurs through the binding of these androgens to specific intracellular receptors. When this complex is associated with nuclear chromatin, it can regulate the expression of a specific gene (PRINS et al., 1991). Thus, the effect of steroid hormones on prostatic physiology is extremely important, presenting antiandrogenic effects, negatively regulating the hypothalamic-pituitary-gonadal axis. This effect leads to a reduction in the production of androgens by Leydig cells and consequent involution of the prostatic epithelium and stromal growth in adult animals (WEIHUA et al., 2002). Thus, this hormone can influence normal prostate functions or injuries (CUNHA et al., 2002).

[023] Several polypeptides, such as insulin homologous growth factors (IGF), fibroblast growth factors (FGF), vascular endothelial growth factors (VEGF) and transforming growth factors (TGF), are responsible for act regulating or influencing several processes, such as cell proliferation and differentiation, mitogenic activity, secretion and tumor growth (DJAVAN et al., 2001; MARSZALEK et al., 2005).

[024] Both benign and malignant changes in the prostate have been the subject of several studies, considering the high incidence of malignant and benign changes in this organ (TIMMS and HOFKAMP, 2011; TINGA et al., 2014). Malignant prostate tumor is considered the most frequent neoplasm

13/55 worldwide, with the exception of basal and squamous cell carcinomas of the skin. It is believed that cancer cases will increase by 50% by the year 2020 (WHO, 2014). In addition, according to the National Cancer Institute, approximately 68,800 new cases of prostate cancer will be diagnosed in Brazil in 2014 (INCA, 2014). In addition to this lesion, benign prostatic hyperplasia (BPH) and prostatitis are very common. In BPH, non-neoplastic tumor growth occurs, which leads to stroma hyperplasia (mainly smooth muscle cells) and epithelial tissue (BILLIS, 1997). Prostatitis, on the other hand, is characterized by the infiltration of inflammatory cells, especially in the prostatic stroma (SHAPPELL et al., 2004).

[025] As seen, prostatic disorders are related to the imbalance of the interaction between epithelium and stroma, with an intense inflammatory process being observed. This process can be illustrated by analyzing the expression pattern of molecules related to the studied tissue. Prostate cancer has been linked to elevated levels of cyclooxygenase-2 (COX-2). This molecule is not commonly detected in the various tissues of the body, but it is rapidly induced in response to cytokines, growth factors and tumor promoters (VANE et al., 1998). It is believed that this molecule is capable of increasing the resistance of cells to the process of apoptosis, altering prostatic homeostasis (BADAWI et al., 2000). Likewise, the nuclear factor k-β (NF-Κβ) pathway plays an important role in controlling cell growth, differentiation, apoptosis, inflammation and stress response (SUN et al., 2010). Like this,

14/55 its overexpression causes an imbalance in these processes, which can lead to the growth and progression of cancer (SWEENEY et al., 2004). Since tumor growth requires an increase in vascularization, VEGF is considered a potent angiogenic factor, with an important action to stimulate cell migration and vascular permeability (ROSE et al., 2004). It was seen that, in case of disturbances, this molecule may be related to the vascularization of solid malignant tumors, facilitating cell invasion and metastasis formation (MISTRY et al., 2007). On the contrary, endostatins, a product of collagen divation in the C-terminal region, act as inhibitors of proliferation and migration of endothelial cells, presenting an antiangiogenic action, and may also present alterations in expression in cases of pathologies (MUCCI et al., 2009 ).

Jabuticaba and its bioactive substances [026] Some fruits have been consumed not only due to their sensory attributes and personal preferences, but due to the nutrients and bioactive substances they present (ROOSEN et al., 2007). In addition to essential nutrients, most fruits contain bioactive substances, such as phenolic compounds (LEITE-LEGATTI et al., 2012).

[027] Phenolic compounds refer to a wide group of molecules that can be chemically defined as substances that have a benzene ring attached to one or more hydroxyls, and may have other substituent groups in their structure, such as esters, methyl esters and glycosides (HO et al., 2010). In addition, they are subdivided

15/55 in two categories, these being flavonoids and non-flavonoids (ABE et al., 2007; HO et al., 2010).

[028] Jabuticaba is a Brazilian fruit, easily found in commercial houses, being widely consumed in the country. It is found in the varieties Myrciaria caullfolia Vell Berg and Myrciaria caullfolia (DC) Berg (MATTOS, 1983; DONADIO, 2000), being consumed mainly in natura.

[029] Furthermore, it is considered the Brazilian fruit with the greatest source of the anthocyanin flavonoid (LEITE-LEGATTI et al., 2012). It is known that there are approximately 315mg anthocyanins in 100g of jabuticaba (TERCI, 2004), these compounds being responsible for most of the blue, violet and red tones present in flowers and fruits (KONG et al., 2003). Although anthocyanins have been described as a major compound, the presence of other phenolic compounds in the home of this fruit has already been reported, such as phenolic acids, quercitin, isoquercitin, tannins (gallic acid and ellagic acid) and terpenes (REYNERTSON et al., 2006; PLAGEMANN et al., 2012). In addition, fruit is a good source of carbohydrates, minerals (calcium, iron, potassium and phosphorus), amino acids (tryptophan, lysine), vitamins (mainly vitamin C), soluble and insoluble fibers (LORENZI et al., 2000; LENQUISTE et al., 2012).

[030] Other important compounds that have been increasingly explored are depisids, especially jaboticabines. Its anti-HIV and anti-proliferative activities have been studied (REYNERTSON et al., 2006). Despite this, these compounds are rarely found in fruit extracts

16/55 and products made from them, such as jellies and liqueurs (WU et al., 2012).

[031] Increased consumption of fruits and vegetables has increasingly been linked to reduced risk of cancer and cardiovascular disease. This fact has been attributed to the presence of phenolic compounds (LEITE et al., 2011). Among the properties of these substances are: antioxidant activity (LEITE et al., 2011), anti-inflammatory activity, anticarcinogenic activity, cellular modulation (acting on the signaling machinery), ability to prevent cardiovascular and neurodegenerative diseases (BRITO et al., 2007; TSUDA et al., 2003), reduction of weight gain, anti-diabetes effect, regulation of hormones related to obesity, as well as improvement of glucose intolerance and insulin resistance (DEFURIA et al., 2009; WU et al., 2012 ).

[032] Leite et al. (2011) demonstrated that ingestion of the lyophilized Jabuticaba bark was able to improve the antioxidant potential in the plasma of adult rats. Still, it was found that the consumption of Jabuticaba bark was able to prevent insulin resistance, improve expression of markers of the insulin signaling pathway, modulate the expression of inflammatory markers IL-6 and IL-Ιβ, increase ghrelin levels , HDL-cholesterol, in addition to reducing hyperinsulinemia in rats treated with a high calorie diet (LENQUISTE et al., 2012; DRAGANO et al., 2013).

[033] In a recent study, Lenquiste et al. (2015) found that consumption of the aqueous extract of the Jabuticaba bark was able to reduce weight gain, increase

17/55 levels of total glutathione, plasma and hepatic peroxidase, as well as hepatic catalase in animals that consumed a high-fat diet. In addition, Baptista et al. (2014) found a reduction in lipid peroxidation in the liver and brain, in addition to increased levels of the enzymes glutathione peroxidase and superoxide dismutase in animals that consumed the bark of lyophilized Jabuticaba legally with the high-fat diet.

[034] Still, Leite-Legatti et al. (2012) studied the effect of Jabuticaba bark on 11 different types of tumor cells, and found strong antiproliferative activity in cases of leukemia and prostate cancer cells. In relation to prostate cancer, it was verified by Khan and Mukhtar (2013) that phenolic compounds from green tea were able to reduce the expression of NF-kp and IGF-1, reducing cell proliferation, confirming the positive activity of these compounds. The administration of omega-3 also had positive effects, reducing the expression of RA, as well as the expression of genes related to the NF-kp pathway, with a reduction in cell proliferation and an increase in apoptosis in the dorsolateral prostate of rats with cancer (AKINSETE et al., 2012). In addition, Vanella et al. (2013) confirmed the ability of ellagic acid to reduce levels of VEGF, FGF and IL-15 in prostate cancer cell culture. Likewise, Yang et al. (2011) found a reduction in VEGF levels in cultured prostate cancer cells. The beneficial activity of anthocyanins in relation to oxidative stress caused by benign prostatic hyperplasia has been reported

18/55 by Li et al. (2013), who found a reduction in lipid peroxidation, as well as an increase in the oxygen radical absorption capacity (ORAC), total glutathione, superoxide dismutase enzymes and glutathione peroxidase.

STATE OF THE TECHNIQUE [035] Some studies suggest the use of jabuticaba extract to treat different types of diseases, as described in the studies below.

[036] The article entitled Vasorelaxant and Hypotensive Effects of Jaboticaba Fruit (Myrciaria cauliflora) Extract in Rats refers to a hydroalcoholic extract obtained from jabuticaba and used in a model of vascular tension and high pressure. This article differs from the present invention, mainly in that the jabuticaba bark was air-dried and simply solubilized in ethanol with undetermined concentration, whereas in the present invention the jabuticaba bark was lyophilized, solubilized in 50% hydroethanolic solution, kept in ultrasound in order to enhance the extraction, the filtrate was re-extracted during the same proportion and again maintained in ultrasound. In addition, in such an article, the solution was evaporated indefinitely until powder was obtained, while in the present application the evaporation occurred at a temperature between 40 and 90 ° C for a determined time for the complete evaporation of the solvent.

[037] The article entitled Evaluation of the Antioxidant Activity and Antiproliferative Effect of the Jaboticaba (Myrciaria cauliflora) Seed Extracts in Oral Carcinoma Cells refers to hydroalcoholic extracts obtained from the bark, pulp and seed of the jabuticaba. These

19/55 extracts were tested in oral cancer cell cultures. The different parts of the jaboticaba were dried in air, solubilized in ethanol (95%) and the solution remained at room temperature for 3 days, being stirred. This process was repeated with the filtrate obtained. In a different way, in the present invention the bark of the jabuticaba was lyophilized, solubilized in a hydroalcoholic solution with a lower ethanol content (50%), maintained in ultrasound in order to enhance the extraction, the filtrate was re-extracted under the same proportion and again kept in ultrasound. In addition, in that article the extract was evaporated at an undetermined time and temperature until powder was obtained, while for the present invention the evaporation occurred at the temperature controlled for a determined time for the complete evaporation of the ethanol present in the solvent.

[038] The article entitled Jaboticaba peel: Antioxidant compounds, antiproliferative and antimutagenic activities refers to extracts obtained from the bark of Jabuticaba. In this article, the lyophilized jaboticaba peel was simply solubilized in dichloromethane and ethanol with undetermined concentration. On the other hand, in the present application the freeze-dried jabuticaba bark was solubilized in a hydroethanolic solution, maintained in ultrasound in order to enhance the extraction, the filtrate was re-extracted under the same proportion and again maintained in ultrasound. Additionally, in that article the solution was evaporated at an undetermined temperature and time until powder was obtained, while in the present application the evaporation occurred at the temperature controlled for a determined time for the

20/55 complete evaporation of the ethanol present in the solvent. In addition, the application test was performed only on cell cultures, with only cell survival analysis being performed, lacking biological evidence to prove the effect.

[039] The article entitled '' Freeze-dried jaboticaba peel powder improves insulin sensitivity in high-fat-fed mice refers simply to the addition of freeze-dried jaboticaba peel to the experimental animal feed. The present invention, in a different way, deals with an extract of the lyophilized jabuticaba bark, standardized, non-toxic, which can be ingested and used in the treatment of metabolic and prostatic alterations.

[040] The articles entitled Antioxidant Potential of Rat Plasma by Administration of Freeze-Dried Jaboticaba Peel (Myrciaria jaboticaba Vell Berg) and Freeze-dried jaboticaba peel added to high-fat diet increases HDLcholesterol and improves insulin resistance in obese rats simply refer to addition of lyophilized jabuticaba bark to the experimental animal feed. For the analysis of the components of this bark, methanolic extract was performed, but it was not administered to the animals. On the other hand, the present invention deals with an extract of the lyophilized jabuticaba bark, standardized, non-toxic, which can be ingested and used in the treatment of metabolic and prostatic alterations.

[041] The article entitled '' Jaboticaba peel and jaboticaba peel aqueous extract shows in vitro and in vivo antioxidant properties in obesity model refers to

21/55 use of aqueous extract of jabuticaba bark and addition of lyophilized jabuticaba bark to experimental animal feed. Only an aqueous extraction of the lyophilized jabuticaba peel was performed, with manual homogenization of the solvent and jabuticaba peel. On the other hand, in the present application the freeze-dried jabuticaba bark was solubilized in a hydroethanolic solution, maintained in ultrasound in order to enhance the extraction, the filtrate was re-extracted under the same proportion and again maintained in ultrasound. Subsequently, the solvent was evaporated at a temperature between 40 and 90 ° C for a determined time for complete ethanol evaporation.

[042] The present invention proposes a composition comprising an extract of lyophilized jabuticaba bark, non-toxic. For the embodiment of the present invention, the standardized extract of jabuticaba bark previously dried (lyophilization, in this case, or any other form of drying, eg spray drier) obtained for food and / or pharmaceutical and / or herbal composition purposes , was extracted in a conventional manner (in this example, ultrasound or any other form of extraction) from a hydroethanolic solvent, following homogenization and evaporation steps, without, however, restricting how to obtain the said extract. Said composition with jabuticaba bark extract comprises 93% higher phenolic compounds, monomeric anthocyanins and flavonoids in relation to extraction with another solvent, such as water. The composition of the present invention has a surprising effect for treating metabolic processes, such as

22/55 weight or reduction in weight gain as a medicine. In addition, this better phenolic profile gave the present composition a potent anti-cholesterolemic, anti-angiogenic, anti-inflammatory, antiproliferative effect, in addition to the ability to modulate hormonal and glucose metabolism, not previously observed.

SUMMARY OF THE INVENTION [043] The purpose of the present invention is to propose a composition comprising alcoholic extract of jabuticaba bark (ECJ) for use in the treatment of metabolic processes, such as weight loss and / or reduction of weight gain, as well as prostatic lesions in aging.

BRIEF DESCRIPTION OF THE INVENTION [044] The present invention relates to a composition comprising alcoholic extract of jabuticaba bark (ECJ) and pharmaceutically acceptable vehicles, such as chelating agents, pH adjusting agents, preserving agents, humectants, thickeners, bacteriostatic agents , active ingredients, dyes and flavorings), with defined chemical composition, for use in the treatment of metabolic processes, such as weight loss and / or reduction of weight gain, as well as prostatic lesions in aging, such as prostate cancer.

BRIEF DESCRIPTION OF THE INVENTION [045] The present invention relates to a composition containing alcoholic extract of jaboticaba peel (ECJ) for use as an antioxidant, anti-inflammatory, for weight loss and / or reduction of weight gain, as well as prostatic injuries from aging.

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BRIEF DESCRIPTION OF THE FIGURES [046] FIG. 1 presents the graphs containing the results of the influence of doses I and II of the ECJ composition on weight gain, feed intake, as well as the energy value ingested, where (A) represents the percentage of weight gain; (B) weekly feed consumption (g); and (C) the energy value consumed weekly. Significant differences were observed: ^a in relation to the JV group;

in relation to the SE group. ^c with respect to the SHP group. Where: * p <0.05; ** p <0.01 and *** p <0.001.

[047] FIG. 2 presents the graphs containing the results of the influence of doses I and II of the ECJ composition on fasting glucose, as well as on insulin and glucose tolerance, where (A) represents the measurement of serum fasting glucose; (B) the glucose tolerance test (AUC); (C) the time-dependent glycemic response after glucose overload; (D) the insulin intolerance test (AUC); and (E) the time-dependent glycemic response after insulin overload. Significant differences were observed: ^a in relation to the JV group; ^b in relation to the SE group. ^c with respect to the SHP group. ^d with respect to SJI groups. Where: * p <0.05; ** p <0.01 and *** p <0.001.

[048] FIG. 3 presents the graphs containing the results of the influence of doses I and II of the ECJ composition on the lipid profile, where (A) represents the total serum cholesterol; (B) serum LDL-cholesterol; (C) serum HDLcholesterol; and (D) Serum triglycerides. Significant differences were observed: ^a in relation to the JV group; ^b in relation to the SE group. ^c with respect to the SHP group. ^d

24/55 with respect to the SJI group. Where: * p <0.05; ** p <0.01 and *** p <0.001.

[049] FIG. 4 presents the graphs of the analysis of hepatic histopathology in the Different Experimental Groups, where (A) represents the percentage of mononucleated hepatocyte; (B) the percentage of binucleated hepatocyte; (C) the percentage of lipid; (D) the percentage of total cytoplasm; (E) the percentage of inflammatory infiltrate; and (F) percentage of blood vessels. Significant differences were observed: ^a in relation to the JV group; ^b in relation to the SE group. ^c with respect to the SHP group. ^d with respect to the SJI group. Where: * p <0.05; ** p <0.01 and *** p <0.001.

[050] FIG. 5 represents the photomicrographs of the liver stained with hematoxylin and eosin from the different experimental groups, where (A) represents the young group; (B) the senile group; (C-D) the senile group + high-fat diet; (E) the senile group + dose I of the ECJ composition; (F) senile group + ECJ dose II; (G) senile group + high-fat diet + dose I of ECJ; (H) senile group + high-fat diet + ECJ dose II. Of which: Thick Arrow (Binucleated Hepatocyte); Thin Arrow (Mononucleated Hepatocyte); Arrowhead (Inflammatory Infiltrate); C (Cytoplasm); L (Lipideo); IN (Cellular Swelling) and * (Blood Vessel). Bar = 50pm.

[051] FIG. 6 represents the graphs of the analysis of the histopathology of the prostatic ventral lobe in the Different Experimental Groups, where (A) represents the% of total epithelium; (B)% of normal epithelium; (C)% NIP; (D) the% of atrophic epithelium; (E) the number of well-differentiated adenocarcinoma observed; (F) the number of micro acids

Observed 25/55; (G)% of total stroma; (H) to% of acinar lumen; (I) the% of the fibromuscular layer around the acini; and (J) the% of the inflammatory infiltrate. Significant differences were observed: ^a in relation to the JV group; ^b in relation to the SE group. ^c with respect to the SHP group. ^d with respect to the SJI group. ^and with respect to the SHJI group. Where: * p <0.05; ** p <0.01 and *** p <0.001.

[052] FIG. 7 represents the photomicrographs of the prostatic ventral lobe stained with masson's trichrome from the different experimental groups, where (A-B) represents the young group; (C-D) the senile group; (E-F) the senile group + high-fat diet; (G-H) the senile group + dose I of the ECJ composition; (I-J) the senile + dose II group of the ECJ composition; (KL) the senile group + high fat diet + dose I of the ECJ composition; (M-N) the senile group + high fat diet + dose II of the ECJ composition. Where: L (lumen); Es (Stroma); Thin Arrow (Epithelium); Thick Arrow (Inflammatory Infiltrate); (*) (Fibromuscular layer). Bar = 50pm.

[053] FIG. 8 represents the photomicrographs of the Immunolocation of AR (A-G), ERa (H-N), VEGF (MU) and CD31 (W-CC) antigens in the prostate ventral lobe in the different experimental groups. Of which: Seta Fina (Epithelium); L (Lumen) and Es (Stroma). Bar = 50pm.

[054] FIG. 9 represents the graph of the Western-Blotting analysis for AR molecule. Significant differences were observed: ^a in relation to the JV group; ^b in relation to the SE group. ^c with respect to the SHP group. ^d with respect to the SJI group. Where: * p <0.05; ** p <0.01 and *** p <0.001.

[055] FIG. 10 represents the graph of the analysis of

26/55

Western-Blotting for VEGF molecule. Significant differences were observed: ^a in relation to the JV group; ^b in relation to the SE group. ^c with respect to the SHP group. ^d with respect to the SJI group. Where: * p <0.05; ** p <0.01 and *** p <0.001.

DETAILED DESCRIPTION OF THE INVENTION [056] The present invention relates to a composition comprising alcoholic extract of jabuticaba bark (ECJ) and pharmaceutically acceptable vehicles for use in the treatment of metabolic processes, such as weight loss and / or weight gain reduction , as well as prostatic lesions in aging, such as prostate cancer.

[057] Since those of pharmaceutically acceptable vehicles can be selected from chelating agents, pH adjusting agents, preserving agents, humectants, thickeners, bacteriostatic agents, active ingredients, dyes and flavorings.

[058] For the embodiment of the present invention, the standardized extract of previously dried jabuticaba bark (lyophilization, in this case, or any other form of drying, eg spray drier) obtained for food and / or pharmaceutical composition purposes and / or phytotherapic, it was extracted in a conventional way (in this example, ultrasound or any other form of extraction) from alcoholic solvent, in this case, ethanol, following homogenization and evaporation steps, without, however, restricting the way of obtaining said extract. Said composition with jabuticaba bark extract comprises 93% higher phenolic compounds, monomeric anthocyanins and flavonoids compared to other extraction solvent such as

27/55 water.

Process carried out to obtain the ethanolic extract of the jaboticaba peel for the referred composition [059] Firstly, the extract of the jaboticaba bark was prepared by selecting the fruits manually, in which they were washed in running water and pulped, in which the pulp was discarded and the shells frozen at temperatures between 0 and -40 ° C, preferably -20 ° C.

[060] Subsequently, the shells were thawed and lyophilized in a freeze dryer at a temperature between 10 and 50 ° C, preferably 30 ° C and a vacuum between 50 and 600 pHg, preferably 300 pHg for 95 h. After this process, the shells were crushed in a micro-chip to obtain a fine powder [Casca da Jabuticaba Liofilizada (CJL)]. The obtained powder was stored at a temperature between 0 and -90 ° C, preferably -80 ° C, in a dark package, until the moment of analysis and preparation of the extract for administration.

[061] To prepare the extract, the dried Jabuticaba bark was solubilized in a 50% ethanol solution in the proportion between 30:70 and 70:30 (mass / volume) for the extraction of the compounds of interest. This material was homogenized and sonicated for 30 minutes. Subsequently, the solution was filtered on No. 1 filter paper, using a vacuum pump, the residue being re-extracted for 1 more time following the same sample and solvent proportions.

[062] Finally, the filtrates were mixed. Then, the extract was rotated at a temperature between 35 and 37 ° C, preferably 36 ° C, until all the ethanol present in the sample was evaporated and recovered in a balloon,

28/55 thus obtaining an aqueous extract, nontoxic for administration to animals and using the residual water of the process itself as an administration vehicle.

[063] The extract of the bark of the jabuticaba was evaluated for the presence of phenolic compounds, anthocyanins and total flavonoids. In addition, its antioxidant capacity was determined using FRAP, DPPH, ORAC and ABTS assays. Table 1 below shows the bioactive compounds and in vitro antioxidant activity presented by the Lyophilized Jabuticaba Peel (CJL) and the CJL Ethanolic Extract (Standardized).

Table 1: Bioactive compounds and antioxidant activity

Extract Ethanol Extract from Parameters ¹ methanolic CJL (g) CJL (g) (Standardized) Compounds Phoenicians mg EAG ' ^lb 59 ± 3.3 114 ± 2.1 Anthocyanin Monomeric mg cyd 3 -gloo 100- * ^c 684.6 ± 60.2 1297 + 12.4 Flavonoids mg CAT ^d 9.8 + 0.25 23 + 0.24 DPPH μΜ T £ him 822.8 ± 80.5 1591 ± 6.8 ORAC μΜ ET ' ¹ 6635.8 + 576.9 3994 ± 16.8 ABTS μΜ ET ' ¹ 652.5 ± 73.2 6419 ± 85.7

^a Analyzes done in triplicate; ^b Values expressed as qallic acid equivalent; ^c Cyanidin 3-glycoside; “Catechin: ^e Values expressed in Trolox equivalent.

[064] The effects of the standardized extract are superior to the consumption of the lyophilized jabuticaba bark or aqueous extract of the lyophilized jabuticaba bark. To

29/55 consuming the same amount of bioactive compounds the effects of the standardized extract are superior to the consumption of the lyophilized jabuticaba bark (CJL) and the aqueous extract of the lyophilized jabuticaba bark. Previous studies (Batista et al., 2013; Lenquiste et al., 2012; Marques et al., 2012; Dragano et al., 2011) administered to the experimental animals a high-fat diet with 2 and 4% freeze-dried jabuticaba peel. By offering these diets supplemented with CJL to experimental animals, they ingest the same amount of bioactive compounds administered in doses I and II of the present work. Despite this, minor biological effects are seen when compared to the standardized extract. In these studies, it is not possible to observe a reduction in weight gain, food consumption, total cholesterol, glucose tolerance index, insulin tolerance index and fasting glucose. In addition, an increase in HDL-cholesterol was not observed by these authors. In the work of Lenquiste et al. (2015), which used aqueous extract from CJL, there was also no reduction in weight gain, despite the fact that these animals ingest a higher dose of bioactive compounds than that used in the present technology. On the other hand, the standardized CJL extract, developed by us, was able to promote a reduction in fasting glucose, glucose tolerance, insulin intolerance, total cholesterol, LDL-cholesterol, reduce fatty liver and level of non-fatty liver disease alcohol and increase HDL cholesterol levels, restoring the glycidic and lipidic homeostasis of the senile and senile obese organisms. In addition, prostatic changes caused by aging,

30/55 which can culminate in prostate cancer and be intensified by obesity, have been evaluated and there is no document in the literature that relates jabuticaba and derivatives with prostatic changes.

[065] The unprecedented results reveal the ability of the standardized extract composition of CJL to reduce foci of well differentiated Adenocarcinoma, cell proliferation and inflammatory and angiogenic processes in this gland, in addition to modulating hormonal profile, restoring the prostatic microenvironment.

Quantification of anthocyanins [066] For the quantification of anthocyanins present in the extract of jabuticaba peel of the present composition, the analytical method previously developed was validated based on the recommendations of the validation guide, made available by VICH (Veterinary International Conference Harmonization, 1999), evaluating the following validation parameters: seectivity / specificity, matrix effect, linearity, accuracy / recovery, intraday precision and intermediary precision, detection limit (LOD) and quantification limit (LOQ).

[067] Initially the matrix effect was evaluated by comparing the slope of the analytical curves prepared in the jaboticaba extract and in methanol. Since the matrix effect was not observed, the quantification of the metabolites was performed through external calibration. For the quantification of anthocyanins, the samples were previously diluted in methanol and filtered before being injected in the UPLC-MS / MS system. Three

31/55 samples, each prepared in duplicate for analysis. The quantities found in the extract of jabuticaba referring to the anthocyanins cyanidin 3-0-glucoside (Kuromaina) and delfinidine 3-0-glucoside (Mirtilina) are described in Tables 2 and 3, respectively. The analysis of the quantification results indicates that 3-0 glucoside cyanidin (Kuromaina) is the majority, being found in a proportion practically 10 times greater than 3-0 glucoside delfinidine (Mirtilina).

Table 2: Quantification of the cyanidin compound 3-Oglucoside (Kuromaina) in jaboticaba extract.

Sample 1 Cone. in the Statement (ug / ml) Detour standard CV% 1 934.99 42.01 4.64 2 875.58 Average 905.28 Sample 2 Cone. in the Statement (ug / ml) Detour standard CV% 1 958.56 2.87 0.30 2 962.62 Average 960.59 Sample 3 Cone. in the Statement (ug / ml) Detour standard CV% 1 1087.97 6.35 0.59 2 1078.98 Average 1083.48

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Table 3: Quantification of the 3-0 glucoside delfinidine compound (blueberry) in jaboticaba extract. Results expressed in ug / ml of blueberry base.

Sample 1 Cone. in the Statement (ug / mL) Detour standard CV% 1 102.49 0.88 0.85 2 103.73 Average 103.11 Sample 2 Cone. in the Statement (ug / mL) Detour standard CV% 1 106.06 0.03 0.03 2 106.02 Average 106.04 Sample 3 Cone. in the Statement (ug / mL) Detour standard CV% 1 109.54 2.20 1.98 2 112.66 Average 111.10

[068] As noted in Tables 3 and 4 above, the present jabuticaba extract showed a concentration of cyanidin 3-O-glucoside (Kuromaina) varying between 900 ug / mL and 1100 ug / mL and a concentration of delfinidine 3-Oglucoside ( blueberry) ranging from 100 µg / ml to 112 µg / ml.

Example of the Invention [069] One of the countless ways of carrying out the invention is demonstrated here, however without limiting the scope of the same, and can be realized in other specific ways

33/55 without running away from its essential attributes.

[070] For the analysis of the effects of jabuticaba bark extract, 70 FVB mice were used, which were separated into 7 experimental groups as defined below and illustrated in FIG. 1 (n = 10 animals / group):

Young Group (JV): mice aged between 2 and 4 months that received daily gavage with water, in addition to water and commercial food ad libitum for 60 days;

Control / Senile Group (SE): mice aged between 9 and 13 months that received daily gavage with water, in addition to water and ration ad libitum for 60 days;

Hyperlipidic Diet Group (SHP): mice aged between 9 and 13 months that received daily gavage with water, in addition to water and hyperlipidic food ad libitum for 60 days;

Senil / Jabuticaba Group (SJI): mice aged between 9 and 13 months that received daily gavage of ethanolic extract of jabuticaba bark (0.003mL of extract / g of animal / day), in addition to water and commercial feed ad libitum for 60 days;

Senil / Jabuticaba Group (SJII): mice aged between 9 and 13 months that received daily gavage of ethanolic extract of jabuticaba bark (0.006mL of extract / g of animal / day), in addition to water and commercial feed ad libitum for 60 days;

Hyperlipidic Diet / Jabuticaba Group (SHJI): mice aged between 9 and 13 months that received daily gavage of ethanolic extract of jabuticaba bark

34/55 (0.003mL of extract / g of animal / day), in addition to water and hyperlipidic feed ad libitum for 60 days;

Hyperlipidic Diet / Jabuticaba Group (SHJII): mice aged between 9 and 13 months who received daily gavage of ethanolic extract of jabuticaba bark (0.006mL of extract / g of animal / day), in addition to water and ad libitum hyperlipidic feed per 60 days.

Determination of the Jabuticaba extract dose [071] The dose I of the jabuticaba bark extract composition was chosen in order to present the same phenolic content ingested when adding 2% of freeze-dried jabuticaba bark to the rodent feed. The dose II used was twice the dose I. Table 4 below shows the number of doses recommended for both mice and adults and children.

Table 4: Recommended doses

Doses I (mL extract / kg body weight) II (mL extract / kg body weight) Mouse 3.4 6, 8 Adult 0.27 0.55 Kid 0.41 0.82

Relative Weight Gain (%), Energy Consumption and Relative Weight of the Liver [072] The relative weight gain was calculated according to the following formula:

Weight gain (%) = (GP x 100) / PI where: GP (weight gain = final weight - initial weight) and PI

35/55 (starting weight). In addition, the control of feed consumption was carried out according to the feed distributed to the animals at the beginning and at the end of the same week. In order to assess energy consumption, the volume of feed consumed was multiplied by the energy value of each feed (these values can be found in Table 1). For these analyzes, the weighing of animals and feed was carried out from 2:00 pm to 4:00 pm. The relative weight of the liver was obtained in percentage, considering its absolute weight and the body weight of the respective animal, according to the formula: (organ weight / body weight) x 100.

[073] Weight gain during the treatment period was significantly elevated in the JV group compared to the SE group. The consumption of a high-fat diet in senile animals increased weight gain in relation to their SE control. The positive effect of consumption of the ECJ composition was seen in the SHJI and SHJII groups, after ingestion of both doses, in relation to the SHP, demonstrating a reduction in weight gain. Despite this effect, there were no significant differences between the SE, SJI and SJII groups. These values are described in FIG. 1.

[074] Food consumption was higher in the SE group compared to the SHP group. Despite this, it was observed a higher energy value ingested in senile animals that consumed the high-fat diet, when compared to those that ingested commercial diet. Another positive aspect of ingesting the ECJ composition was the reduction in feed intake and energy value ingested in SHJI and SHJII in relation to SHP.

[075] Thus, it was found that dose II of

36/55 composition of the jabuticaba bark extract of 0.006 mL / g was more effective, promoting greater reduction of weight loss in senile animals and greater weight loss in obese senile animals. Despite this, excellent results were observed with the consumption of dose I (0.003 mL / g), which also promoted a greater reduction in weight loss in senile animals and greater weight loss in obese senile animals, but to a lesser extent when compared to dose II (0.006mL / g). These results are shown in FIG. 1.

Fasting Glucemia, Insulin Tolerance Test and

Glucose Tolerance Test [076] The ability of the ECJ composition to modulate glucose metabolism has been proven both in senile animals with normopeso and overweight, observing a reduction in fasting glucose to perform such an assessment, the insulin tolerance test (ITT), glucose tolerance test (GTT) and enzyme fasting glucose measurement AA. GTT and ITT tests were performed using blood from the animal's tail and glucometer in the times after administration of glucose solution (2g / kg) or insulin (0.5U / kg) of 0, 10, 15, 30 and 60 minutes. The consumption of dose I of the ECJ composition by senile animals promoted a reduction in fasting glucose in relation to senile animals. In this parameter, dose II of the ECJ composition proved to be more effective, since animals in the SJII group had significantly reduced fasting blood glucose compared to the SE and SJI groups. On the other hand, the consumption of the high-fat diet by senile animals promoted an increase in this parameter in relation to the SE group. In senile animals with

37/55 overweight, both doses of the ECJ composition were able to reduce fasting blood glucose.

[077] In addition, consumption of a high-fat diet by senile animals increased insulin intolerance and glucose tolerance, when compared to senile animals that consumed a commercial diet. Both doses of the ECJ composition were able to reduce insulin intolerance in overweight senile animals. However, considering glucose tolerance, a significant reduction was observed only after ingestion of Dose II of the ECJ composition. The results described above can be seen in FIG. 2.

Lipid Profile [078] It was possible to prove the anti-cholesterolemic potential of the ECJ composition and its ability to raise HDL levels in elderly and overweight elderly animals. Total cholesterol, HDL-cholesterol and triglycerides were evaluated using the Colestat AA enzyme kits, HDL-Precipitating Reactive Cholesterol and TG Color GPO / PAP AA. LDL-Cholesterol was estimated considering the formula:

CLDL = Cplasma - CHDL - TG / 5.

[079] Aging promoted an increase in serum levels of total cholesterol and LDL-cholesterol compared to that found in young animals. Ingestion of both doses I and II of the ECJ composition promoted a reduction in the levels of total cholesterol and LDL-cholesterol. The consumption of the high-fat diet by senile animals promoted an intensification of the changes observed in senile animals that consumed a commercial diet, with an increase in the levels of total cholesterol, LDL-cholesterol and HDL-cholesterol in relation to

38/55 to the SE group. Doses I and II of the ECJ composition when ingested by senile animals that consumed the high-fat diet, were able to reduce the levels of total cholesterol and LDL-cholesterol, in addition to increasing the level of HDL-cholesterol when compared to animals that consumed the diet hyperlipidic and did not receive the ECJ composition. No significant differences were observed between the experimental groups, considering serum triglyceride levels. The results can be seen in FIG. 3.

Hepatic Histopathological Analysis [080] The histopathological analysis of the liver allowed the observation of the ability of the ECJ composition to reduce the accumulation of fat, in this organ, in senile animals that consumed the high-fat diet. In addition, a reduction in the presence of inflammatory infiltrates was seen in both models after consumption of the ECJ composition. The rest of the morphology remained regular after consumption of the ECJ composition, presenting strands of hepatocytes organized in lobes, with a central nucleus and presence of blood vessels with apparent regular thickness between these strands. It was also possible to prove a reduction in the weight of this organ after consuming the composition of ECJ in both models evaluated. In addition, a histological score for Non-Alcoholic Fatty Liver Disease was applied which considered: steatosis (score 0-3), inflammation (score 0-3) and cell swelling (score 0-2). The sum of these values produces the activity score for Non-Alcoholic Fatty Liver Disease (score 0-8). The results were as follows:

Youth Group (JV)

39/55 [081] The young group had liver tissue with typical morphology. The hepatocytes had a hexagonal structure and central nucleus, which could be mononuclear or binuclear, organized in the form of cords. Blood vessels were distributed among hepatocytes and possible inflammatory infiltrates were also observed. The Youth group scored 0, considering the histological score for Non-Alcoholic Fatty Liver Disease (FIGS. 4 and 5-A).

Senile Group (SE) [082] Aging promoted a significant increase in the accumulation of lipids in the hepatocyte cytoplasm in relation to the JV group, characterizing an initial steatosis (score 2). This accumulation promoted an increase in the total cytoplasm of these cells, with cell swelling (score 1) and displacement of nuclei towards the cell periphery. In addition, it was possible to observe a higher frequency of inflammatory infiltrates compared to the JV group. Thus, this group is represented by note 3 in the histological score for Non-Alcoholic Fatty Liver Disease (FIGS. 4 and 5-B).

Senile Group + High-Fat Diet (SHP) [083] The consumption of high-fat diet by senile animals promoted an intensification of the changes observed with aging. A significant increase in the accumulation of lipids in the cytoplasm of hepatocytes was observed in relation to the SE group, characterizing a condition of intense steatosis (score 3). This accumulation promoted a greater increase in the total cytoplasm of these cells, with a greater

40/55 frequency of cell swelling (score 2) and displacement of nuclei to the cell periphery. In addition, there was a significant reduction in the frequency of blood vessels and an increase in the frequency of inflammatory infiltrates (score 3), in relation to SE. This group is represented by note 8 in the histological score for Non-Alcoholic Fatty Liver Disease (FIGS. 4 and 5-C; D).

Senile + group of ECJ-Dose I composition (SJI) [084] The consumption of Dose I of ECJ composition by senile animals promoted a significant reduction in lipid accumulation in relation to the SE group, reducing the level of steatosis (score 1) . Despite this change, there was no reduction in the total percentage of cytoplasm. On the other hand, cell swelling (score 0) was not observed in this group, with an increase in the frequency of blood vessels, as well as a reduction in the frequency of inflammatory infiltrates (score 0) in relation to the SE group. Thus, this group is represented by note 1 in the histological score for Non-Alcoholic Fatty Liver Disease. These results can be seen in FIGs. 4 and 5-E.

Senile + group of ECJ-Dose II composition (SJII) [085] The consumption of Dose II of ECJ composition by senile animals promoted a significant reduction in lipid accumulation in relation to the SE group, reducing the level of steatosis (score 1) . This change was accompanied by a reduction in the total cytoplasm and cellular swelling (score 0), with a reduction in the frequency of inflammatory infiltrates (score 0) in relation to the SE group. In addition, there was an increase in the frequency of blood vessels in

41/55 regarding the SE and SJI groups. Thus, this group is represented by note 1 in the histological score for Non-Alcoholic Fatty Liver Disease. These results can be seen in FIGs. 4 and 5-F.

Senile Group + Hyperlipidic Diet + composition of

ECJ-Dose I (SHJI) [086] The consumption of Dose I of the ECJ composition by senile animals that ingested the high-fat diet promoted a significant reduction in the accumulation of lipids in relation to the SHP group, reducing the level of steatosis (score 1). This change was accompanied by a reduction in the total cytoplasm, although cells with typical swelling are still observed (score 1). In addition, there was an increase in the frequency of blood vessels, as well as a reduction in the frequency of inflammatory infiltrates (score 0) in relation to the SHP group. Thus, this group is represented by note 1 in the histological score for Non-Alcoholic Fatty Liver Disease. These results can be seen in FIGs. 4 and 5-G.

Senile Group + Hyperlipidic Diet + composition of

ECJ-Dose II (SHJII) [087] The consumption of Dose II of the ECJ composition by senile animals that ingested the high-fat diet promoted a significant reduction in the accumulation of lipids in relation to the SHP group, reducing the level of steatosis (score 1). This change was accompanied by a reduction in the total cytoplasm and absence of cells with typical swelling (score 0). In addition, there was an increase in the frequency of blood vessels, as well as a reduction in the frequency of infiltrates.

42/55 inflammatory (score 1) in relation to the SHP group. Thus, this group is represented by note 1 in the histological score for Non-Alcoholic Fatty Liver Disease. These results can be seen in FIGs. 4 and 5-H.

Histopathological Analysis of the Prostatic Ventricular Lobe [088] The histopathological analysis of the prostatic ventricular lobe was developed using a photomicroscope and appropriate software. A lattice with 432 intersections was projected on 10 random images captured with a 40x objective, for each animal. 4320 points were quantified per animal, which were divided into the following categories: normal epithelium, intraepithelial neoplasia (PIP), atrophic epithelium, total epithelium, acinar lumen, total stroma, muscle cell around the acino and inflammatory infiltrate. From this, it was possible to calculate the proportion (%) of each of these components. In order to assess the amount of well-differentiated microacin and foci of adenocarcinoma, these were quantified in 10 random fields captured with a 40x objective for each animal.

Youth Group (JV) [089] In this group, the prostatic ventral lobe showed acini with simple epithelium and columnar cells with nuclei located in the basal region of the cell. Acinar regions with pleated epithelium have been verified, which is characteristic of this glandular lobe. In relation to the stroma, it presented fibroblasts and blood vessels, in addition to smooth muscle cells and collagen fibers located around the acins of this organ (Figures 6 and 7 A-B).

Senile Group (SE)

43/55 [090] The animals in the Senile group showed a significant increase in epithelial atrophy and NIP, compared to the JV group. In the atrophic regions, the epithelium was cubic and not pleated. The NIP regions, on the other hand, showed intense cell proliferation, with bulky nuclei being characteristic of these cells. These changes led to a reduction in the percentage of normal epithelium and lumen in relation to the JV group. In addition, an increase in foci of well-differentiated adenocarcinoma was observed, characterized by points of discontinuity of the basement membrane, culminating in the stromal invasion of epithelial cells, in addition to the occurrence of microacids. The prostatic stroma was hypertrophic and hyperplastic, with a significant increase in the percentage of total stroma and the fibromuscular layer around the acini, with stromal alterations being more frequently seen in the vicinity of the proliferation regions. In addition, a higher frequency of inflammatory infiltrates was found in relation to the JV group (FIGS. 6 and 7 C-D).

Senile + Hyperlipidic Diet (SHP) Group [091] The consumption of a high-fat diet intensified the changes observed with aging, promoting a significant reduction in regions of normal epithelium in relation to the SE group. Thus, a significant increase in PIN was observed when compared to the SE group, despite the fact that they still present foci of epithelial atrophy in the ventral lobe of the prostate. In this group, the NIPs presented filiform patterns and in some cribriform points. As in the SE group, the regions with NIP presented cells in process

44/55 proliferative with bulky nuclei and atrophy points showing cubic cells with reduced acinar pleating. In addition, there was an increase in the percentage of total epithelium and a reduction in the percentage of lumen for this group, in relation to senile animals. In this group, a pronounced increase in the number of points with disruption of the basement membrane was observed, demonstrating epithelial cells towards the stroma, characterizing foci of well-differentiated adenocarcinoma, as well as an increase in microacids, when compared to its SE control. Ingestion of the high-fat diet also promoted stromal changes in these animals. The stroma was modified with an intense hypertrophic and hyperplastic process. Due to these processes, thickening of the fibromuscular layer that surrounds the prostatic acini was observed, in addition to a significant increase in inflammatory infiltrates, in relation to the senile control group (FIGS. 6 and 7 E-F).

Senile + group of the ECJ-Dose I composition (SJI) [092] In the ventral lobe of the senile animals that consumed Dose I of the ECJ composition, a reduced frequency of NIP was found when compared to the SE control group. Despite this, an increase in atrophic acini with simple cubic epithelium and without pleating was observed. Still, it was possible to notice a significant reduction in the frequency of well-differentiated adenocarcinoma foci in relation to its senile control. The prostatic stroma showed an apparent reduction in hyperplasia and hypertrophy, although there was no significant reduction in the percentage of the fibromuscular layer that surrounds the acino. On the other hand, it was

45/55 possible to notice significant reduction in the frequency of inflammatory infiltrates. Thus, it was generally observed that the consumption of Dose I of the ECJ composition by senile animals contributed to the morphological recovery of the epithelial and stromal compartments, particularly by relating the regions of epithelial proliferation and stromal inflammatory process (FIGS. 6 and 7 GH).

Senile + group of ECJ-Dose II composition (SJII) [093] In the ventral lobe of the senile animals that consumed Dose II of the ECJ composition, a reduced frequency of NIP and atrophy was observed, culminating in an increase in the percentage of normal epithelium , when compared to its SE control. Thus, these changes indicated a significant increase in the percentage of normal epithelium in the SJII group compared to the SJI group. In addition, a significant reduction in the frequency of well-differentiated adenocarcinoma foci was observed in relation to its senile control. In the stroma, there was a reduction in hyperplasia and hypertrophy, identifying a significant reduction in the percentage of the fibromuscular layer that surrounds the acini and in the frequency of inflammatory infiltrates, in relation to the SE group. Thus, it was generally indicated that the consumption of Dose II of the ECJ composition by senile animals was more effective for the morphological recovery of the epithelial and stromal compartments than Dose I, particularly related to the regions of epithelial proliferation and atrophy, stromal thickening and inflammatory process (Figures 6 and 7 IJ).

Senile Group + Hyperlipidic Diet + da com da

46/55 ECJ composition -Dose I (SHJI) [094] The consumption of Dose I of the ECJ composition by senile animals that ingested the hyperlipidic diet led to a higher frequency of areas of regular prostate epithelium, presenting simple columnar epithelium with pleating regions. Thus, a significant reduction in characteristic areas of NIP was observed, in addition to an increase in atrophic areas in relation to its SHP control. These changes led to a reduction in the total epithelium and an increase in the acinar lumen in relation to senile animals that consumed only the high-fat diet. In addition, a significant decrease in the number of microbes and well-differentiated adenocarcinoma foci was observed in relation to the SHP group. Dose I of the ECJ composition also had a positive effect on the stroma preservation of animals in this group. Reduction of the hyperplastic and hypertrophic processes with a significant reduction in the percentage of the fibromuscular layer surrounding the acini was observed, as well as in the frequency of inflammatory infiltrates. Thus, it was evidenced in general that the consumption of Dose I of the ECJ composition by senile animals that ingested a high-fat diet contributed to the morphological recovery of the epithelial and stromal compartments, considering, particularly, the regions of proliferation and epithelial atrophy, thickening and stromal inflammatory process (FIGS. 6 and 7 KL).

Senile Group + Hyperlipidic Diet + composition of

ECJ -Dose II (SHJII) [095]

Consumption of Dose II of the ECJ composition by

47/55 senile animals that ingested the hyperlipidic diet led to the occurrence of more frequent areas of regular prostate epithelium, presenting simple columnar epithelium with folding regions, when compared to the SHP and SHJI groups. Thus, a significant reduction in characteristic NIP areas and atrophic areas was observed in relation to their SHP control and the SHJI group. These changes led to a reduction in the total epithelium and an increase in the acinar lumen in relation to senile animals that consumed only the high-fat diet. In addition, a significant decrease in the number of microbes and well-differentiated adenocarcinoma foci was observed in relation to the SHP group. Dose II of the ECJ composition also had a positive effect on the preservation of the stroma of animals in this group, with a reduction in the hyperplastic and hypertrophic processes, with a significant reduction in the percentage of the fibromuscular layer surrounding the acini, as well as in the frequency of inflammatory infiltrates. when compared to the SHP control. In addition, there was a reduced frequency of inflammatory infiltrate in animals that consumed a high-fat diet and Dose II of the ECJ composition compared to those that ingested Dose I of the ECJ composition. Thus, it was generally identified that the consumption of Dose II of the ECJ composition by senile animals that ingested a hyperlipidic diet was more effective for the morphological recovery of the epithelial and stromal compartments than Dose I, particularly related to the regions of proliferation and epithelial atrophy, which led to an increase in areas of normal epithelium, as well as thickening and process

Inflammatory stromal (FIGS. 6 and 7 M-N).

Immunohistochemistry for AR, ERg, CD31 and

VEGF [096] Samples of the ventral lobe of the prostate from 5 animals from each experimental group, the same ones used for light microscopy, were used. Then, 5 μιτι thick slices in the microtome were obtained and collected on silanized slides. Antigenic recovery was performed by incubating the cuts in citrate buffer (pH 6.0) at 100 ° C in a microwave or treatment with proteinase K, depending on the characteristics of each antibody. The blocking of endogenous peroxidases was obtained with H2O2 (0.3% in methanol) with subsequent incubation in a blocking solution with 3% bovine serum albumin (BSA), in TBS-T buffer for 1 hour at room temperature. Subsequently, the VEGF, ERa, AR and CD31 antigens were located through the monoclonal antibodies mouse VG-1 for VEGF, mouse 2Q418 for ERa, and polyclonal rabbit N-20 for AR and goat M-20 for CD31. These were localized via antibodies diluted (1: 35-50) in 1% BSA and stored overnight at 4 ° C. After washing with TBS-T buffer, the sections were incubated with secondary HRP antibody conjugated, from the Envision kit, for 40 minutes and later revealed with diaminobenzidine (DAB), counterstained with Harris Hematoxylin and evaluated in the photomicroscope. The prostate sections of 5 animals from each experimental group were evaluated using the brownish precipitate of DAB, which indicates the immunoreactivity of the antibodies. The intensity of the immunoreactivity was graded as 0 (zero) for staining

49/55 negative (0%), 1 for weak staining (<33%), 2 for moderate staining (33% -66%) and 3 for intense staining (> 66%), according to the frequency and positivity of the antigens in sections of prostatic tissue.

Western Blotting for AR and VEGF Molecules [097] Samples of the ventral lobe were collected from 5 animals from each experimental group and weighed, homogenized through the homogenizer for 1 min in 50 μΐ / mg of RIPA extraction buffer containing 10% (v / v ) Triton X-100 and 10 μΐ / ml of protease inhibitor cocktail. Tissue extracts were obtained by centrifugation for 20 minutes at 14000 rpm at 4 ° C. An aliquot of each sample was used to determine protein concentration, using Bradford's reagent.

[098] The samples were mixed (1: 1) with 3X sample buffer (100mM Tris-HCl pH 6.8, 10% p-mercaptoethanol, 4% SDS and 20% glycerol), incubated in a dry bath at 95 ° C for 5 minutes. The corresponding 50 micrograms of protein was applied to the SDS-polyacrylamide gel. After electrophoresis, the material was transferred electrically (Hoefer System) to 70 V nitrocellulose membranes for 3 hours. The membranes were blocked with 3% BSA diluted in TBS-T for one hour and incubated with the same primary antibodies used in the immunostaining procedures for mouse monoclonal antigens VG-1 for VEGF and polyclonal rabbit N-20 for AR. The dilution of these antibodies ranged from 1: 300 - 1: 500. After washing with TBS-T buffer, the membranes were incubated for 2 hours with the secondary anti-rabbit and anti-mouse HRP antibodies conjugated at a dilution of 1: 2000

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- 1: 6000 in 1% BSA. After a new series of washes with TBS-T, 10 ml of chemiluminescent solution was added and the peroxidase activity was revealed by a luminescent signal from the Western Blotting bands, which were captured by the G-BOX and chemicamera equipment. The labeling intensities obtained for the different molecules were determined by densitometry using the NIS-Elements image analysis program. Antibody to β-actin was used as an endogenous control.

Androgen Receptor (RA) [099] Positive immunostaining of RA was observed in the epithelium and prostatic stroma in all experimental groups. Intense marking was observed in the JV group, representing more than 66% of the regions analyzed both in the stroma and in the prostatic epithelium. With aging, a reduction in the frequency of immunostaining in the epithelium and stroma was observed, representing an interval of 33 - 66% of the regions evaluated. On the other hand, the consumption of a high-fat diet by senile animals promoted an increase in the positive immunostaining of this receptor, representing more than 66% of the regions analyzed in both prostatic compartments. The consumption of Doses I and II of the ECJ composition promoted a reduction in the immunostaining of RA in animals that concomitantly ingested the hyperlipidic diet, representing an interval of 33 - 66% of the regions evaluated in the epithelium and stroma (FIG. 8; Table 5).

[100] Considering Western Blotting analyzes, it was possible to observe a reduction in RA with aging when compared to young animals. Diet consumption

51/55 hyperlipidic by senile animals was able to increase the level of this molecule when compared to the SE group. In senile animals, the consumption of Dose II of the ECJ composition promoted a reduction in the RA level, in relation to SE. The two doses of the ECJ composition reduced the level of this molecule in senile animals that consumed the high-fat diet, compared to SHP. (FIG. 9).

Α Estrogen Receptor (ERot) [101] ERa immunostaining was observed in the prostatic stroma in all experimental groups. Marking was considered weak in the JV group, occupying less than 33% of the regions analyzed. With aging, an increase in the frequency of immunostaining was observed, which now occupies 33 - 66% of the evaluated regions. The consumption of a high-fat diet by senile animals intensified the immunoexpression of this molecule, promoting an increase in immunostaining, which started to be present in more than 66% of the analyzed regions. In senile animals the daily consumption of Doses I and II of the ECJ composition was able to alter the immunoexpression of ERa, occupying less than 33% of the analyzed regions. Likewise, in senile animals that consumed the high-fat diet, both doses of the ECJ composition were able to alter the immunoexpression of ERa, which now occupies 33 - 66% of the evaluated regions (FIG. 8; Table 5) .

Vascular Endothelial Growth Factor (VEGF) [102] Positive immunostaining of VEGF was observed in the epithelium and prostatic stroma in all experimental groups. Marking was weak on the epithelium and stroma of the

52/55 JV group, representing less than 33% of the analyzed regions. With aging, an increase in the frequency of epithelial immunostaining was observed, representing more than 66% of the regions assessed in the epithelium and 33 - 66% in the stroma. The consumption of a high-fat diet by senile animals maintained the intense immunoexpression of this molecule, in the same way observed for the SE group. In senile animals Dose I of the ECJ composition was able to partially reduce the immunoexpression of VEGF in the epithelium, representing a range of 33 - 66% of the evaluated regions. On the other hand, Dose II consumed by senile animals allowed an even greater reduction in the immunoexpression of this molecule, representing less than 33% of the regions evaluated, both in the epithelium and in the stroma. In senile animals that consumed a high-fat diet, both doses of the ECJ composition led to a reduction in VEGF immunostaining, representing less than 33% of the evaluated fields. (Table 5).

[103] Considering Western Blotting analyzes, it was possible to observe an increase in VEGF with aging when compared to young animals (FIG. 10). The consumption of the high fat diet by senile animals was able to increase the level of this molecule when compared to the SE group. In senile animals, the consumption of both doses of the ECJ composition promoted a reduction in the level of VEGF, in relation to SE. Likewise, the two doses of the ECJ composition reduced the level of this molecule in senile animals that consumed the high-fat diet, compared to SHP. In addition, in the latter case, consumption of Dose II of the ECJ composition showed a significant reduction when compared to the SHJI group

53/55 (FIGS. 8 and 9; Table 5).

CD31 [104] The total number of microvessels immunoreactive to CD31 was significantly elevated in the SE group compared to young animals. According to this result, a higher microvessel density in a given area was observed in senile animals when compared to animals in the JV group. The senile animals that consumed the high fat diet showed similar results to the SE group in these parameters. The consumption of both doses of the ECJ composition by senile animals was effective in reducing total microvessels immunoreactive to CD31, presenting a lower microvessel density in a given area, when compared to its SE control. Likewise, the two doses of the ECJ composition reduced total microvessels immunoreactive to CD31 and the microvessel density, in a given area, in senile animals that consumed the hyperlipidic diet concomitantly, when compared to their SHP control. In addition, the microvessel density in a given area was reduced in the SHJII group compared to the SHJI group (FIG. 8; Table 5).

[105] In this way, the present invention allowed the obtaining of a natural extract, of food origin, from the peel of Jabuticaba, non-toxic, through a green extraction procedure, using GRAS solvent (Generally Recognized As Safe) that allowed to obtain an extract highly rich in phenolic compounds and with potent antioxidant activity, anti-inflammatory power and acting against obesity induced by a high-fat diet in an animal model.

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These characteristics gave the extract a proven anti-cholesterolemic, anti-inflammatory, antiproliferative, anti-angiogenic action, as well as the ability to modulate glucose metabolism, lipid accumulation and hormonal profile. Thus, the properties of said extract allow possible modulation of aspects involving metabolic syndrome, considered a current public health problem, which covers about 34% of the Brazilian adult population. In addition, its consumption promotes prevention of prostatic changes present in approximately 50% of men over 50 years of age and who are directly related to the development of a malignant prostate tumor. Thus, the composition proposed in the present invention is able to act positively in these pathologies, being able to reduce the incidence of these alterations with great population scope. In addition, the product is natural, non-toxic, with no side effects noted. Usual treatments usually have side effects. Although the invention has been widely described, it is obvious to those skilled in the art that various changes and modifications can be made, in order to improve the design without the aforementioned changes not being covered by the scope of the invention.

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Claims (6)

1. Composition characterized by comprising a standardized extract of jabuticaba bark with a concentration of cyanidin 3-0-glucoside ranging between 900 ug / mL and 1100 ug / mL and a concentration of delfinidine 3-O-glucoside varying between 100 ug / mL and 112 ug / ml, and pharmaceutically acceptable vehicles. 2. Composition according to claim 1, characterized by the fact that pharmaceutically acceptable vehicles are selected from chelating agents, pH adjusting agents, preserving agents, humectants, thickeners, bacteriostatic agents, active ingredients, dyes and flavorings. 3. Composition, according to claim 1, characterized by the fact that it is administered orally in doses from 0.27 ml / kg to 6.8 ml / kg. 4. Use of the composition, as defined in claims 1 to 3, characterized by the fact that it is to treat metabolic processes, such as loss or reduction of weight gain, and to modulate glucose metabolism and reduce the accumulation of fat in the liver. 5. Use of the composition, as defined in claims 1 to 3, characterized by the fact that it is used to treat prostatic lesions, such as prostate cancer, and for hormonal modulation in the prostate microenvironment. 6. Use of the standardized extract of jabuticaba bark characterized by the fact that it is for the preparation of a drug to treat metabolic processes, such as weight loss or reduced gain, to modulate glucose metabolism and reduce fat accumulation in the body. liver for 2/2 treating prostatic lesions, such as prostate cancer, hormonal modulation in the prostatic microenvironment. is for 1/11