Aqueous extract of the bark of Uncaria tomentosa, an amazonian medicinal plant, promotes gastroprotection and accelerates gastric healing in rats.

ETHNOPHARMACOLOGICAL IMPORTANCE: Uncaria tomentosa Willd. DC., is used in the Amazonian region of South America, wherein ethnic groups use the plant to treat diseases, including gastric disorders. However, despite its widespread popular use, this species has yet to be assessed for its anti-ulcer effects. AIM OF THE STUDY: In this study, we aimed to evaluate the in vivo gastroprotective and gastric healing activities of an aqueous extract of the bark of Uncaria tomentosa (AEUt) and sought to gain an understanding of the pharmacological mechanisms underlying these biological effects. MATERIALS AND METHODS: To verify the gastroprotective properties rats were treated with AEUt (30, 60, or 120 mg/kg) prior to inducing gastric ulceration with ethanol or piroxicam. Additionally, the involvement of nitric oxide, non-protein sulfhydryl compounds (NP-SH), α-2 adrenergic receptors, and prostaglandins was investigated. Furthermore, a pylorus ligature model was employed to investigate the antisecretory activity of AEUt. The gastric healing effects of AEUt (60 mg/kg) were examined in rats in which ulceration had been induced with 80% acetic acid, whereas the quality of healing was evaluated in mice with interleukin-induced recurrent ulcers. We also evaluated the in vivo thickness of the gastric wall using ultrasonography. Moreover, the levels of reduced glutathione (GSH) and malondialdehyde (MDA) were evaluated in ulcerated mucosa, and we determined the activities of the enzymes myeloperoxidase (MPO), N-acetyl-ß-D-glycosaminidase, superoxide dismutase, catalase, and glutathione S-transferase. In addition, we assessed the effects of AEUt on cell viability and subjected the AEUt to phytochemical analyses. RESULTS: Administration of the AEUt (60 or 120 mg/kg) prevented ethanol- and piroxicam-induced ulceration, which was also confirmed histologically. Moreover, we observed that pre-treatment with NEM and indomethacin abolished the gastroprotective effects of AEUt, thereby indicating the involvement of NP-SH and prostaglandins in these protective effects. In addition, we found that the administration of AEUt had no appreciable effects on the volume, acidity, or peptic activity of gastric juice. Furthermore, the AEUt (60 mg/kg) accelerated the gastric healing of acetic acid-induced ulcers by 46.2% and ultrasonographic findings revealed a reduction in the gastric wall thickness in this group. The gastric healing effect of AEUt was also accompanied by a reduction in MPO activity. The AEUt (60 mg/kg) also minimized ulcer recurrence in mice exposed to IL-1ß and was associated with the maintenance of GSH levels and a reduction in MDA contents. We deduce that the biological effects of AEUt could be associated with the activities of polyphenols and the alkaloids isomitraphylline and mitraphylline, identified as predominant constituents of the AEUt. Furthermore, we found no evidence to indicate that AEUt would have any cytotoxic effects. CONCLUSION: Collectively, our findings provide compelling evidence indicating the therapeutic efficacy of U. tomentosa. Our data indicate that compounds in AEUt confer gastroprotection and that this preventive effect of AEUt was accompanied by gastric healing and a reduction in gastric ulcer recurrence. Moreover, we provide evidence to indicate that the gastroprotective and gastric healing effects involve the antioxidant system and anti-inflammatory responses that contribute to preserving the gastric mucosa.

Neuropharmacology Potential of the Hydroalcoholic Extract from the Leaves of Piper cernuum: Anxiolytic, Hypnotic, and Antidepressant-Like Effects.

Aim: The use of medicinal plants in the treatment of mental illnesses is a reality that accompanies the history of civilizations, and the Piper genus exhibits many species with pharmacologically proven central effects. Then, this study evaluated the neuropharmacological effects of the hydroalcoholic extract from Piper cernuum (HEPC) leaves to validate its uses in folk medicine. Materials and Methods: Primarily Swiss mice (female, 25-30 g) were pretreated with HEPC (50-150 mg/kg, p.o.), vehicle, or the positive control, and submitted to open-field test (OFT), inhibitory avoidance test (IAT), tail suspension test (TST), and forced swim test (FST). Also, mice were exposed to pentylenetetrazol- and strychnine-induced seizure assay, pentobarbital-induced hypnosis test, and elevated plus-maze (EPM). The GABA levels and MAO-A activity were measured in the animal's brain after 15 days of HEPC administration (150 mg/kg, p.o.). Results: Mice pretreated with HEPC (100 and 150 mg/kg) and exposed to pentobarbital presented decreased sleep latency and increased sleep duration (HEPC 150 mg/kg). In EPM, the HEPC (150 mg/kg) increased the frequency of entry and the time of exploration of mice in the open arms. The antidepressant-like properties of HEPC were demonstrated by the decrease in the mice's immobility time when tested in FST and TST. The extract did not show anticonvulsant activity, in addition to not improving the memory parameters of animals (IAT) or interfering with their locomotor activity (OFT). Besides, HEPC administration decreased the MAO-A activity and increased the GABA levels in the animal's brain. Conclusion: HEPC induces sedative-hypnotic, anxiolytic-, and antidepressant-like effects. These neuropharmacological effects of HEPC could be, at least in part, related to the modulation of the GABAergic system and/or MAO-A activity.

Gastroprotective effect of Artemisia absinthium L.: A medicinal plant used in the treatment of digestive disorders.

ETHNOPHARMACOLOGICAL RELEVANCE: Wormwood (Artemisia absinthium L.) is traditionally used for stomach pain and gastric relief. However, its possible gastroprotective effect has not yet been experimentally evaluated. AIM OF THE STUDY: This study evaluated the gastroprotective effect of aqueous extracts obtained through hot and room temperature maceration of A. absinthium aerial parts in rats. MATERIALS AND METHODS: The gastroprotective effect of hot aqueous extract (HAE) and room temperature aqueous extract (RTAE) from A. absinthium aerial parts were evaluated in rats using a model of acute gastric ulcer induced by ethanol p.a. The stomachs were collected to measure the gastric lesion area and histological and biochemical analysis. UHPLC-HRMS/MS analysis was used to determine the chemical profile of the extracts. RESULTS: Eight main peaks in the UHPLC chromatogram were identified in both HAE and RTAE extracts: tuberonic acid glycoside (1), rupicolin (2), 2-hydroxyeupatolide (3), yangabin (4), sesartemin (5), artemetin (6), isoalantodiene (7), and dehydroartemorin (8). For RTAE, a higher diversity of sesquiterpene lactones was observed. The groups treated with RTAE at 3%, 10%, and 30% presented a gastroprotective effect, reducing the lesion area by 64.68%, 53.71%, and 90.04%, respectively, when compared with the vehicle (VEH)-treated group. On the other hand, the groups treated with HAE at 3%, 10%, and 30% presented values of lesion areas higher than those of the VEH group. Changes in the submucosa layer, inflammatory process with edema, cellular infiltration, and mucin depletion were detected in the gastric mucosa exposed to ethanol, which was fully prevented by RTAE treatment. Neither HAE nor RTAE could increase the reduced glutathione levels in the injured gastric tissue, but RTAE (30%) reduced the formation of lipid hydroperoxides. When the rats were pre-treated with NEM (a chelator of non-protein thiols) or L-NAME (non-selective nitric oxide synthase inhibitor), the RTAE lost the ability to protect the gastric mucosa. CONCLUSIONS: This study corroborates the ethnopharmacological use of this specie to treat gastric disorders revealing the gastroprotective effect of the room-temperature aqueous extract of A. absinthium aerial parts. Its mode of action may involve the ability of the infusion to maintain the gastric mucosal barrier integrity.

Traditional Plants Used in Southern Brazil as a Source to Wound Healing Therapies.

In southern Brazil, the biodiversity is great and the traditional use of medicinal plants for wound healing has been documented in ethnobotanical studies and pharmacological studies have assessed their wound properties and phytochemistry. Therefore, this study evaluated ethnobotanical surveys regarding medicinal plants used in southern Brazil for wound healing and studies about the healing properties of these plants published between 2000 and 2022. To retrieve articles related to the study, Web of Science, PubMed (NLM), Open Access Journals, Scielo, Lilacs, and Google Scholar, with keywords including medicinal plants, wound healing, and South of Brazil, have been used. As a result, 73 medicinal plants belonging to 39 families were found in ethnobotanical surveys as a traditional resource used for wound healing in southern Brazil, 15 of which were cited more than once. Besides, 14 of these 15 plants were also used as healing agents worldwide. The most cited plant with healing actions in southern Brazil was Symphytum officinale L. (comfrey). From 2000 to date, 44 articles scientifically demonstrated the wound-healing effects of the southern Brazilian plants found in ethnobotanical surveys reviewed. The folk medicine of southern Brazil presents a variety of medicinal plants for wound-healing purposes, and scientific data were found for some of those plants. However, the wound-healing properties of many plants have yet to be investigated, and the current literature still needs more phytochemical information about the plants studied. Aside from this, the future focus should be on the standardization of herbal extracts, and further research is required to investigate the pharmacological mechanisms. Clinical research in this area remains in its infancy and warrants more robust further clinical studies.

Brazilian Red Propolis Accelerates Gastric Healing and Reduces Gastric Submucosal Layer Inflammation in Ultrasound-Monitored Rats.

Propolis has been used for the treatment of gastric disturbances in folk medicine, nevertheless, the gastric healing effects of Brazilian red propolis have not been unveiled. This study aimed to assess the gastric healing effect of the hydroalcoholic extract of red propolis (HERP) in the acetic acid-induced ulcer model. Rats under acetic acid-induced-ulcer were treated with HERP (100 mg/kg, p.o.) twice a day for seven days. Histological changes, oxidative stress, and inflammatory parameters were analyzed in the gastric tissue. Moreover, the gastric wall thickness was measured by ultrasound. The in vitro cytotoxicity of HERP and cellular migration of fibroblasts were evaluated. The treatment with HERP promoted gastric healing, reducing gastric wall thickness, macroscopic lesion area, and histopathological damages compared to the vehicle. Moreover, HERP reduced oxidative stress and inflammation in the gastric tissue but did not change mucin or collagen levels. HERP did not show signs of toxicity either in vivo or in vitro. HERP displayed a healing effect in vivo by reducing oxidative stress and inflammation. These data contribute to validating the popular use of this product in the treatment of gastric disorders and advance scientific knowledge in the search for new drugs for the management of gastric ulcers.

Gastroprotective and gastric healing effects of the aqueous extract of Casearia sylvestris in rodents: Ultrasound, histological and biochemical analyzes.

ETHNOPHARMACOLOGICAL IMPORTANCE: Casearia sylvestris Sw. (Salicaceae) is a native plant from the Americas, where it is also known as "guaçatonga" or "erva-de-bugre." Although its leaves have been commonly used to treat inflammation and gastrointestinal disorders in South America, the antiulcer effects of an aqueous extract from this medicinal plant, similar to popular use, have not to be investigated yet. AIM OF THE STUDY: This study evaluated the hypothesis that the aqueous extract a of C. sylvestris (AEC) prevents the gastric ulcers and accelerates the healing of ulcers already installed, by assessing ultrasound imaging, histological and biochemical analyses. MATERIALS AND METHODS: Rats (females) were treated with AEC (3, 30 or 300 mg/kg) prior to the ethanol or piroxicam-induced gastric ulcers. The healing effect of AEC (300 mg/kg) was examined in 80% acetic acid-induced ulcer in rats, whereas the quality of healing was evaluated in recurrent 10% acetic acid-induced ulcer in mice with recurrence induced by interleukin 1ß. To assess the responses of the lesions, in addition to the classical methods used to analyze gastroprotection (ex vivo), we also measured the gastric wall thickness (in vivo) using ultrasonography. After euthanasia, the extent of ulcer was determined and the levels of reduced glutathione (GSH), lipid hydroperoxides (LOOH), nitrate, and the activities of myeloperoxidase (MPO), N-acetyl-ß-D-glycosaminidase (NAG), superoxide dismutase (SOD), and glutathione S-transferase (GST) were measured. The antisecretory activity of AEC was also examined based on pylorus ligated rats. Furthermore, gastric tissue samples were analyzed histologically, and phytochemical analyses of the C. sylvestris extract were parallelly performed. RESULTS: The AEC (30 or 300 mg/kg) prevented ulcers in the ethanol- and piroxicam-induced acute. Moreover, the AEC at a dose of 300 mg/kg also accelerated the gastric healing of acetic acid-induced ulcer in rats by 48% and the ultrasonography records shown a decrease in the wall thickness and the extent of edema of ulcerous lesions promoted by the extract. The gastric healing effect of AEC was also accompanied by reduced MPO and NAG activities at acetic acid-induced ulcer in rats; as well as was by the reduction in the nitrate and LOOH levels, the increase in mucin and SOD activity, and by a partial recovery of GSH levels. The AEC (300 mg/kg) minimized the ulcer recurrence in mice exposed to IL-1ß, but the extract administration did not change pH or peptic activity of gastric juice in pylorus ligated rats. CONCLUSION: The results of this study provide convincing evidence for the therapeutic efficacy of C. sylvestris with respect to gastroprotection and indicate that ultrasound examination would be a potentially promising approach for evaluating gastroprotective effects in vivo. Collectively, our findings indicate that the gastric the gastroprotective and healing effects of aqueous extract C. sylvestris involve a reduction in acid secretion, promotion of the antioxidant system, reductions in the migration of neutrophils and mast cells, with a consequent lower inflammatory response, and the preservation of mucin.

The PPARγ-dependent effect of flavonoid luteolin against damage induced by the chemotherapeutic irinotecan in human intestinal cells.

Irinotecan (CPT-11) is one of the main agents used to treat colorectal cancer; unfortunately, it is associated with increased intestinal mucositis developing. Luteolin has been shown to prevent damage induced by this chemotherapeutic in mice; thus, in this research, we have investigated luteolin's action mechanism in human intestinal epithelial cells. The potential of luteolin in reducing inflammation and oxidative stress induced by irinotecan in Caco-2 cells was evaluated by PCR through mRNA expression of inflammatory and oxidative genes and by ELISA at the protein level. To assess whether luteolin's ability to control irinotecan-induced damage occurs in a PPARγ dependent manner, experiments were performed on PPARγ downregulated cells. Irinotecan downregulated PPARγ expression and upregulated inflammatory and oxidative genes, while luteolin upregulated PPARγ, HO-1, SOD and decreased expression of IL-1ß and iNOS. Interestingly, when the cells were co-stimulated with luteolin and irinotecan, the flavonoid reversed the inflammation and oxidative imbalance evoked by the chemotherapeutic. However, when these experiments were performed in cells downregulated for PPARγ, luteolin lost the capacity to increase PPARγ and reverse the effect of irinotecan in all tested genes, except by IL-1ß. The present study showed that the protective effect of luteolin against irinotecan is PPARγ dependent.

Myrsinoic acid B from Myrsine coriacea reverses depressive-like behavior and brain oxidative stress in streptozotocin-diabetic rats.

AIMS: Major depressive disorder (MDD) affects approximately 322 million people worldwide and is a common comorbidity in patients with diabetes mellitus (DM). A possible pathophysiological mechanism correlating both diseases is the increased oxidative stress in brain regions due to hyperglycemia. Myrsine coriacea (Primulaceae) is popularly known as "capororoca" and studies have been shown that this plant exhibits several pharmacological properties attributed to myrsinoic acid A (MAA) and B (MAB). Indeed, previous results have been shown its effects on the central nervous system, leading us to explore possible psychotropic effects. MAIN METHODS: The effects of treatment with hydroalcoholic extract of the barks from Myrsine coriacea (HEBMC, 150 mg/kg, o.g.), MAA (5 mg/kg, o.g.), and MAB (3 mg/kg, o.g.) were evaluated in streptozotocin (75 mg/kg, i.p.)-induced diabetic female rats. After 28 days of treatments, rats were submitted to the forced swim test (FST) and open field test (OFT). Also, superoxide dismutase (SOD) and catalase (CAT) activities, reduced glutathione (GSH) and lipid hydroperoxides (LOOH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC) of these rats. KEY FINDINGS: The treatment with MAA or MAB increased the latency of first immobility in diabetic rats, and the HEBMC administration decreased the immobility time, and increase the climbing in FST. However, only MAB treatment reduces the immobility time, increases the climbing, and swimming in FST, and increases the crossing of diabetic animals in the OFT. Besides, this behavioral improvement promoted by MAB administration was accompanied by reducing in oxidative stress in the HIP and PFC, but not reducing hyperglycemia in diabetic rats. SIGNIFICANCE: The results suggest that MAB's antioxidant effect in the HIP of diabetic animals may be essential to its antidepressant-like effect.

Tagetes erecta L. flowers, a medicinal plant traditionally used to promote diuresis, induced diuretic and natriuretic effects in normotensive and hypertensive rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tagetes erecta L., known as marigold, belongs to the Asteraceae family and is mainly found in South America. Despite reports that T. erecta flowers are used in folk medicine to treat cardiovascular and renal diseases, there is no study regarding its diuretic effect. AIM: This study aimed to evaluate the chemical composition and the diuretic efficacy of the hydroethanolic extract from T. erecta (HETE) in normotensive (NTR) and hypertensive (SHR) rats. MATERIAL AND METHODS: The HETE was analyzed by liquid chromatography coupled to diode array detector and mass spectrometry (LC-DAD-MS). Female and male NTR and SHR received the treatment with vehicle, HETE (0.01 mg/kg, 0.1 mg/kg, and 1 mg/kg) or hydrochlorothiazide (HCTZ; 5 mg/kg) orally. The urinary parameters were measured at the end of the 8-h experiment. RESULTS: From HETE, saccharides and triterpenes were the main annotated compounds, such as erythrodiol and ß-amyrin. The urine volume was significantly increased in the groups treated with HETE, in both male and female NTR and SHR rats, compared to the respective vehicle-treated groups. Regarding electrolytes elimination, the treatment with HETE did not reveal significant changes in the urine levels of K+ or Cl-, but it showed a natriuretic and Ca2+-sparing effects. The HETE beneficial result in reducing Ca2+ excretion was confirmed through the protective effect found in front of the urinary calcium oxalate precipitation and crystallization. The combination with HCTZ, a classic diuretic and saluretic medicine, significantly enhanced HETE-induced diuresis, natriuresis, and the Ca2+-sparing effect. On the other hand, the K+-sparing action was improved in the combination of HETE with amiloride, a standard K+-sparing diuretic. In contrast, the combination of HETE with atropine (a non-selective muscarinic receptor antagonist) and indomethacin (an inhibitor of the cyclooxygenase enzyme), promoted an important reduction in urinary volume, but interestingly the natriuretic effect was maintained. CONCLUSION: This study contributed to the preclinical validation of the diuretic efficacy of T. erecta, highlighting this species as promising for the development of new pharmacological strategies for the management of kidney disorders.

Prolonged Diuretic and Renoprotective Effects of a Xanthone Obtained from Garcinia achachairu Rusby in Normotensive and Hypertensive Rats.

The previous study showed that 1,5,8-trihydroxy-4',5'-dimethyl-2H-pyrano(2,3 : 3,2)-4-(3-methylbut-2-enyl) xanthone (TDP) obtained from Garcinia achachairu Rusby (Clusiaceae) branches induces acute diuresis in normotensive (NTR) and spontaneously hypertensive rats (SHR) after 8 h of the experiment. In complementarity, the present study evaluated the prolonged diuretic and renoprotective effects of TDP in both NTR and SHR. The animals received, once a day, oral treatment with TDP (0.1 mg/kg), hydrochlorothiazide (10 mg/kg), or vehicle (VEH; 10 mL/kg). At the end of 7 days, the urine, blood, and kidney samples were collected for biochemical and histological analyzes. The urinary volume of both NTR and SHR after 7 days of treatment with the TDP was significantly increased, associated with augmented urinary electrolyte excretion levels. The treatments did not modify the urinary pH values nor the parameters analyzed in plasma (Na+, K+, Cl-, and Ca2+). Concerning the renal analyzes, when compared with the VEH-treated NTR group, while the activity of the enzymes catalase (CAT) and N-acetyl-ß-D-glucosaminidase (NAG), as well as nitrite levels, were increased, the generation of lipid hydroperoxides and the activity of the enzyme myeloperoxidase (MPO) were unaltered. On the other hand, the activities of superoxide dismutase (SOD) and glutathione S-transferase (GST) and the levels of reduced glutathione (GSH) in kidney homogenates of the SHR group were decreased. However, TDP augmented the levels of GSH and GST activities and reduced the levels of nitrite and the activities of CAT and MPO, when compared with VEH-treated only SHR. Besides, the treatment with TDP alleviated the morphological changes of the renal corpuscle region of SHR. Together, these results revealed the prolonged diuretic effect of TDP and their renal protective effect by improving the antioxidative capacity.

1,3,5,6-tetrahydroxyxanthone promotes diuresis, renal protection and antiurolithic properties in normotensive and hypertensive rats.

OBJECTIVES: This study investigated the prolonged diuretic and renal effects of 1,3,5,6- tetrahydroxyxanthone (THX) in rats. METHODS: Normotensive (NTR) and hypertensive rats (SHR) received orally the treatment with THX, hydrochlorothiazide or vehicle (VEH). Urine volume, urinary, plasma and kidney parameters were evaluated daily or at the end of 7 days of the experiment. KEY FINDINGS: The urinary volume of both NTR and SHR were significantly augmented with the THX treatment, an effect associated with increased levels of urinary Na+ and K+, besides a Ca2+-sparing effect. As well, THX decreased the quantity of monohydrate crystals in urines from NTR and SHR when compared with VEH-group. Regarding the renal analyses, the glutathione levels and the activities of superoxide dismutase, glutathione S-transferase and myeloperoxidase in kidney homogenates of the SHR group were decreased. In contrast, the generation of lipid hydroperoxides (LOOH) and catalase activity was significantly increased. THX reduced the content of LOOH and increased nitrite levels in kidney homogenates obtained from SHR. Additionally, THX also augmented the levels of nitrite in the plasma from the SHR group. CONCLUSIONS: Therefore, THX can be highlighted as a natural diuretic agent with renal protective properties and antiurolithic action.

Phytochemistry and Pharmacology of the Genus Equisetum (Equisetaceae): A Narrative Review of the Species with Therapeutic Potential for Kidney Diseases.

The Equisetum genus, Equisetaceae family, is widely distributed worldwide and may be the oldest nonextinct genus on Earth. There are about 30 known species, which are very often used in traditional medicine with diverse applications. This review aimed to compile scientific reports about Equisetum species with relevant pharmacological properties and/or therapeutic potential for kidney diseases. Our bibliographic survey demonstrates that the most widespread traditional use of Equisetum is as a diuretic, followed by the treatment of genitourinary diseases (kidney diseases, urethritis, kidney stones, and others), inflammation, wound healing, rheumatic diseases, prostatitis, and hypertension. The most popular species from the Equisetum genus with medicinal use is E. arvense L., whose diuretic effect was confirmed in animal models and clinical trials. The species E. bogotense Kunth also demonstrated the beneficial effect of inducing diuresis in both experimental and clinical assays. Several other species have also been studied regarding their therapeutic potential, showing different biological actions. Regarding the chemical composition, it contains many active constituents, such as alkaloids, flavonoids, phenol, phytosterols, saponins, sterols, silicic acid, tannin, triterpenoids, and volatile oils. However, despite the widespread traditional use, many species need to be explored in detail for scientific validation of popular use. Indeed, the species of the Equisetum genus have great potential in the management of kidney disorders.

The acute diuretic effects with low-doses of natural prenylated xanthones in rats.

The diuretic effect of 3-demethyl-2-geranyl-4-prenylbellidypholine xanthone (DGP) and 1,5,8-trihydroxy-4',5'-dimethyl-2H-pyrano(2,3:3,2)-4-(3-methylbut-2-enyl) xanthone (TDP), two natural prenylated xanthones, was investigated in female normotensive (NTR) and spontaneously hypertensive rats (SHR). The rats received a single treatment with DGP, TDP, hydrochlorothiazide (HCTZ), or vehicle (VEH) after an oral load of physiological saline. The effects of DGP and TDP in combination with diuretics of clinical use, as well as with L-NAME, atropine and indomethacin were also explored. The urinary parameters were measured at the end of the 8-h experiment. When orally given to rats, DGP was able to increase the urine volume, at doses of 0.03-0.3 mg/kg, associated with a K+-sparing effect. TDP, in turn, at doses of 0.03-0.3 mg/kg, induced diuresis and saluresis (i.e. augmented urinary levels of Na+ and Cl-) in NTR, while decreased the urinary content of Ca2+ in both NTR and SHR. The combination with HCTZ, but not with furosemide or amiloride, significantly enhanced DGP and TDP induced diuresis, which was accompanied by an increase of the electrolytes content in the urine. Instead, amiloride in combination with DGP or TDP enhanced urinary Na+ and Cl- and decreased K+ elimination. Furthermore, the effect of DGP and TDP were heightened after pretreatment with L-NAME. While atropine was able to prevent DGP-induced diuresis, the pretreatment with indomethacin precluded TDP-induced diuresis. Besides, TDP exerted protective effects against urinary calcium oxalate crystals formation. Taken together, our data revealed the diuretic effect of two xanthones in rats and their possible underlying mode of action.

Antidepressant-like effects of solidagenone on mice with bacterial lipopolysaccharide (LPS)-induced depression.

BACKGROUND: Considering the pharmacological potential of solidagenone from Solidago chilensis, the present investigation was carried out to evaluate its antidepressant-like effect in mice with bacterial lipopolysaccharide (LPS)-induced depressive like behavior and its mode of action through the measurement of neuroinflammatory and oxidative markers. MATERIALS AND METHODS: In the prophylactic test, the mice were pretreated with solidagenone (1, 10 or 100 mg/kg, p.o) and after one hour received LPS. In therapeutic test, the mice received LPS and after 5 h were treated with solidagenone (1, 10 or 100 mg/kg, p.o). In both experimental approaches, the animals were submitted to OFT and to the TST after 6 and 24 h of the LPS administration, respectively. One hour after the TST the animals were euthanized, the blood was collected, the cortex was removed and biochemical analyzes were performed for measurement of the inflammatory and oxidative stress markers. RESULTS: The LPS induced sickness- and depressive-like behaviors and increased the cortical activity of myeloperoxidase (MPO), as well as the IL-6 and TNF amount. Interestingly, the pretreatment with solidagenone at 100 mg/kg avoided the behavioral alterations in OFT. In the mice post treated with solidagenone, all tested doses of resulted in an antidepressant-like effect evidenced by the decrease in immobility time in the TST. This effect was accompanied by a decrease in the MPO activity and in the IL-6 and TNF levels in the cortex in parallel to the increase in catalase activity. CONCLUSIONS: The solidagenone has a promissor antidepressant-like potential, which can result of its beneficial action in the neuroinflammation process and due its antioxidant capability at the central nervous system.

Gastroprotective activity of hydroalcoholic extract of the leaves of Urera baccifera in rodents.

ETHNOPHARMACOLOGICAL IMPORTANCE: The species Urera baccifera (L.) Gaudich. ex Wedd. (Urticaceae) is native to the Americas and is distributed widely throughout Brazil, where it is known as urtiga-brava, urtiga-vermelha, or urtigão. The leaves are often used as anti-inflammatory and antirheumatic agents and for the treatment of gastric disorders. However, the pharmacological mode of action underlying the gastroprotection induced by this species has not been investigated. AIM OF THE STUDY: To contribute to the knowledge of the gastroprotective mode of action of the hydroalcoholic extract of U. baccifera (HEU) leaves. MATERIALS AND METHODS: Antiulcerogenic effect of HEU against ethanol-induced acute gastric ulcer was evaluated in rats and mice at doses of 3-300 mg/kg. NO-synthase inhibitor (L-NAME), SH blocker (NEM), cyclooxygenase inhibitor (indomethacin) and alpha 2-adrenergic receptor antagonist yohimbine were used to evaluate the participation of cytoprotective factors in HEU gastroprotection. Moreover, the levels of reduced gluthatione (GSH) and cytokines (TNF, IL-6, IL4 and IL-10), as well as the enzymatic activity of gluthatione S-transferase (GST), myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT) were measure. Moreover, the samples were analyzed histologically and the antisecretory capability of HEU were quantified using pylorus ligated rats. RESULTS: The phytochemical analysis of HEU (UPLC/ESI-IT-MS) identified the flavonoids diosmetin and apigenin glucuronide. Furthermore, HEU decreased the occurrence of ethanol-induced ulcers at 30 and 300 mg/kg by 57% and 66%, respectively, compared with the vehicle. The gastroprotective effects were accompanied by increased GSH levels and GST and SOD activity as well as by reduced MPO activity in vivo and in vitro, revealing antioxidant effects and inhibition of neutrophil infiltration. The beneficial effects of 30 and 300 mg/kg HEU were also observed upon histological analyses. Regarding the mode of action, the gastroprotective effect of HEU was abolished by the pre-administration of L-NAME, NEM, indomethacin or yohimbine. Moreover, HEU was able to decrease the IL-6, IL-4 and IL-10 in ulcerated tissue, as well as the pepsin activity of the gastric juice in pylorus-ligated rats. CONCLUSION: Together, the results confirmed that the gastroprotection elicited by HEU was due reduction in oxidative damage, neutrophil migration, and peptic activity. This work validates the popular use of U. baccifera to treat gastric disorders and supports important future research for the identification of gastroprotective molecules from this species.

1,3,5,6-Tetrahydroxyxanthone, a natural xanthone, induces diuresis and saluresis in normotensive and hypertensive rats.

The aim of the present study was to evaluate the diuretic effect of 1,3,5,6-tetrahydroxyxanthone (THX), isolated from preparations of Garcinia achachairu Rusby (Clusiaceae) branches, in rats. Wistar normotensive (NTR) and spontaneously hypertensive rats (SHR) received a single oral treatment with THX, hydrochlorothiazide (HCTZ) or just vehicle (VEH). The effects of THX in combination with diuretics of clinical use, as well as with l-NAME, atropine, and indomethacin were also explored. Cumulative urine volume and urinary parameters were measured at the end of the 8-h or 24-h experiment. THX was able to stimulate 8-h and 24-h diuresis in both NTR and SHR, as well as urinary Na+ and K+ excretion, at a dose of 0.1 mg/kg; while 8-h urinary Cl- levels were only significantly increased in the group of animals treated with THX at the dose of 0.3 mg/kg. In addition, Ca2+ content was reduced in the 24-h urine of THX-treated NTR and SHR, like that obtained in the HCTZ (10 mg/kg) group. The combination with HCTZ or furosemide, but not with amiloride, significantly enhanced THX-induced diuresis. The diuretic effect with HCTZ plus THX treatment was accompanied by an increase of the urinary Na+, K+, and Cl- excretion. On the other hand, when given THX in combination with amiloride, there was a significant increase in Na+ and a decrease in K+ excretion, an effect characteristic of this class of diuretics. Moreover, the diuretic effect of THX was heightened after pretreatment with l-NAME, and its ability to induce diuresis was prevented neither in the presence of indomethacin nor in the presence of atropine. However, the pretreatment with atropine completely avoided the saluretic effect stimulated by THX, suggesting, at least in part, the role of muscarinic receptors in the renal effects of THX disclosed in this study.

Flavonoid-rich fraction of Bauhinia forficata Link leaves prevents the intestinal toxic effects of irinotecan chemotherapy in IEC-6 cells and in mice.

This study evaluated the effects of flavonoid-rich fraction from Bauhinia forficata leaves (FRF-BF), against intestinal toxicity induced by irinotecan. The leaves of this plant are used like tea in Brazilian folk medicine, and it is rich in flavonoids, mainly kaempferitrin. First, the chemopreventive effects of FRF-BF and kaempferitrin were evaluated in intestinal cells (IEC-6 cells) exposed to irinotecan. Next, the effects were evaluated against irinotecan-induced mucositis in mice. Lastly, melanoma was induced in C57BL/6 mice to evaluate FRF-BF interference on irinotecan antitumor activity. The results showed that FRF-BF and kaempferitrin exert no cytotoxic effects in IEC-6 cells and confirmed that pretreatment with FRF-BF and kaempferitrin displays chemoprotective effects against cytotoxicity induced by irinotecan. Interestingly, the FRF-BF (100 mg/kg, p.o) reduced the intestinal motility in mice and attenuated parameters linked to irinotecan-induced intestinal mucositis, including diarrhea, histological damage, depletion of duodenal GSH, amount of TNF-α, and MPO activity in the small intestine. Also, FRF-BF does not interfere in the antitumor activity of irinotecan and exerted antitumoral activity in murine melanoma. In conclusion, FRF-BF (100 mg/kg, p.o) presents promising pharmacological potential to prevent and attenuate the severity of intestinal mucositis during chemotherapy treatment, related to the presence of kaempferitrin.

Gastroprotective and anti-secretory mechanisms of 2-phenylquinoline, an alkaloid isolated from Galipea longiflora.

BACKGROUND: We previously described the gastroprotective effect of 2-phenylquinoline (2-PQ), the main alkaloid isolated from the bark of Galipea longiflora (Rutaceae). However, despite the significant and promising results, the pharmacological mechanisms of the gastroprotection induced by 2-PQ have not been investigated. PURPOSE: To evaluate the mechanisms underlying the gastroprotective effects of 2-PQ. STUDY DESIGN: We used an in vivo mouse ulcer model and in vitro methodologies involving H⁺/K⁺-ATPase and L929 murine fibroblasts. METHODS: The gastroprotective activity of 2-PQ (10-100 mg/kg, orally, p.o) was assessed against gastric ulcer induced by 60% ethanol/0.03 M hydrochloric acid (HCl) in mice or that induced by indomethacin (80 mg/kg, p.o) in rats. The cytotoxicity was assessed in L929 murine fibroblasts. Ulcerated tissues were analyzed histologically, histochemically, and biochemically. The antisecretory activity of 2-PQ was evaluated in vivo and in vitro. RESULTS: 2-PQ showed no cytotoxicity, reduced the lesion area induced by ethanol/HCl (log half-maximal effective dose, ED50 = 1.507), and the histological evaluation supported these results. Furthermore, 2-PQ reduced indomethacin-induced gastric ulceration. The gastroprotection was accompanied by normalization of superoxide dismutase (SOD) and glutathione-S-transferase (GST) activity, an intense increase in reduced glutathione (GSH) levels, and reduction in lipid peroxide (LPO) and tumor necrosis factor (TNF)-α levels in the gastric mucosa. The antisecretory properties of 2-PQ were confirmed by the decreased volume and total acidity of the gastric juice, and it reduced histamine- or pentagastrin-stimulated gastric acid secretion. However, 2-PQ did not change the in vitro H⁺/K⁺-ATPase activity or the content of gastric-adhered mucous in mice. In addition, pretreatment with N-ethylmaleimide, NG-nitro-l-arginine methyl esters, yohimbine, or indomethacin reversed the gastroprotective effect of 2-PQ, suggesting nitric oxide, nonprotein sulfhydryl compounds, α-2-receptors, and prostaglandin were involved. CONCLUSION: 2-PQ provides gastroprotection by reducing oxidative damage and inhibiting acid secretion mediated by histaminergic and gastrinergic regulatory pathways.

Pharmacological reports about gastroprotective effects of methanolic extract from leaves of Solidago chilensis (Brazilian arnica) and its components quercitrin and afzelin in rodents.

Solidago chilensis Meyenmost (Asteraceae), popularly known as "Brazilian arnica" or "arnica-do-campo," is widely used in the folk medicine to treat gastric disorders. Based on this, the gastroprotective activity of S. chilensis methanolic extract was investigated. Besides, a phytochemical study allowed isolation of two flavonoids (quercitrin and afzelin). The gastroprotective effects were investigated in acute gastric ulcer models, and the antisecretory activity was assessed in vivo and in vitro. The adhered mucus levels, reduced glutathione (GSH) content and myeloperoxidase (MPO) activity were quantified in ulcerated tissues. The contribution of isolated compounds in extract effects was evaluated, and its doses were calculated according to its yield. To evaluate the in vivo healing properties of S. chilensis methanolic extract, a chronic gastric ulcer was induced in mice by 10 % acetic acid. Evaluation of tumor necrosis factor (TNF) levels was also performed at the site of the acetic acid-induced gastric ulcer. In parallel, effects on cell viability and cell proliferation of fibroblasts (L929 cells) were determined by in vitro trials. Firstly, the S. chilensis methanolic extract (100 or 300 mg/kg) reduced the ulcer area induced by ethanol/HCl in mice when compared to the vehicle group. Moreover, the S. chilensis extract (300 mg/kg) prevented the mucus depletion, the increase in MPO activity and the decrease in the GSH levels in the ulcerated gastric tissue. The S. chilensis extract also was able to decrease the indomethacin-induced gastric ulcer in rats at a dose of 100 mg/kg. The antisecretory effect of the extract (100 mg/kg, intraduodenal (i.d.)) was confirmed by the reduction in the volume and acidity in parallel to an increase in the pH of gastric content. In addition, quercitrin (1.38 mg/kg, but not 0.46 mg/kg) and afzelin (0.026 and 0.078 mg/kg) decreased the ethanol/HCl-induced gastric ulcer. In this model, quercitrin (1.38 mg/kg) prevented the depletion of gastric GSH content and both quercitrin (1.38 mg/kg) and afzelin (0.078 mg/kg) reduced the MPO activity. These compounds also inhibited the H(+),K(+)-ATPase activity at a concentration of 1-100 µg/ml. In addition, the participation of quercitrin and afzelin in these effects also was confirmed. Furthermore, after 4 days of the treatment, an oral administration of S. chilensis methanolic extract (100 mg/kg) reduced the area of the gastric ulcer induced by acetic acid and the regeneration of the gastric mucosa was accompanied by a reduction in gastric TNF levels. The healing properties of the extract also were confirmed by enhancement of proliferation and coverage of scratched wounds in a fibroblast monolayer. Together, our results confirmed the gastroprotective effect of S. chilensis methanolic extract as well as its gastric healing potential and provided some support to the traditional use of S. chilensis for prevention and treatment of gastric lesions in complementation to its known anti-inflammatory properties.

Gastroprotective bio-guiding study of fruits from Mimusops balata.

Mimusops spp. is used as plant-based antiulcer drugs in Indian traditional medicine. In this study, a bio-guiding study of methanolic extracts of Mimusops balata edible fruits was performed to identify an antiulcer gastric compound. The gastric lesions induced by HCl/ethanol in mice were significantly improved by methanolic extract from seed (MESe, 300 mg/kg), but not by methanolic extract from peel (MEPe, 300 mg/kg) or pulp (MEPu, 300 mg/kg), when compared to the vehicle group. Treatment with MESe also decreased gastric ulceration induced by indomethacin. The antiulcerogenic activity of MESe appears to involve the maintainance of GSH levels, reduction of LPO content, inhibition of neutrophil migration (as evidenced by a decrease in the MPO activity) and a potent free radical scavenger activity (IC50 = 3.4 µg/ml). Moreover, MESe decrease the gastric volume, pH, total acidity, and pepsin activity in the gastric juice. Exceptionally, MESe showed a high content of phenolic compound, identified by layer chromatography and Folin-Ciocalteu reagent. Considering the better pharmacological and phytochemical profile, MESe was successively partitioned and resulted in isolation and identification of a constituent, the flavonoid taxifolin, identified by spectroscopic methods ((1)H, (13)C NMR, and HPLC). Taxifolin also inhibited the ulcerogenic effect of HCl/ethanol at a low dose of 1.14 mg/kg and inhibited in vitro H+/K(+)-ATPase activity by 41% at a concentration of 100 µg/ml. Taken together, these results evidenced the gastroprotective potential of fruits from M. balata and showed that this effect is exclusive to the seeds.