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Dermatitis is defined as a set of inflammatory diseases that affect the skin, with varied causes. Among the different types of dermatitis, contact dermatitis is the most prevalent. Although the current therapy is often effective, it is associated with adverse effects and the possibility of drug tolerance. N-Methyl-(2S, 4R)-trans-4-hydroxy-L-proline is a L-proline amino acid derivative found in the leaves of Sideroxylon obtusifolium, a species traditionally used to treat inflammatory diseases. The aim of this study was to investigate the topical anti-inflammatory effect of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritant contact dermatitis in mice. Topically administered NMP, at doses of 0.03 - 0.50 mg/ear, reduced TPA-induced ear edema and neutrophil migration, as evidenced by low tissue myeloperoxidase activity and verified by histological examination. In addition, NMP (0.06 mg/ear) reduced tissue levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, INF-γ and MCP-1) and of the anti-inflammatory cytokine IL-10, and reduced gene expression of TNF-α, IL-6 and IL-1β increased by TPA. The data suggest that N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline acts as a topical anti-inflammatory agent that decreases the expression of inflammatory cytokines, making it useful for the treatment of skin inflammation. Further investigations are necessary for its development as a therapeutic agent.

Ethnopharmacological Relevance: Egletes viscosa (L.) (macela) is a native wild herb that can be found in different states of northeastern Brazil. The infusions of its flower buds are traditionally used for the treatment of gastrointestinal disorders. E. viscosa possesses two chemotypes (named A and B), distinguishable by the composition of the essential oil from the flower buds. Although there are previous studies of the gastroprotective effect of the isolated constituents of E. viscosa, its infusions have not been investigated yet., Aim of the Study: The present study aimed to evaluate and compare the chemical composition and the gastroprotective effect of flower bud infusions of E. viscosa from chemotype A (EVCA) and chemotype B (EVCB)., Materials and Methods: Sixteen infusions were brewed with flower buds according to the traditional preparation mode and were analyzed through a UPLC-QTOF-MS/MS based metabolomic approach for determination of their metabolic fingerprints and quantification of bioactive compounds. Afterward, these data were analyzed by chemometric methods (OPLS-DA) for discrimination of the two chemotypes. Additionally, infusions of EVCA and EVCB (50, 100 and 200 mg/kg, p.o.) were evaluated on gastric ulcers induced by absolute ethanol (96%, 0.2 mL, p.o.) in mice. To elucidate the gastroprotective mechanisms, the effect of EVCA and EVCB on gastric acid secretion and gastric wall mucus was determined and the role of TRPV1 channels, prostaglandins, nitric oxide and K ATP channels were assessed. Moreover, the oxidative stress-related parameters and the histological aspects of the stomach tissue were analyzed., Results: The chemotypes can be discriminated from each other using UPLC-QTOF-MS/MS chemical fingerprints. Both chemotypes presented similar chemical compositions, consisting basically of caffeic acid derivatives, flavonoids and diterpenes. The quantification of bioactive compounds demonstrated that chemotype A possesses more ternatin, tanabalin and centipedic than chemotype B. EVCA and EVCB (50, 100 and 200 mg/kg, p.o.) significantly decreased the severity of ethanol-induced gastric lesions, as shown by a reduction in histological alterations and leucocyte infiltration in gastric tissue. The gastroprotective mechanism of both infusions involves an antioxidant effect, maintenance of gastric mucus and reduction gastric secretion. Stimulation of endogenous prostaglandins and nitric oxide release, activation of TRPV1 channels, and K ATP channels are also involved in the gastroprotection of the infusions., Conclusion: The gastroprotective effect of EVCA and EVCB was equivalent and mediated through antioxidant and antisecretory actions, including the activation of TRPV1 receptors, stimulation of endogenous prostaglandins and nitric oxide, and opening of K ATP channels. The presence of caffeic acid derivatives, flavonoids and diterpenes in both infusions is involved in mediating this protective effect. Our findings support the traditional use of infusions of E. viscosa for gastric disorders regardless of the chemotype., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Peptic ulcers are lesions in the gastric and duodenal mucosa generated by an imbalance between protective factors (gastroduodenal mucus secretion, bicarbonate production, adequate blood flow) and harmful factors (excess pepsin or hydrochloric acid). Some drugs used in peptic ulcer therapy are associated with adverse effects. The aim of this study was to evaluate the antiulcerogenic and healing activity of hecogenin acetate (HA) in acute and chronic models of gastric lesions in rodents. The antiulcerogenic activity of HA was evaluated in models of gastric lesions induced by absolute ethanol and in acidified ethanol with HA (5, 10, and 20 mg/kg). For the model of gastric lesions induced by ischemia and reperfusion, rats were pre-treated with HA (5, 10, 20 mg/kg). After that, they were submitted to 30 min of ischemia, followed by 1 h of reperfusion. To evaluate the healing activity was induced gastric ulcer using acetic acid (80%) in rats. After 24 h, they were treated for 7 consecutive days with HA (10 and 20 mg/kg). They were evaluated the possible signs of toxicity, measurement of the lesions, collagen deposition, and histological analysis. HA significantly reduced the area of the lesion in models of gastric lesions induced by absolute and acidified ethanol, ischemia-induced gastric lesions and reperfusion, and regarding healing. In the collagen deposition, the presence and increase of collagen demonstrate the healing effect. The AH has antiulcerogenic and healing potential demonstrated by the decrease in gastric injury and presence of collagen fibers, respectively., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Neoglaziovia variegata (Arruda) Mez (Bromeliaceae) is a medicinal plant popularly known as "caroá." The leaves are made up of highly resistant fibers, which is of great commercial value to the handicraft and textile industry. Some studies have demonstrated that ethanolic extract of N. variegata have gastroprotective properties. This study aimed to investigate the gastroprotective activity and cytoprotective mechanisms of ethyl acetate (Nv-AcOEt), hexane (Nv-Hex), and chloroform (Nv-CHCl 3 ) fractions of N. variegata leaves. The gastroprotective activity of Nv-AcOEt, Nv-Hex, and Nv-CHCl 3 was evaluated using the ethanol and ethanol/HCl-induced gastric injury model. To elucidate the gastroprotective mechanisms, the functions of prostaglandins (PGs), nitric oxide (NO), and K ATP channels were evaluated. In addition, the nonprotein sulfhydryl groups and the mucus content in the gastric tissues were analyzed. All fractions of N. variegata leaves at oral doses of 100, 200, and 400 mg/kg significantly decreased ethanol and ethanol/HCl-induced gastric lesions, leading to gastroprotection, accompanied by an increase in reduced glutathione (GSH) and gastric mucus. Gastroprotective activity of Nv-AcOEt was inhibited after pretreatment with ibuprofen and N(G)-nitro-L-arginine (L-NOARG). Gastroprotective effect of Nv-Hex and Nv-CHCl 3 was also inhibited after pretreatment with L-NOARG and with glibenclamide. The results indicate that N. variegata (Arruda) Mez exhibits promising gastroprotective activity with the possible participation of NO, PGs, mucus, sulfhydryl groups, and K ATP .

This study investigated the acute blockade of endogenous melatonin (MLT) using Luzindole with or without systemic lipopolysaccharide (LPS) challenge and evaluated changes in inflammatory and oxidative stress markers in the mouse jejunum. Luzindole is an MT1/MT2 MLT receptor antagonist. Both receptors occur in the small intestine. Swiss mice were treated with either saline (0.35 mg/kg, ip), Luzindole (0.35 mg/kg, ip), LPS (1.25 mg/kg, ip), or Luzindole+LPS (0.35 and 1.25 mg/kg, ip, respectively). Jejunum samples were evaluated regarding intestinal morphometry, histopathological crypt scoring, and PAS-positive villus goblet cell counting. Inflammatory Iba-1, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, nuclear factor (NF)-kB, myeloperoxidase (MPO), and oxidative stress (NP-SHs, catalase, MDA, nitrate/nitrite) markers were assessed. Mice treated with Luzindole, LPS, and Luzindole+LPS showed villus height shortening. Crypt damage was worse in the LPS group. Luzindole, LPS, and Luzindole+LPS reduced the PAS-goblet cell labeling and increased Iba-1-immunolabelled cells compared to the saline group. Immunoblotting for IL-1β, TNF-α, and NF-kB was greater in the Luzindole group. The LPS-challenged group showed higher MPO activity than the saline and Luzindole groups. Catalase was reduced in the Luzindole and Luzindole+LPS groups compared to saline. The Luzindole group showed an increase in NP-SHs, an effect related to compensatory GSH activity. The acute blockade of endogenous MLT with Luzindole induced early changes in inflammatory markers with altered intestinal morphology. The other non-detectable deleterious effects of Luzindole may be balanced by the unopposed direct action of MLT in immune cells bypassing the MT1/MT2 receptors.

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatosteatosis and steatohepatitis, is intrinsically related to obesity. Our previous study reported on the anti-obese activity of α,β-amyrin (AMY), a pentacyclic triterpene isolated from Protium heptaphyllum. This study investigated its ability to prevent fatty liver and the underlying mechanism using the mouse model of NAFLD. NAFLD was induced in male Swiss mice fed a high fat diet (HFD) for 15 weeks. The controls were fed a normal chow diet (ND). The mice were simultaneously treated with AMY at 10 and 20 mg/kg or fenofibrate at 50 mg/kg. Lipid levels along with metabolic and inflammatory parameters were assessed in liver and serum. The liver sections were histologically examined using H&E staining. RT-qPCR and western blotting assays were performed to analyze signaling mechanisms. Mice fed HFD developed severe hepatic steatosis with elevated triglycerides and lipid droplets compared with ND controls. This was associated with a decrease in AMP-activated protein kinase (AMPK) activity, an increase of mechanistic target of rapamycin complex 1 (mTORC1) signaling, and enhanced sterol regulatory element binding protein 1 (SREBP1) expression, which have roles in lipogenesis, inhibition of lipolysis, and inflammatory response. AMY treatment reversed these signaling activities and decreased the severity of hepatic steatosis and inflammatory response, evidenced by serum and liver parameters as well as histological findings. AMY-induced reduction in hepatic steatosis seemed to involve AMPK-mTORC1-SREBP1 signaling pathways, which supported its beneficial role in the prevention and treatment of NAFLD.

Ethnopharmacological Relevance: In folk medicine Hyptis suaveolens (Lamiaceae) has been reported to relieve respiratory and gastrointestinal infections, indigestion, cold, pain, fever, cramps, skin diseases, gastric ulcer and inflammatory disorders. This study investigated the effects and the mechanisms of action of Hyptis suaveolens (L.) Poit (Lamiaceae) ethanol extract (Hs-EtOH) and hexane phase (Hs-HexF) against intestinal inflammation., Material and Methods: Acute and relapse TNBS-induced ulcerative colitis protocols were used to evaluate intestinal anti-inflammatory activity. Damage evaluations, biochemical, histological and immunostaining parameters were determined., Results: Both extracts decreased macroscopic colonic inflammation and the area of lesion induced by TNBS. Nevertheless, only Hs-HexF was able to reduce colonic wall thickness, edema and diffuse inflammatory cell infiltration and to prevent GSH depletion in the acute model of ulcerative colitis. In the chronic phase with relapse of colonic ulceration, yet again only Hs-HexF significantly attenuated inflammatory parameters and presented a decrease in nitrite/nitrate, MDA, MPO, IL-1-β and TNF-α and increased levels of SOD, CAT, GSH and IL-10. Hs-HexF also significantly reduced positive cells immunostained for PCNA., Conclusion: The data indicate intestinal anti-inflammatory activity for H. suaveolens, due to the participation of the antioxidant system, decreased neutrophil infiltration and cytokine modulation, as well as, owing to regulation of cell proliferation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The gastroprotective property of (-)-myrtenol, a monoterpenoid, has been demonstrated previously against acute gastric ulceration induced by ethanol. However, the healing property of (-)-myrtenol in a chronic gastric ulcer model remains to be verified. This study evaluated its healing efficacy and the mechanism involved using the rat model of chronic gastric ulcer induced by serosal injection of 80% acetic acid in vivo, and human gastric adenocarcinoma cells (AGS) in vitro. The results showed that compared to vehicle-treated ulcer controls, oral administration of (-)-myrtenol (50 and 100 mg/kg/day) for 7 days promoted ulcer healing, as indicated by significant decreases in ulcer area and volume. The macroscopic and microscopic findings confirmed the healing potential of (-)-myrtenol. The ulcer healing activity was also associated with significant increases in gastric mucin content, collagen deposition, number of cells with positive marking for proliferating cell nuclear antigen (PCNA), and by changes in the expression of the inflammatory parameters tumor necrosis factor (TNF)-α, interleukin (IL)-1β and cyclooxygenase (COX)-2, as well as a decrease of metalloproteinases (MMP-9 and MMP-2) activity. Furthermore, in vitro assays using the AGS cultures revealed that (-)-myrtenol favors wound healing activity via stimulation of cell proliferation and migration without altering the cell viability. Taken together, these findings indicate that (-)-myrtenol has gastro-cytoprotective and ulcer healing properties that can be further explored to develop a new therapeutic agent from a natural source for the treatment of gastric ulcer., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dietary fiber intake plays an important role in the prevention of obesity. This study aimed at investigating the effect of cashew fiber without low molecular weight compounds (CABwc) on obesity prevention and metabolomics in a murine model of diet-induced obesity. Mice were fed a chow diet (CD), a high-fat diet (HFD) or a high-fat diet supplemented with CABwc (10%) (HFD-CABwc) for 15 weeks. The body weight, abdominal fat, serum glucose levels, insulin and lipid profiles, satiety hormones such as leptin and ghrelin, digestive enzymes such as amylase and lipase, and inflammatory mediators such as TNF-α, IL-6, and adiponectin were measured, in addition to performing serum and hepatic tissue analyses. The metabolomic analysis was based on nuclear magnetic resonance (NMR) spectroscopy of serum and feces. The effects observed with ingestion of CABwc were appetite control and prevention of hyperglycemia, hyperinsulinemia and hypertriglyceridemia, as well as the prevention of the inflammatory process and reduction of liver injury caused by the HFD. In addition, NMR evidenced the presence of SCFAs in serum and feces of mice fed with HFD-CABwc. These findings suggest that CABwc promoted satiety in mice, improving the metabolism of glucose and lipids. Positive effects of obesity prevention may be associated with SCFA production.

Ethnopharmacological Relevance: Mucuna pruriens (Mp) belongs to Leguminosae family, it is native of tropical regions and used to treat several maladies such as urinary, neurological, and menstruation disorders, constipation, edema, fever, tuberculosis, ulcers, diabetes, arthritis, dysentery, and cardiovascular diseases. Mp seeds are rich in bioactive compounds, for instance, lectins, a heterogeneous group of proteins and glycoproteins with a potential role as therapeutic tools for several conditions, including gastric disorders. This study investigated the acute toxicity, gastroprotective, and antioxidant activities of a lectin from Mucuna pruriens seeds (MpLec) on ethanol-induced gastropathy model in mice., Material and Methods: Mice received MpLec (5 or 10 mg/kg; i.v.) and were observed for acute toxicity signs; in another experimental series, mice were pre-treated with MpLec (0.001; 0.01 or 0.1 mg/kg, i.v.), ranitidine (80 mg/kg, p.o.), or saline (0.3 mL/30g, i.v.) before ethanol 99.9% (0.2 mL/animal, p.o.), and euthanized 30 min after ethanol challenge. Macroscopic and microscopic gastric aspects, biochemical parameters (tissue hemoglobin levels, iron-induced lipid peroxidation, GSH content, SOD activity, and gastric mucosal PGE2) were measured. Additionally, pharmacological tools (yohimbine, indomethacin, naloxone, L-NAME) were opportunely used to clarify MpLec gastroprotective mechanisms of action., Results: No toxicity signs nor death were observed at acute toxicity tests. MpLec reduced ethanol-induced gastric damage, edema, and hemorrhagic patches formation, as well as decreased lipid peroxidation, SOD activity, and increased GSH content. Yohimbine and indomethacin prevented MpLec effects, suggesting the involvement of alpha-2 adrenoceptors and prostaglandins in the MpLec-mediated effects., Conclusion: MpLec does not present toxicity signs and shows gastroprotective and antioxidant activities via alpha-2 adrenoceptors and prostaglandins in the ethanol-induced gastropathy model., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Wound healing involves the interaction of blood cells, proteins, proteases, growth factors, and extracellular matrix components. Inflammation is one of the first events occurring during this process. Previously, we showed that the N-Methyl-(2S,4R)-trans-4-Hydroxy-L-Proline (NMP) from Sideroxylon obtusifolium leaves (a Brazilian medicinal species) presents an anti-inflammatory action. Considering inflammation as an important event in the wound healing process, the objectives were to investigate the topical effects of the NMP gel on a mice wound-induced model. Male Swiss mice were divided into 4 groups: Sham (surgical procedure only), Control (gel-base treated), and 3% or 10% NMP gel-treated groups. Measurements of wound areas and microscopic analyses (HE [hematoxylin-eosin] and PSR [picrosirius red] stainings) were carried out, at the 7th and 12th, days after the wound induction. Furthermore, immunohistochemical assays for iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) and biochemical measurements for TBARS (thiobarbituric acid reactive substances), GSH (glutathione), and myeloperoxidase (MPO) were also performed, at the second day after the wound induction. The work showed that NMP decreases the wound areas, after topical application, relatively to the Sham and Control groups. In addition, microscopic alterations were reduced and collagen deposition was increased, at the 7th and 12th days, in the 10% NMP group. While iNOS and COX-2 immunostainings and GSH contents increased, in relation to the Sham and Control groups, TBARS and MPO decreased. Altogether, the results showed NMP to improve the wound healing process, by upregulating iNOS and COX-2 activities, reducing lipid peroxidation and MPO activity, and increasing GSH contents. In addition, NMP certainly contributes to the increased collagen deposition. These data may stimulate translational studies dealing with the possible use of NMP from Sideroxylon obtusifolium or from other sources for the management of wound healing.

Ethnopharmacological Relevance: Pilosocereus gounellei Cactaceae), popularly known as "xique xique", is a species native from Caatinga region of Northeast Brazil, which is used by traditional communities in folk medicine for a variety of health problems, especially inflammatory processes and gastritis., Aim of the Study: The present study investigates the possible gastric antiulceractivity of ethanol extracts obtained from the cladodes and roots of Pilosocereus gounellei (EECPG and EERPG, respectively) and mechanisms of action underlying this effect., Materials and Methods: Mice were used for the evaluation of the acute toxicity, and mice and rats to study the gastroprotective activity. The gastroprotective action of EECPG and EERPG was analyzed in the absolute ethanol in mice, ischemia-reperfusion and cold restraint stress in rats. In the investigation of the gastroprotective mechanisms of EECPG and EERPG, the participation of the NO and prostaglandins, the levels of the non-protein sulfhydril groups (NP-SH) and the catalase activity using the ethanol-induced gastric mucosa lesion model and the quantification of the gastric mucus and the antisecretory activity through pylorus ligature model in rats were analyzed., Results: The animals did not present any signs of acute toxicity for the EECPG and EERPG, and it was not possible to calculate the DL50. EECPG and EERPG (200 and 400 mg/kg) exhibited a significant gastroprotective effect in absolute ethanol, ischemia-reperfusion-induced and cold restraint stress gastric lesion models. Gastroprotection of EECPG and EERPG (200 mg/kg) was significantly decreased in pre-treated mice with L-NAME. Our studies revealed that EECPG and EERPG (200 mg/kg) prevented the decrease of the non-protein sulfhydril groups (NPSH) and increased the catalase levels in ethanol-treated animals. However, the gastric secretion parameters (volume, [H+], pH) did not show any alteration., Conclusions: Our results indicate that the ethanolic extract from the cladodes and roots of Pilosocereus gounellei exhibits a significant gastroprotection, because it inhibits the formation of gastric lesions using different models. The participation of the nitric oxide, prostaglandins, the non-protein sulfhydril groups (NP-SH), catalase seem to be involved in the gastroprotection activity of the EECPG and EERPG. Nevertheless, this activity does not seem to be related to antisecretory mechanisms., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To characterize the protective effects of the triterpenoid mixture alpha, beta-amyrin (AMY, 20 mg/kg, during 15 days) on the reactivity of isolated aorta of high-fat diet (HFD)-induced obese mice. Male Swiss mice were fed with HFD or normal diet (ND) for 15 weeks. Contractions of thoracic aorta in response to KCl or phenylephrine (PHE) and relaxation by acetylcholine (ACh) or sodium nitroprusside (SNP) were analyzed. HFD-fed mice developed hyperglycemia, hyperlipidemia, and significant body weight gain, parameters prevented by AMY treatment. Whereas aortic contractility did not differ in response to KCl, contractions induced by PHE (1 μM) as well as relaxation induced by ACh (1-30 μM) or SNP (1 nM-0.1 mM) on PHE-contracted aorta were decreased (p < 0.05) in tissues of HFD compared to ND mice, phenomenon significantly (p < 0.05) diminished in HFD mice treated with AMY. The relaxant actions of ACh and SNP were inhibited (p < 0.05) by tetraethylammonium (TEA, 5 mM), apamin (0.1 μM), and 4-aminopyridine (4-AP; 3 mM) in aortae from ND group, but not from HFD. Treatment of HFD mice with AMY rescued the inhibitory effect of TEA (p < 0.05) on vasorelaxant actions of ACh and SNP. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) inhibited similarly the relaxant effects of SNP in all groups. 8-Br-cGMP relaxed with similar profile aortae of all groups. By preventing HFD-induced obesity in mice, AMY rescued the blunted contractile response to PHE, and the attenuated vasorelaxation and K + channel activation (opening) induced by ACh and SNP in isolated aorta.