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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.

Objective: Oral candidiasis is a common fungal infection that affects the oral mucosa, and happens when Candida albicans interacts with bacteria in the oral microbiota, such as Streptococcus mutans, causing severe early childhood caries. C. albicans and S. mutans mixed biofilms are challenging to treat with conventional antimicrobial therapies, thus, new anti-infective drugs are required. This study aimed to test a drug delivery system based on chitosan microparticles loaded with geranium and lemongrass essential oils to inhibit C. albicans and S. mutans mixed biofilms., Methodology: Chitosan microparticles loaded with essential oils (CM-EOs) were obtained by spray-drying. Susceptibility of planktonic were performed according CLSI at 4 to 2,048 µg/mL. Mixed biofilms were incubated at 37ºC for 48 h and exposed to CM-EOs at 256 to 4,096 µg/mL. The antimicrobial effect was evaluated using the MTT assay, with biofilm architectural changes analyzed by scanning electron microscopy. RAW 264.7 cell was used to evaluate compound cytotoxicity., Results: CM-EOs had better planktonic activity against C. albicans than S. mutans. All samples reduced the metabolic activity of mixed C. albicans and S. mutans biofilms, with encapsulated oils showing better activity than raw chitosan or oils. The microparticles reduced the biofilm on the slides. The essential oils showed cytotoxic effects against RAW 264.7 cells, but encapsulation into chitosan microparticles decreased their toxicity., Conclusion: This study demonstrates that chitosan loaded with essential oils may provide an alternative method for treating diseases caused by C. albicans and S. mutans mixed biofilm, such as dental caries.

Diabetes is a disease linked to pathologies, such as chronic inflammation, neuropathy, and pain. The synthesis by the Claisen-Schmidt condensation reaction aims to obtain medium to high yield chalconic derivatives. Studies for the synthesis of new chalcone molecules aim at the structural manipulation of aromatic rings, as well as the replacement of rings by heterocycles, and combination through chemical reactions of synthesized structures with other molecules, in order to enhance biological activity. A chalcone was synthesized and evaluated for its antinociceptive, anti-inflammatory and hypoglycemic effect in adult zebrafish. In addition to reducing nociceptive behavior, chalcone (40 mg/kg) reversed post-treatment-induced acute and chronic hyperglycemia and reduced carrageenan-induced abdominal edema in zebrafish. It also showed an inhibitory effect on NO production in J774A.1 cells. When compared with the control groups, the oxidative stress generated after chronic hyperglycemia and after induction of abdominal edema was significantly reduced by chalcone. Molecular docking simulations of chalcone with Cox -1, Cox-2, and TRPA1 channel enzymes were performed and indicated that chalcone has a higher affinity for the COX-1 enzyme and 4 interactions with the TRPA1 channel. Chalcone also showed good pharmacokinetic properties as assessed by ADMET., Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03696-8., Competing Interests: Conflict of interestAll authors have no conflicts of interest to declare with respect to the research, authorship, and/or publication of this work., (© King Abdulaziz City for Science and Technology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

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.)

Methylmercury (MeHg) is highly toxic to the human brain. Although much is known about MeHg neurotoxic effects, less is known about how chronic MeHg affects hippocampal amino acids and other neurochemical markers in adult mice. In this study, we evaluated the MeHg effects on systemic lipids and inflammation, hippocampal oxidative stress, amino acid levels, neuroinflammation, and behavior in adult male mice. Challenged mice received MeHg in drinking water (2 mg/L) for 30 days. We assessed weight gain, total plasma cholesterol (TC), triglycerides (TG), endotoxin, and TNF levels. Hippocampal myeloperoxidase (MPO), malondialdehyde (MDA), acetylcholinesterase (AChE), amino acid levels, and cytokine transcripts were evaluated. Mice underwent open field, object recognition, Y, and Barnes maze tests. MeHg-intoxicated mice had higher weight gain and increased the TG and TC plasma levels. Elevated circulating TNF and LPS confirmed systemic inflammation. Higher levels of MPO and MDA and a reduction in IL-4 transcripts were found in the hippocampus. MeHg-intoxication led to increased GABA and glycine, reduced hippocampal taurine levels, delayed acquisition in the Barnes maze, and poor locomotor activity. No significant changes were found in AChE activity and object recognition. Altogether, our findings highlight chronic MeHg-induced effects that may have long-term mental health consequences in prolonged exposed human populations.

Insufficient sleep compromises lipid/glucose homeostasis. In opposition, exercise increases energy expenditure and has positive effects on glucose and fatty acid metabolism. Presently, it is hypothesized that exercise ameliorates metabolic dysfunction associated with sleep deprivation (SD). The effects of exercise (EX), SD and EX before SD. (EX+SD) on lipid and glucose metabolism were evaluated. Swiss mice were assigned to 4 groups (N=12, each) control, exercise (EX, 8 weeks, 1-hour of treadmill/9cm/s, 5x/week, from noon to 1:00 p.m.), SD (SD-72h, multiple platforms method), and exercise before SD (EX+SD). Exercise increased blood glucose, lactate and triglycerides ( p <0.05). Both, SD and EX+SD reduced blood triglycerides ( p <0.05). EX increased VLDL and reduced LDL; conversely, SD and EX+SD reduced VLDL and increased LDL. Hepatic triglycerides were markedly reduced by SD ( p <0.05) and this was prevented by previous exercise (EX+SD). In summary, exercise improved essential cholesterol fractions and exercise before SD increased hepatic cholesterol and prevented hepatic triglycerides depletion.

Mercury (Hg) is one of the most toxic environmental pollutants, especially when methylated, forming methylmercury (MeHg). MeHg affects DNA repair, increases oxidative stress, and predisposes to cancer. MeHg neurotoxicity is well-known, but recently MeHg-associated cardiovascular effects were recognized. This study evaluated circulating lipids, oxidative stress, and genotoxicity after MeHg-chronic exposure (20 mg/L in drinking water) in C57BL/6J wild-type and APOE knockout (ko) mice, the latter, being spontaneously dyslipidemic. Experimental mice were assigned to four groups: non-intoxicated and MeHg-intoxicated wild-type mice and non-intoxicated and MeHg-intoxicated APOE ko mice. Plasma levels of triglycerides, total cholesterol (TC), HDL, and LDL were analyzed. Liver lipid peroxidation and splenic gene expression of xeroderma pigmentosum complementation groups A, C, D, and G (XPA, XPC, XPD, and XPG), X-ray repair cross-complementing protein 1 (XRCC1), and telomerase reverse transcriptase (TERT) were measured. Fur Hg levels confirmed chronic MeHg intoxication. MeHg exposure raises TC levels both in wild-type and APOE ko mice. HDL and LDL-cholesterol levels were increased only in the MeHg-challenged APOE ko mice. MeHg increased liver lipid peroxidation, regardless of the genetic background. Unintoxicated APOE ko mice showed higher expression of TERT than all other groups. APOE deficiency increases XPA expression, regardless of MeHg intoxication. Furthermore, MeHg-intoxicated mice had more cytogenetic abnormalities, effect which was independent of APOE deficiency. More studies are needed to dissect the interactions between circulating lipids, MeHg intoxication, and DNA-repair pathways even at young age, interactions that likely play critical roles in cell senescence and the risk for chronic disorders later in life., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.

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.

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.