Citral ((2E)-3,7-dimethylocta-2,6-dienal), a bioactive component of lemongrass, inhibits oxidant activity, nuclear factor kappa B (NF-κB) activation, and cyclooxygenase-2 (COX-2) expression, even as it activates peroxisome proliferator-activated receptor (PPAR)-α and γ. Additionally, citral produces long-lasting inhibition of transient receptor potential (TRP) channels that are found in sensory neurons, such as TRPV1–3 and TRPM8, while it transiently blocks TRPV4 and TRPA1. Here, the effect of citral in experimental models of acute inflammation and hyperalgesia in mice, and the underlying citral mechanisms of action were investigated. ADMET properties and molecular targets were predicted using the online server. The immunomodulatory and antihyperalgesic effects of citral were evaluated, using mechanical and thermal stimuli, at different time-points on carrageenan, lipopolysaccharides (LPS), and zymosan-induced paw edema and hyperalgesia in mice. ADMET analysis ensures that the citral has not violated Lipinski’s rule of five, indicating its safety consumption, and molecular target prediction software identified that citral is a potential fatty acid amide hydrolase (FAAH) inhibitor. Oral treatment with citral (50–300 mg/kg) significantly inhibited carrageenan-induced paw edema and thermal allodynia. Furthermore, citral modulated the inflammation induced by LPS and zymosan, toll-like receptor (TLR) 4, and TLR2/dectin-1 ligands, respectively. Moreover, pretreatment with cannabinoid receptor type 2 (CB2R) antagonists and ATP-sensitive K+ channel inhibitor, but not with a cannabinoid receptor type 1 (CB1R) antagonist, significantly reversed the anti-inflammatory effect of citral. Intriguingly, citral did not cause any relevant action in the central nervous system, and it was safe when assessed in a 14 day toxicity assay in male mice. Therefore, citral constitutes a promising, innovative, and safe molecule for the management of immunoinflammatory conditions and pain states.

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Rosmarinic acid (RA), an ester of caffeic acid and 3, 4-dihydroxyphenyllactic acid, has anti-inflammatory and neuroprotective activities. Herein, this study investigated in silico the drug-likeness and the potential molecular targets to RA. Moreover, it tested the antidepressant-like potential of RA in the lipopolysaccharide (LPS)-induced depression model. RA (MW = 360.31 g/mol) meets the criteria of both Lipinski's rule of five and the Ghose filter. It also attends to relevant pharmacokinetic parameters.Target prediction analysis identified RA's potential targets and biological activities, including the peroxisome proliferator-activated receptor (PPAR) and the cannabinoid receptors CB 1 and CB 2 . In vivo, RA's acute, repetitive, and therapeutic administration showed antidepressant-like effect since it significantly reduced the immobility time in the tail suspension test and increased grooming time in the splash test. Further, the pretreatment with antagonists of CB 1 , CB 2 , and PPAR-γ receptors significantly blocked the antidepressant-like effect of RA. Altogether, our findings suggest that cannabinoid receptors/PPAR-γ signaling pathways are involved with the antidepressant-like effect of RA. Moreover, this molecule meets important physicochemical and pharmacokinetic parameters that favor its bioavailability. RA constitutes a promising, innovative, and safe molecule for the pharmacotherapy of major depressive disorder.

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Jaboticaba, Plinia cauliflora (Mart.) Kausel, is a Brazilian berry traditionally used in folk medicine as a treatment for some health conditions. Phenolic compounds such as flavonoids and anthocyanins have previously been detected in the fruit. This current study aimed to evaluate the toxicological effects of jaboticaba peel extract (JPE) on Artemia salina, L929, and MDA-MB-231 cell lines. Besides, JPE antioxidant, acetylcholinesterase, and antifungal activities, and elemental analysis CHNS were also tested. JPE had moderate toxicity (LD 50 = 360.92 g mL −1 ) on A. salina, the non-toxic effect on L929 cell line, and decreased the viability of cancer cell line MDA at 1,000 µg mL -1 and 500 µg mL -1 concentrations. The antioxidant activity toward 2,2-diphenyl-1-picrylhydrazyl (DPPH) performed IC 50 = 37.45 ± 0.17 µg mL -1 , whereas 45.7% of acetylcholinesterase activity was inhibited. By its elemental composition, JPE is an alternative food supplement and dermocosmetic component. Antifungal potential toward Candida strains was not observed. Experimental section Plant material and chemicalsJaboticaba belongs to the Plinia cauliflora (Mart.) Kausel specie. However, synonyms such as Myrciaria cauliflora (Mart.) O.Berg may be used to name it (Sobral et al. 2015). Powder of macerated P. cauliflora peel was commercially purchased from Chá & Cia -Ervas Medicinais, M40382 (Sao Paulo, Brazil). Standard ascorbic acid, 2,2-diphenyl-1-picrylhydrazyl (DPPH), acetylcholine iodide (AChI), 5,5´-dithiobis-(2-nitrobenzoic acid) (DTNB), physostigmine (Eserin), dimethyl sulfoxide (DMSO), dulbecco's modified Eagle's medium (DMEM)glutamax, thiazolyl blue tetrazolium bromide (MTT), Roswell Park Memorial Institute medium (RPMI), (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES), and fetal bovine serum (FBS) were purchased from Sigma Aldrich (USA). Penicillin and streptomycin were obtained from Vitrocell, Brazil. Candida standard strains C. albicans, American Type Culture Collection (ATCC) 10231; C. glabrata (Taniwaki, M.H.), Collection of Tropical Cultures (CCT) 0728; C. krusei, (FTI) CCT 1517; and C. guilliermondii (CCT), 1890 were obtained from Foundation André Tosello, Brazil, (3-(N-morpholino)-propane sulphonic acid (MOPS) was purchased from J.T. Backer (Germany). Tryptic Soy Broth (TSB) was obtained from HiMedia (India).Amphotericin B was obtained from Laboratório Cristália (Brazil). Extract preparationTo prepare the jaboticaba peel extract (JPE), 10 g of the vegetal material was extracted with 400 mL of 70% ethanol for 72 h in the dark, and the yield was 13%. The extract was filtered, evaporated under low pressure (Rotavapor® R-210, Buchi, Switzerland) and lyophilized (ALPHA 1-4 LD plus, Christ, Germany) under 1.9 mbar pressure and -14 °C.