A chemical investigation of the brown seaweed Dictyota mertensii (Hoyt) Schnetter, Hörning & Weber-Peukert, a member of the Dictyotaceae, was carried out. The ethyl acetate extract led to the isolation of two prenylated guaiane, including a new one (1) and the known dictyol H (2). In addition, the dolabellane diterpene 10,18-dihydroxy-dolabella-2,7-diene (3) and two benzalkonium chlorides (4-5) were also isolated. The structures of all compounds were elucidated by an extensive analysis of their one- and two-dimensional nuclear magnetic resonance data (1D and 2D NMR), and high-resolution electrospray ionization mass spectrometry (HRESIMS). The cell viability and the anti-inflammatory activity of diterpenes 1 and 2 were evaluated against lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages.

Background/Objectives: The main biologically active molecules of Cannabis sativa L. are cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). Both exert anticonvulsant effects when evaluated as single drugs, but their possible interaction as components of C. sativa extracts has been scarcely studied. For this reason, we evaluated CBD and THC, combined or not, in two seizure models in mice, using an improved vehicle formula. Methods: Firstly, acute seizures were induced by intraperitoneal (i.p.) pentylenetetrazole (PTZ, 80 mg/kg), and mice received CBD or THC at 1, 3, 6, and 10 mg/kg, or a CBD/THC 1:1 combination at 1.5, 3, and 6 mg/kg, per os (p.o.), one hour before PTZ administration. Secondly, mice received p.o. CBD (10 mg/kg), CBD/THC (1.5, 3, and 6 mg/kg), valproic acid (50 mg/kg), or vehicle (nanoemulsions without CBD or THC), one hour before PTZ (30 mg/kg, i.p.) every other day for 21 days. Behavioral, biochemical, and immunohistochemical analyses were performed to assess the response to PTZ, oxidative stress, and astroglial activation. Results: In the acute model, CBD and THC at 3–10 mg/kg, and their combinations, significantly increased latency to generalized seizures and death, and improved survival rates. In the chronic model, similarly to valproic acid, CBD 10 mg/kg and CBD/THC at 1.5 and 3 mg/kg delayed kindling acquisition, while CBD/THC 6 mg/kg had no effect. CBD and CBD/THC treatments reduced oxidative and nitrosative stress and attenuated astrogliosis, as indicated by decreased glial fibrillary acidic protein and GABA transporter 1 expression and increased inwardly rectifying potassium channel 4.1 expression in hippocampal regions. However, no cannabinoid treatment prevented the impairment in novel object recognition and Y maze tests. Conclusions: These findings support the potential role of cannabinoids in counteracting seizures, possibly by reducing oxidative stress and astrogliosis. The study also highlights the importance of nanoemulsions as a delivery vehicle to enhance cannabinoid effectiveness while considering the risks associated with direct cannabinoid receptor activation.

Withanolides are a substantial bio-diverse group of naturally occurring steroidal lactones. Herein, ten still undescribed withanolides (1-10), along with the knowns withaferin A (11), 2,3-dihidrowithaferin A (12), and two other non-withanolides, vomifoliol (13) and the N-trans-p-coumaroyltyramine (14), were isolated from the hexane/EtOAc 1:1 leaf extract of Athenaea velutina (Sendtn.) D'Arcy (Solanaceae). The structures of the undescribed withanolides were elucidated by an extensive analysis of their spectroscopic data: 1D and 2D NMR, HRESIMS, single-crystal X-ray diffraction, and ECD calculations. The antiproliferative properties of the withanolides were evaluated against the human cancer cell lines: central nervous system (SNB-19), prostate (PC-3), colon (HCT-116), and leukemia (HL-60), and a murine fibroblast-like cell (L-929). Withanolides 15-17, isolated from the same plant in a previous work, were included for the pharmacological tests. Compounds 15 and 16 exhibited cytotoxic activity for all cancer cells, while 2 was selectively more cytotoxic to HL-60 cells. In addition, the withanolides were evaluated in guinea pig cardiac tissues. Compounds 15 and 16 showed cardiotonic activity, devoid of a positive chronotropic effect which is a good pharmacological profile for an inotrope agent.

The interaction between cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) in exerting anticonvulsant effects has been scarcely studied. To improve this knowledge, we evaluated CBD and THC, combined or not, in two seizure models in mice, using an improved vehicle formula. Firstly, acute seizures were induced by intraperitoneal (i.p.) pentylenetetrazole (PTZ, 80 mg/kg), and mice received CBD or THC at 1, 3, 6, and 10 mg/kg, or a CBD/THC 1:1 combination at 1.5, 3, and 6 mg/kg, per os (p.o.), one hour before PTZ administration. Secondly, mice received p.o. CBD (10 mg/kg), CBD/THC (1.5, 3, and 6 mg/kg), valproic acid (50 mg/kg), or vehicle, one hour before PTZ (30 mg/kg, i.p.) every other day for 21 days. Behavioral, biochemical, and immunohistochemical analyses were performed to assess the response to PTZ, oxidative stress, and astroglial activation. In the acute model, CBD and THC at 3-10 mg/kg, and their combinations, significantly increased latency to generalized seizures and death, and improved survival rates. In the chronic model, similarly to valproic acid, CBD 10 mg/kg and CBD/THC at 1.5 and 3 mg/kg delayed kindling acquisition, while CBD/THC 6 mg/kg had no effect. CBD and CBD/THC treatments reduced oxidative and nitrosative stress and attenuated astrogliosis, as indicated by decreased glial fibrillary acidic protein and GABA transporter 1 expression, and increased inwardly rectifying potassium channel 4.1 expression in hippocampal regions. However, no cannabinoid treatment prevented the impairment in novel object recognition and Y maze tests. These findings support the potential role of cannabinoids in counteracting seizures, possibly by reducing oxidative stress and astrogliosis. The study also highlights the importance of nanoemulsions as a delivery vehicle to enhance cannabinoid effectiveness while considering the risks associated with direct cannabinoid receptor activation.

Background/Objectives: In Brazil, Leishmania braziliensis is the main etiological agent of cutaneous leishmaniasis and represents an important public health problem. The actual pharmacotherapy of leishmaniasis has several disadvantages, making the development of new therapeutic options essential. The present study aimed to carry out the bioprospecting and selection of products of Amburana cearensis, including extracts and active principles with a leishmanicidal effect and to evaluate its possible mechanism of action. Methods: A dry extract of A. cearensis (DEAC) was characterized by HPLC, with the following active markers: coumarin (CM), amburoside A (AMR), and vanillic acid (VA). The leishmanicidal effect of DEAC was assessed, and the in vitro inhibitory action of the phenolic fraction, including CM, AMR, and VA, on promastigote and amastigote forms were determined. Results: CM showed the best reductions (maximal inhibition: 57%) of the promastigote form of L. braziliensis, followed by the plant extract (40% inhibition) and other test drugs (maximal reduction: 29%). The treatment of macrophages infected by L. brasiliensis with CM (10 μg/mL) reduced the intracellular parasite load (amastigote form, maximal reduction: 50%), increased the production of nitric oxide, TNF-α, IL-12, and IL-10, and decreased the production of IL-4. These effects were not related to cytotoxicity (MTT test). Glucantime (4 mg/mL, standard drug) reduced the amastigote form by 65%. Conclusions: CM showed promising leishmanicidal activity against both forms of L. brasiliensis, and this effect seems to be associated, at least in part, to its immunomodulatory action by tilting the Th1/Th2 imbalance in favor of Th1.

Parkinson's disease (PD) is a neurodegenerative disease characterized by motor and non-motor symptoms, often associated with the accumulation of α-synuclein, neuroinflammation and oxidative stress in the central and peripheral systems. Considering that patients with Parkinson's disease often have gastrointestinal symptoms, this study aimed to investigate whether a rotenone-induced rat model of PD can induce intestinal changes and the neuroprotective effects of a cannabidiol (CBDne) nanoemulsion formulation, focusing on the striatum and intestine. Wistar rats were divided into six groups: control, rotenone (2.75 mg/kg), CBDne (1.25 mg/kg) and rotenone, CBDne (2.5 mg/kg) and rotenone, CBDne (5.0 mg/kg) and rotenone and CBDne alone (1.25 mg/kg). Behavioral assessments, including open field, Y maze and novel object recognition tests, were performed to evaluate motor and cognitive functions. Biochemical, histological and immunohistochemical analyses were performed to assess markers of neuroinflammation, oxidative stress (iNOS, nNOS, nitrite levels, lipid peroxidation, glutathione content, GFAP, IBA1) and α-synuclein aggregation in the striatum and duodenum. The results showed that rotenone treatment significantly increased α-synuclein accumulation in both the striatum and duodenum, along with elevated levels of GFAP and IBA1, indicating elevated glial activation. In addition, rotenone significantly increased oxidative stress markers, including nitrite levels and lipid peroxidation in the prefrontal cortex, hippocampus and striatum. CBDne normalized these markers, returning them to control levels. In addition, rotenone caused a 38-47 % reduction in glutathione (GSH) content, with the most significant decrease in the striatum. CBDne effectively restored GSH levels to those of the control group. Behavioral improvements were observed in the CBDne-treated groups, along with attenuation of rotenone-induced weight loss. These findings suggest that CBDne exerts broad neuroprotective, anti-inflammatory and antioxidant effects, targeting central and peripheral α-synucleinopathies and oxidative damage. Its ability to modulate inflammation, oxidative stress and protein aggregation highlights its therapeutic potential for controlling the motor and non-motor symptoms of PD.

Ethnopharmacological relevance Plectranthus ornatus is a medicinal plant originally from Africa but adapted to Brazil's climate conditions. It is recognized for its therapeutic properties, particularly for treating liver and stomach diseases, gastritis control, heartburn, and hangover. Therefore, studies on its chemical composition and pharmacological evaluation are important for the safe use of the plant. Aim of the study To investigate the chemical composition and pharmacological activity of leaf decoction of P. ornatus. Materials and methods The lyophilized herbal decoction from P. ornatus leaves was extracted with MeOH (methodology A), and CHCl3 and n-BuOH (methodology B). The compounds were isolated using chromatographic techniques. Their structures were determined using spectroscopic methods (1H and 13C NMR, IR, and HRESIMS) and comparison with published data. The lyophilized herbal decoctions DPO A (decoction from methodology A) and DPO B (methodology B), and compounds 8, 9, 15, and 16 (4, 20, and 40 mg/kg) were evaluated for their toxicity, anti-nociceptive, and anti-inflammatory effects in experimental adult zebrafish (Danio rerio) models. Results The present study focused on the CHCl3 and MeOH soluble fractions from the lyophilized leaf decoction leading to the isolation of five new diterpenes (1, 4-7) and two new glucuronide flavonoid derivatives (2 and 3). In addition, four diterpenes (14-17), two glucuronide flavonoid derivatives (10 and 11), three phenolics (8, 12, and 13), and one disaccharide (9) previously reported were also isolated. In zebrafish essays, all samples showed no toxicity and exhibited an anti-nociceptive effect in at least one of the tested doses: 9, 15, 16, and DPO B (4 mg/kg), 8 (20 mg/kg), and DPO A (40 mg/kg). Moreover, the compounds 15 (4, 20, and 40 mg/kg) and 16 (4, 20, and 40 mg/kg) exhibited anti-inflammatory effects. Conclusion The lyophilized decoctions (DPO A and DPO B) including the compounds 8, 9, 15, and 16 exhibited significant anti-nociceptive effects in adult zebrafish and showed no toxicity. Since pain can be a symptom of liver, stomach, and gastrointestinal disorders, and all the samples proved to be non-toxic, the herbal decoction of P. ornatus leaf could be considered a potential therapeutic option in pain management, supporting the ethnopharmacological use of the plant.

Three undescribed non-cyanogenic cyanoglycosides, designated as trichotomoside A (1), B (2), and C (3) along with three known ones (4-6) were isolated from the roots of Cordia trichotoma. In addition, miscellaneous compounds such as acid (1’R,3’S,5’R,8’S,2Z,4E)-dihydrophaseic 3’-O-β-D-glycopyranoside (7), N-(2E)-3-[(2S,3R)-2-(4-hydroxy-3-methoxyphenyl)- 3-(hydroxymethyl)-7-methoxy-2,3-dihydro-1-benzofuran5-yl]acryloylglycine (8), syringaldehyde (9), scoparone (10), 12,16-epoxyglobiferin (11), α-cadinol (12), trichotomol (13), and 1-(3’-methoxypropanoyl)-2,4,5-trimethoxybenzene (14) were also isolated. The structures of all compounds were elucidated by an extensive analysis of spectroscopic data (infrared (IR), nuclear magnetic resonance (NMR), and high-resolution electrospray ionization mass spectrometry (HRESIMS)). The non-cyanogenic cyanoglycosides (1-6) were screened for their α-glucosidase inhibitory activities. None of the compounds exhibited antioxidant or xanthine oxidase activity. Compound 3 exhibited considerable inhibitory ability on α-glucosidase, showing a halfmaximal inhibitory concentration (IC50) = 646 ± 69 µmol L-1 close to the standard acarbose (IC50 = 521 ± 23 µmol L-1), demonstrating its promising antidiabetic action.

Cannabidiol (CBD) is a phytocannabinoid which holds benefit for anxiety-related disorders. This study evaluated the effects of a lipid-based CBD nanoemulsion in anxiety- and panic-related responses. Male Wistar rats were acutely or chronically orally treated (21 days) with CBD (2.5 and 5 mg/kg, 1 mL/kg) or vehicle (1 mL/kg) and tested in the avoidance and escape tasks of the elevated T-maze (ETM) and in an open field. We quantified chronic CBD in the whole brain of the animals and evaluated FosB/deltaFosB immunoreactivity (Fos-ir) in non-serotonergic cells of the dorsal raphe (DR) and periaqueductal gray matter and in serotonergic cells of the DR. Acute CBD did not alter behavior. Chronic CBD 2.5 mg yielded (mean ± SEM) 64.25 ± 28.82 and CBD 5.0 mg 21.22 ± 6.46 ng of CBD/g of brain tissue. Chronic CBD 2.5 mg induced anxiolytic and panicolytic-like effects. Immunohistochemical results showed that chronic CBD significantly decreased Fos-ir in the lateral and dorsomedial periaqueductal gray and in the dorsal region (DRD) and ventrolateral periqueductal gray/lateral wings (lwDR) of the DR. Fos-ir in the dorsolateral periaqueductal gray was only decreased by CBD 2.5 mg. CBD increased tryptophan hydroxylase immunoreactivity in the lwDR and DRD. CBD 2.5 mg also increased tryptophan hydroxylase immunoreactivity in the ventral DR. Additionally, double immunostaining was increased in the ventrolateral periaqueductal gray/lwDR by CBD 2.5 mg. These results point to the anxiolytic- and panicolytic-like effects of a CBD lipid-based nanoemulsion and suggest that they may be related to the modulation of DR serotonin neurons.

The phytochemical study of the CH2Cl2 and EtOAc soluble fractions from the leaf ethanol extract of Athenaea velutina resulted in the isolation of the new withanolides 1-3, two of which substituted at the C-3 by a disaccharide 3β-O-[α-L-rhamnopyranosyl-(1 → 4)-β-d-glucopyranosyl], and four others previously reported (4-7). The structures of the new withanolides were elucidated by detailed interpretation of their 1D- and 2D-NMR spectra and the HRESIMS analysis. An anti-inflammatory screening was performed using the two major withanolides (1 and 2), analyzing their effects on the viability of RAW 264.7 cells and their ability to inhibit cellular nitric oxide production. While withanolide 1 exhibited pro-inflammatory activity by increasing nitrite production in LPS-stimulated macrophages, compound 2, in opposition, demonstrated anti-inflammatory action by reducing those levels.

Myracrodruon urundeuva, popularly known as ‘aroeira-do-sertão’, a large tree, with a tall trunk. Belonging to the Anacardiaceae family, it occurs in the ‘caatinga’ and dry forests of Brazil, from Ceará to the states of Paraná and Mato Grosso do Sul. The present study aimed to analyse the whitening and antioxidant activities of the aqueous extract of the leaves of Myracrodruon urundeuva (AELMU). Inhibition of the tyrosinase enzyme, as well as its copper chelating capacity and antioxidant effect were evaluated. The AELMU (at 2000 µg/mL) showed excellent inhibitory action (83.76%) on tyrosinase by chelating the copper ion while kojic acid at the same concentration inhibited 97.81%. Moreover, the extract displayed important antioxidant activity (inhibited 76,46% of the 2,2-diphenyl-1-picrylhydrazyl radical - DPPH; 49,59% of thiobarbituric acid reactive substances and 51,07% of the hydroxyl radical). Thus, the extract under study is promising for use in cosmetics, given its multifactorial action.

Ethnopharmacological relevance: Aspidosperma nitidum Benth (Apocynaceae) is a tree found in Brazil especially in the Amazonia region, known as "carapanauba", being used by indigenous and cabloco population in folk medicine in the treatment of malaria, leprosy, rheumatism, cancer, diabetes and inflammatory disorders. However, there are no scientific reports, up to now, to evidence its popular use as anti-inflammatory and healing agent. Aim of the study: This study aimed to isolate indole alkaloids, as well as investigate the safety, anti-inflammatory and healing properties of hydroethanol extract from the stem barks of Aspidosperma nitidum Benth (An). Material and methods: The compounds were isolated using diverse chromatographic methodologies and the structures were determined by extensive spectroscopic analyses. The safety was evaluated in vitro through 3-methyl-[4-5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay using murine fibroblast (3T3) and monkey kidney (Vero E6) cell lines and by the hemolytic assay, as well as, in vivo, through acute toxicity model, which the mice received a single dose of 2000 mg/kg of An, by intra-gastric (i.g.) route, and behavioral, hematological and biochemical parameters were evaluated. The anti-edematogenic effect was monitored through carrageenan-induced paw edema model, in which the rodents were treated with 50, 100 and 200 mg/kg of An by i. g., the percentage of edema (0-4 h), myeloperoxidase (MPO) and pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1 beta) levels were quantified. The anti-inflammatory activity was demonstrated through the zymosan-air-pouch model, in which the animals were treated with 50, 100 and 200 mg/kg of An by i. g, and the leukocytes number, MPO, total protein and cytokines levels were determined. In addition, the healing potential was evaluated through a skin wound model, in which the mice received 50, 100 and 200 mg/mL of An in wound area, and the wound skins were photographed and the area calculated. Results: In total, five compounds were isolated in the An, being a new 8,9-dinorneolignan glucoside and four known indole alkaloids. The MTT and hemolytic assays, in all concentrations of the extract, demonstrated not be cytotoxic. Acute toxicity model also evidenced no sign of toxicity or significant changes on the behavior, biochemical and hematological parameters after use of the extract. In the edematogenic model, the An reduced significantly the percentage of edema, as well as, the MPO and pro-inflammatory cytokines levels. The same form, An revealed to be efficient in decreasing the leukocytes migration (mainly polymorphonuclears), total proteins, MPO and cytokines concentrations in the zymosan-air-pouch assay. Moreover, the An revealed a healing effect, reducing the area of the skin wound. Conclusion: Ours results evidence in the first time, the anti-inflammatory and healing property of An, justifying its use in traditional medicine. Moreover, include cytotoxicity in vitro and acute toxicity in vivo tests, which indicate the safety of use of the extract.

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.

General anxiety disorders are among the most prevalent mental health problems worldwide. The emergence and development of anxiety disorders can be due to genetic (30-50%) or non-genetic (50-70%) factors. Despite medical progress, available pharmacotherapies are sometimes ineffective or can cause undesirable side effects. Thus, it becomes necessary to discover new safe and effective drugs against anxiety. This study evaluated the anxiolytic effect in adult zebrafish (Danio rerio) of a natural pyrroloformamide (PFD), N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, isolated from a Streptomyces sp. bacterium strain recovered from the ascidian Eudistoma vannamei. The complete structure of PFD was determined by a detailed NMR analysis, including 1H-13C and 1H-15N-HBMC data. In addition, conformational and DFT computational studies also were performed. A group of fishes (n = 6) was treated orally with PFD (0.1, 0.5 and 1.0 mg/mL; 20 μL) and subjected to locomotor activity and light/dark tests, as well as, acute toxicity 96 h. The involvement of the GABAergic and serotonergic (5-HT) systems was investigated using flumazenil (a silent modulator of GABA receptor) and 5-HT1, 5-HT2A/2C and 5-HTR3A/3B receptors antagonists, known as pizotifen, granisetron and cyproheptadine, respectively. PFD was nontoxic, reduced locomotor activity and promoted the anxiolytic effect in zebrafish. Flumazenil did not inhibit the anxiolytic effect of the PFD via the GABAergic system. This effect was reduced by a pretreatment with pizotifen and granisetron, and was not reversed after treatment with cyproheptadine. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.Communicated by Ramaswamy H. Sarma.

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 gastro-protective 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 KATP 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, fla-vonoids 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 KATP 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 KATP 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.

Five unusual kaurane diterpenes, designated as bezerraditerpenes A-E (1-5), along with six known ones (6-11), were isolated from the hexane extract of the stems of Erythroxylum bezerrae. Their structures were elucidated based on the interpretation of the NMR spectroscopy and mass spectrometry. The anti-inflammatory potential of the diterpenes 1 − 11 was screened through cellular viability and lipopolysaccharide (LPS)-induced nitric oxide (NO) production on murine macrophage-like cells RAW 264.7. Diterpene 6 (cauren-6β-ol) showed potent cytotoxicity and increased ability to inhibit NO production. Diterpenes 1 (bezerraditerpene A), 2 (bezerraditerpene B) and 8 (ent-kaur-16-ene-3β,15β-diol) exhibited the same significant anti-inflammatory activity with NO CI50 inhibition (3.21 − 3.76 µM) without cytotoxicity, in addition to decreasing the levels of pro-inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 cells. Keywords:Erythroxylum bezerrae; kaurane diterpenes; anti-inflammatory activity; X-ray crystallography.

Nanoemulsions modified with chitosan (NE-Q) or hyaluronic acid (NE-HA), developed for intraductal administration of piplartine (piperlongumine) and local breast cancer treatment, were evaluated for cytotoxic effects in vitro in 2D and 3D breast cancer models and in vivo in a chemically induced carcinogenesis model. Droplet size was lower than 100 nm, and zeta potential varied from +17.9 to -25.5 mV for NE-Q and NE-HA, respectively. Piplartine nanoencapsulation reduced its IC50 up to 3.6-fold in T-47D and MCF-7 monolayers without differences between NE-Q and NE-HA, and up to 6.6-fold in cancer spheroids. Cytotoxicity improvement may result from a more efficient NE-mediated delivery, as suggested by stronger fluorescent staining of cells and spheroids. In 1-methyl-1-nitrosourea -induced breast cancer models, intraductal administration of piplartine-loaded NE-HA inhibited breast tumor development and histological alterations. These results support the potential applicability of piplartine-loaded NE-HA for intraductal treatment of breast cancer.

Glial cells have been implicated in temporal lobe epilepsy in humans and in its models. Astrocytes are lost in several brain regions after acute seizures induced by pilocarpine and may suffer hyperplasia at subsequent time points. This study investigated the effect of N-methyl-(2S,4R)-trans-4-hydroxy-L-proline (NMP) on astrocytes exposed to cytotoxic concentrations of pilocarpine. Astrocytes were incubated with pilocarpine (half maximal inhibitory concentration (IC50)=31.86 mM) for 24 h. Afterwards, they were treated with NMP at concentrations ranging from 3.12 to 100 μg/mL for 24 h. Cell viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cytoplasmic reactive oxygen species (ROS) and mitochondrial transmembrane potential (ΔΨm) were analyzed by flow cytometry using 2',7'-dichlorofluorescein diacetate (DCFH-DA) and rhodamine-123 (Rho123), respectively. Expression of glial fibrillary acidic protein (GFAP) and voltage-dependent anion channel-1 (VDAC-1) were measured by western blot. Pilocarpine significantly decreased cell viability and mitochondrial potential and increased ROS concentration significantly by 6.7 times compared to the control. NMP concentrations ≥25 µg/mL protected astrocytes against pilocarpine-induced injury in a concentration-dependent manner. Concomitantly, NMP reduced cytoplasmic ROS accumulation to 27.3, 24.8, and 12.3% in the groups treated with 25, 50, and 100 µg/mL NMP, respectively. NMP also protected mitochondria from pilocarpine-induced depolarization. These effects were associated with improvement of pilocarpine-induced GFAP and VDAC-1 overexpression, which are important biomarkers of astrocyte dysfunction. In conclusion, the improvement of ROS accumulation, VDAC-1 overexpression, and mitochondrial depolarization are possible mechanisms of the NMP protective action on reactive astrocytes.

Metabolic diseases are increasing at staggering rates globally. The peroxisome proliferator-activated receptors (PPARα/γ/δ) are fatty acid sensors that help mitigate imbalances between energy uptake and utilization. Herein, we report compounds derived from phenolic lipids present in cashew nut shell liquid (CNSL), an abundant waste byproduct, in an effort to create effective, accessible, and sustainable drugs. Derivatives of anacardic acid and cardanol were tested for PPAR activity in HEK293 cell co-transfection assays, primary hepatocytes, and 3T3-L1 adipocytes. In vivo studies using PPAR-expressing zebrafish embryos identified CNSL derivatives with varying tissue-specific activities. LDT409 (23) is an analogue of cardanol with partial agonist activity for PPARα and PPARγ. Pharmacokinetic profiling showed that 23 is orally bioavailable with a half-life of 4 h in mice. CNSL derivatives represent a sustainable source of selective PPAR modulators with balanced intermediate affinities (EC50 ∼ 100 nM to 10 μM) that provide distinct and favorable gene activation profiles for the treatment of diabetes and obesity.