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• A new tropane alkaloid was isolated from Brazilian species Erythroxylum macrocalyx. • A tropane alkaloid ester is cytotoxic (IC 50 3.66 μg mL−1) to HepG2 cell line. • Alkaloids, triterpenes and a flavonoid have been isolated from E. macrocalyx. • A detailed X-ray crystallography analysis was carried out for a tropane alkaloid. A new tropane alkaloid 7β-acetoxy-6β-benzoyloxy-3α-hydroxytropane (1) was isolated from the twigs of Erythroxylum macrocalyx Mart. (Erythroxylaceae), along with the known substances: 6β,7β-dibenzoyloxy-3α-hydroxytropane (2), 6β,7β-dihydroxy-3α-(phenylacetoxy)tropane (3), 3α-benzoyloxy-6β,7β-dihydroxytropane (4), 6β-benzoyloxy-3α-(4-hydroxy-3,5-dimetoxybenzoyloxy)tropane (5), ombuin-3-rutinoside-5-glucoside (6), lupeol (7), taraxerol (8) and lupenone (9). Compounds 1 and 2 were also isolated from the leaves. The structures were established by analyses of 1D- and 2D-NMR and MS data, as well as by comparison with literature data for known compounds. The structure of 2 was also supported by X-ray crystallography analyses. The compounds were evaluated in vitro for their antibacterial and antiproliferative activities. Compound 5 showed high antiproliferative activity on liver hepatocellular carcinoma cells (HepG2) with IC 50 value of 3.66 μg mL−1 (8.29 μmol L-1), but no cytotoxic effect (IC 50 > 25 μg mL-1) on human lymphoblast cell line. This study reveals the potential use of 5 as prototype for the synthesis of new antiproliferative agents. [ABSTRACT FROM AUTHOR]

Purpose: The objective of the present study was to evaluate the systemic anti-inflammatory activity of the hydroalcoholic extract of the leaves of Licania rigida Benth (EHFLR) on models of systemic inflammation in mice.Methods: The quantitative chemical profiles of phenolic acids and flavonoids were performed by High-Performance Liquid Chromatography (HPLC). Systemic anti-inflammatory activity was determined from carrageenan and dextran-induced paw edema models and the animals were orally treated (p.o.) with EHFLR at doses of 25, 50, 100 mg/kg, indomethacin (10 mg/kg) for carrageenan-induced paw edema and promethazine (6 mg/kg) for dextran-induced paw edema. The possible mechanisms involved in the anti-inflammatory action of the extract were evaluated by the paw edema models induced by histamine and arachidonic acid, and by the model of carrageenan-induced peritonitis, where vascular permeability and leukocyte migration to the peritoneal cavity were evaluated.Results: The results of the HPLC identified the presence of phenolic acids and flavonoids, with chlorogenic acid (1.16%) and Caempferol (0.81%) as the main constituents. From the results, it was concluded that the extract has an LD50 ≥5000 mg/kg when administered orally in mice as this dose did not trigger deaths in any of the observed groups. EHFLR (25 mg/kg) showed a significant antiderematogenic effect on histamine and arachidonic acid-induced paw edema at the third hour of the tests, with a percentage of inhibition of 46.64% and 18.33%, respectively. The extract (25 mg/kg, p.o.) also significantly reduced vascular permeability and leukocyte migration in the peritoneal cavity.Conclusions: It is concluded that EHFLR exerts a systemic anti-inflammatory action, which seems to depend, at least in part, on the inhibition of arachidonic acid metabolism and the action of vasoactive amines. In addition, the extract reduced the leukocyte migration in the peritoneal cavity, indicating that its action may be linked to the inhibition of pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Current antiepileptic drugs can inhibit seizure occurrence but are not effective in preventing its onset. Moreover, they produce several side effects, which may impact the efficacy of the treatment. In addition, it has been stimulating the prospection of new molecules isolated from aromatic plants, with potential anticonvulsant and neuroprotective activities and less side effects. This study aimed to evaluate, though behavioural and neurochemical methodologies, the anticonvulsant, and neuroprotective effects of eucalyptol on mice subjected to the pilocarpine-induced seizure model. Eucalyptol (100, 200 and 400 mg/kg, p.o.) was administered in mice prior to pilocarpine (350 mg/kg, i.p.) and the following behavioural parameters were assessed: Latency to First Seizure (LFS), Seizure Intensity (SI) and Latency to Death (LD). In addition, an oxotremorine-induced tremors test was performed to evaluate the cholinergic system involvement on the eucalyptol effects. Neurochemical tests were also performed, including determination of hippocampal (HC) concentration of thiobarbituric acid reactive substances (TBARS) and nitrite/nitrate and striatal (ST) concentration of noradrenaline, dopamine, and serotonin. Lastly, histopathological, and morphometric hippocampal analysis were conducted. Eucalyptol increased the latency to first seizure and latency to death, inhibited oxotremorine-induced tremors, decreased hippocampal TBARS and nitrite/nitrate overproduction, increased striatal noradrenaline and dopamine levels and prevented hippocampal neurodegeneration. These results demonstrate the potential anticonvulsant, neuroprotective and antioxidant effects of eucalyptol, probably through a conjunction of mechanisms including muscarinic cholinergic antagonism, oxidative stress mitigation and the monoaminergic system modulation, which appears to effectively control the seizure onset. [ABSTRACT FROM AUTHOR]

Background: Remirea maritima has been widely used in the treatment of diarrhea, kidney disease, and high fever and for therapeutic purposes, such as an analgesic and anti-inflammatory. However, few scientific research studies on its medicinal properties have been reported.Purpose: The present study aimed to investigate the anticancer potential of aqueous extract (AE), 40% hydroalcoholic extracts (40HA) and 70% (70HA) from R. maritima in experimental models and to identify its phytochemical compounds.Methods: The chemical composition of AE, 40HA and 70HA was assessed by HPLC-DAD and ESI-IT-MS/MS. In vitro activity was determined on cultured tumor cell, NCI-H385N (Broncho-alveolar carcinoma), OVCAR-8 (Ovarian carcinoma) and PC-3M (prostate carcinoma) by the MTT assay, and the in vivo antitumor activity was assessed in Sarcoma 180-bearing mice. Toxicological parameters were also evaluated as well as the humoral immune response.Results: Among the aqueous and hydroalcoholic extracts of R. maritima, only 40HA showed in vitro biological effect potential, presenting IC50 values of 27.08, 46.62 and >50µg/ml for OVCAR-8, NCI-H385M and PC-3M cells lines, respectively. Regarding chemical composition, a mixture of isovitexin-2''-O-β-D-glucopyranoside, vitexin-2''-O-β-D-glucopyranoside, luteolin-7-O-glucuronide and 1-O-(E)-caffeoyl-β-D-glucose were identified as the major phytochemical compounds of the extracts. In the in vivo study, the tumor inhibition rates were 57.16-62.57% at doses of 25mg/kg and 50mg/kg, respectively, and the tumor morphology presented increasing numbers of apoptotic cells. Additionally, 40HA also demonstrated significantly increased of OVA-specific total Ig.Conclusions: 40HA exhibited in vitro and in vivo anticancer properties without substantial toxicity that could be associated with its immunostimulating properties. [ABSTRACT FROM AUTHOR]

This study aims to investigate the toxicity and possible effects and mechanism of action of the essential oil obtained from the Piper tuberculatum Jacq.'s fruit (EOPT) on the central nervous system (CNS) of mice. In the Hippocratic test, it was observed ambulation reduction, sedation, piloerection and mortality of 25% at the dose of 1000 mg/kg and 50% at the dose of 5000 mg/kg. The results found demonstrate that the EOPT is endowed with a possible depressant effect, and is characterized by a likely sedative (open field test), anxiolytic-like (elevated plus maze test), anticonvulsant (pentylenetetrazole-induced seizure test) and hypnotic action (pentobarbital-induced sleeping time). These effects may possibly occur due to the interaction between the monoterpenes, present in its essential oil, and the GABAergic pathway confirmed by reversion of the effects by flumazenil. Then, these results demonstrate the therapeutic potential and the validation of the ethnopharmacological use of this species in the treatment of disorders affecting the central nervous system. [ABSTRACT FROM AUTHOR]

Medicinal plants are one of the most important sources of drugs used in the pharmaceutical industry. Among traditional medicinal plants, Lippia gracilis Schauer (Verbenaceae) had been used for several medicinal purposes in Brazilian northeastern. In this study, leaf essential oil (EO) of L. gracilis was prepared using hydrodistillation. Followed by GC-MS analysis, its composition was characterized by the presence of thymol (55.50%), as major constituent. The effects of EO on cell proliferation and apoptosis induction were investigated in HepG2 cells. Furthermore, mice bearing Sarcoma 180 tumor cells were used to confirm its in vivo effectiveness. EO and its constituents (thymol, p-cymene, [gamma]-terpinene and myrcene) displayed cytotoxicity to different tumor cell lines. EO treatment caused G1 arrest in HepG2 cells accompanied by the induction of DNA fragmentation without affecting cell membrane integrity. Cell morphology consistent with apoptosis and a remarkable activation of caspase-3 were also observed, suggesting induction of caspase-dependent apoptotic cell death. In vivo antitumor study showed tumor growth inhibition rates of 38.5-41.9%. In conclusion, the tested essential oil of L. gracilis leaves, which has thymol as its major constituent, possesses significant in vitro and in vivo antitumor activity. These data suggest that leaf essential oil of L. gracilis is a potential medicinal resource. [ABSTRACT FROM AUTHOR]

Abstract: (+)-Cordiaquinone J is a 1,4-naphthoquinone isolated from the roots of Cordia leucocephala that has antifungal and larvicidal effects. However, the cytotoxic effects of (+)-cordiaquinone J have never being explored. In the present study, the effect of (+)-cordiaquinone J on tumor cells viability was investigated, showing IC50 values in the range of 2.7–6.6μM in HL-60 and SF-295 cells, respectively. Studies performed in HL-60 leukemia cells indicated that (+)-cordiaquinone J (1.5 and 3.0μM) reduces cell viability and 5-bromo-2-deoxyuridine incorporation after 24h of incubation. (+)-Cordiaquinone J showed rapid induction of apoptosis, as indicated by phosphatidylserine externalization, caspase activation, DNA fragmentation, morphologic changes, and rapid induction of necrosis, as indicated by the loss of membrane integrity and morphologic changes. (+)-Cordiaquinone J altered the redox potential of cells by inducing the depletion of reduced GSH intracellular content, the generation of reactive oxygen species and the loss of mitochondrial membrane potential. However, pre-treatment of cells with N-acetyl-l-cysteine abolished most of the observed effects related to (+)-cordiaquinone J treatment, including those involving apoptosis and necrosis induction. [Copyright &y& Elsevier]

Objectives: We aimed to evaluate the relationship between social distancing, stroke admissions and stroke mortality during the COVID-19 pandemic, while accounting for the rate of COVID-19 admissions.Methods: We performed a longitudinal analysis of a multicenter, prospective, hospital-based registry of intensive care units from 19 hospitals from Brazil, comprising a 14-month period of the COVID-19 pandemic. We investigated whether the daily rate of admissions (DRAstroke) and daily mortality rate for stroke were associated with the social distancing index (SDI), taking into account the daily rate of admissions for COVID-19 (DRACOVID) in univariate and multivariate regression models. We also compared the clinical characteristics of patients with stroke admitted before and during the pandemic.Results: We found that DRAstroke decreased significantly in association with a strong rise in the SDI during the early months of the pandemic. However, in the latter period of the pandemic, only minor changes were observed in the SDI, and still, DRAstroke was inversely associated with the DRACOVID. Throughout the pandemic, higher SDI and DRACOVID were associated with higher in-hospital mortality for stroke.Conclusions: The severity of surges of the COVID-19 pandemic were independently and persistently associated with declines in stroke admissions, even during periods when social distancing policies were not intensified. [ABSTRACT FROM AUTHOR]

Background: Oncological pain is one of the most prevalent and difficult-to-treat symptoms in patients with cancer. p-Cymene (PC) is a monoterpene found in more than 100 different plant species, endowed with various pharmacological properties-particularly antinociceptive.Hypothesis/purpose: PC has antinociceptive effect in a model of oncologic pain due to the activation of the descending inhibitory pathway of pain.Study Design: A pre-clinical, longitudinal, blind and randomized study.Methods: Male Swiss mice were induced with S180 cells in the right hind paw, then treated daily with PC (12.5, 25 and 50 mg/kg, s.c.) and screened for mechanical hyperalgesia, spontaneous nociception, nociception induced by non-noxious palpation, tumor growth, changes in the neuromuscular function and existence of bone degradation in the tumor area. The effect of PC on Ca2+ currents (electrophysiological records), histological and neurochemical changes (immunofluorescence for Fos) were also evaluated.Results: PC reduced (p < 0.05) the mechanical hyperalgesia, the spontaneous (p < 0.001) and non-noxious palpation (p < 0.001) nociceptions, not changing the tumor development, neuromuscular function or histopathological aspects of the paw affected. PC reduced Fos expression in the spinal cord (p < 0.001) and increased this expression in the PAG (p < 0.05) and in the NRM (p < 0.01). PC decreased the density of calcium channel currents (p < 0.05).Conclusion: These results suggest the antinociceptive effect of PC on oncologic pain, probably acting in both ascending and descending pain pathways, and modulating the calcium channel currents in order to exert its effects. [ABSTRACT FROM AUTHOR]

Abstract: (4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) belongs to the phenstatin family. This compound has been studied due to its potent cytotoxicity and ability to inhibit tubulin assembly. The present study aimed to evaluate the mutagenic potential of PHT in human lymphocytes. PHT displayed cytotoxicity in human lymphocytes with an IC50 value of 5.68μM, and therefore, concentrations of 0.25, 0.5, 1.0, 2.0, and 4.0μM were used for all protocols. The alkaline comet assay and chromosome aberration (CA) analysis were performed in different phases of the cell cycle (G1, G1/S, transition, and G2), to evaluate the DNA-damaging and clastogenic effects of PHT, respectively. CA analysis was carried out in the presence or absence of colchicine to evaluate the action of PHT in the mitotic phase. PHT was cytotoxic and significantly reduced the mitotic index with drug exposure in all phases of cell cycle. Interestingly, it induced an increase in mitotic index in experimental protocols without colchicine, corroborating its action as an antitubulin agent. It also induced DNA damage and was clastogenic with drug exposure in all phases of the cell cycle, in the presence or absence of colchicine. In conclusion, PHT induces DNA damage and exerts clastogenic effects in human lymphocytes. [Copyright &y& Elsevier]

Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF 6 , to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs. [Display omitted] • RCT exhibits potent cytotoxicity to solid and haematological cancer cells. • RCT causes elimination of hepatic CSCs from HCC HepG2 cells. • RCT inhibits HCC HepG2 cell motility. • RCT suppresses Akt/mTOR signalling in HCC HepG2 cells. • RCT induces apoptotic and autophagic cell death in HCC HepG2 cells. [ABSTRACT FROM AUTHOR]

Abstract Carvacrol, a phenolic monoterpene derived from thyme oil has gained wide interest recently because of its anticancer activities. To improve the solubility of carvacrol, the formation of inclusion complexes with β-cyclodextrin was performed by ultrasound and freeze-drying methods and characterized using thermal analysis, FTIR, XRD, SEM, NMR and HPLC analysis. From these results, carvacrol was successfully complexed within β-cyclodextrin cavity. Moreover, HPLC analysis demonstrated a higher entrapment efficiency for freeze-drying method (81.20 ± 0.52%) in contrast to ultrasound method (34.02 ± 0.67%). Hence, freeze-drying inclusion complex was evaluated for its antiproliferative effect and cytotoxicity against prostate cancer cell line (PC3) in vitro. Further, freeze-drying complex led to a dose-dependent inhibition in tumor cell growth in 2D and 3D cell culture systems. Altogether, the inclusion of carvacrol in β-cyclodextrin led to the formation of stable complexes with potent antiproliferative effects against PC3 cells, in vitro. Such an improved cytotoxic effect can be attributed to the enhanced the aqueous solubility and bioavailability of carvacrol by effective complexation in β-cyclodextrin. Graphical abstract Image 1 Highlights • CARV/β-CD complexes have been developed to improve the anticancer activity. • The FD method showed high efficiency in the formation of inclusion complexes. • FD complexes enhanced in vitro anticancer activity and cytotoxicity against PC3. • FD complex also reduced the cell viability of PC3 encapsulated in GelMA hydrogels. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Salacia impressifolia (Miers) A. C. Smith (family Celastraceae) is a traditional medicinal plant found in the Amazon Rainforest known as "miraruíra", "cipó-miraruíra" or "panu" and is traditionally used to treat dengue, flu, inflammation, pain, diabetes, male impotency, renal affections, rheumatism and cancer. Aim of the study: The aim of this study was to investigate in vitro and in vivo anti-leukemia activity of the stem bark of S. impressifolia in experimental models. Materials and methods: The in vitro cytotoxic activity of extracts, fractions and quinonemethide triterpenes (22-hydroxytingenone, tingenone and pristimerin) from the stem bark of S. impressifolia in cultured cancer cells was determined. The in vivo antitumor activity of the ethyl acetate extract (EAE) and of its fraction (FEAE.3) from the stem bark of S. impressifolia was assessed in C.B-17 severe combined immunodeficient (SCID) mice engrafted with human promyelocytic leukemia HL-60 cells. Results: The extract EAE, its fraction FEAE.3, and quinonemethide triterpenes exhibited potent cytotoxicity against cancer cell lines, including in vitro anti-leukemia activity against HL-60 and K-562 cells. Moreover, extract EAE and its fraction FEAE.3 inhibited the in vivo development of HL-60 cells engrafted in C.B-17 SCID mice. Tumor mass inhibition rates were measured as 40.4% and 81.5% for the extract EAE (20 mg/kg) and for its fraction FEAE.3 (20 mg/kg), respectively. Conclusions: Ethyl acetate extract and its fraction from the stem bark of S. impressifolia exhibit in vitro and in vivo anti-leukemia activity that can be attributed to their quinonemethide triterpenes. These data confirm the ethnopharmacological use of this species and may contribute to the development of a novel anticancer herbal medicine. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

The chemical composition of V. pyrantha resin (VpR) and fractions (VpFr1–7 and VpWS) were assessed by LC-MS and NMR. Twenty-eight metabolites were identified, including 16 diterpenoids, seven nor-diterpenoids, one fatty acid, one bis-diterpenoid, one steroid, one flavonoid, and one triterpenoid. The pharmacological potential of VpR, VpFr1–7, and isolated compounds was assessed by determining their antioxidant, antimicrobial, and cytotoxic activities. VpFr4 (IC 50 = 205.48 ± 3.37 μg.mL−1) had the highest antioxidant activity, whereas VpFr6 (IC 50 = 842.79 ± 10.23 μg.mL−1) had the lowest. The resin was only active against Staphylococcus aureus (MIC 62.5 μg.mL−1) and Salmonella choleraesius (MIC and MFC 500 μg.mL−1), but fractions were enriched with antibacterial compounds. V. pyrantha resin and fractions showed great cytotoxic activity against HCT116 (IC 50 = 20.08 μg.mL−1), HepG2 (IC 50 = 20.50 μg.mL−1), and B16-F10 (12.17 μg.mL−1) cell lines. Multivariate statistical analysis was used as a powerful tool to pinpoint possible metabolites responsible for the observed activities. [Display omitted] [ABSTRACT FROM AUTHOR]

Cyclodextrins (CDs) have been used as important pharmaceutical excipients for improve the physicochemical properties of the drugs of low solubility as the essential oil of Hyptis martiusii. This oil is important therapeutically, but the low solubility and bioavailability compromises your use. Therein, the aim of this study was to obtain and to characterize physico-chemically the samples obtained by physical mixture (PM), paste complexation (PC) and slurry complexation (SC) of the essential oil Hyptis martiusii (EOHM) in β-CD, and to compare the antibacterial and modulatory-antibiotic activity of products obtained and oil free. The physicochemical characterization was performed by differential scanning calorimetry (DSC), thermogravimetry/derivative thermogravimetry (TG/DTG), scanning electron microscopy (SEM), X-ray diffraction (XRD) and Karl Fischer titration. Additionally, the antibacterial tests were performed by microdilution technique. Thus, it was observed that the PM method showed low complexing capacity, unlike PC and SC in which it was observed the formation of inclusion complexes. In addition, the second stage of the TG/DTG curves showed that SC was the best method inclusion with mass loss of 6.9% over the PC that was 6.0%. The XRD results corroborate with the results above suggesting the formation of new solid phase and the SEM photomicrographs showed the porous surface of the samples PC and SC. The essential oil alone demonstrated an antibacterial and modulatory effect against the S. aureus and the Gram negative strain, respectively. However, the β-CD and the inclusion complex did not demonstrate any biological activity in the performed antibacterial assays. [ABSTRACT FROM AUTHOR]

Heteroleptic Cu(II) complexes with monoanionic 2-hydroxybenzophenones and diimines interact with DNA that may be a possible target to their cytotoxic against tumor cells, such as HCT116 and HepG2. [Display omitted] Here, we report four new heteroleptic Cu(II) complexes with the formula [Cu(bipy)(2H4MeBz)]NO 3 (1), [Cu(phen)(2H4MeBz)]NO 3 (2), [Cu(bipy)(2H4OcBz)]NO 3 (3) and [Cu(phen)(2H4OcBz)]NO 3 (4), where the ligands are 2-hydroxy-4-methoxybenzophenone (2H4MeBz), 2-hydroxy-4-(octyloxy)benzophenone (2H4OcBz), 2,2′-bipiridine (bipy) and 1,10-phenantroline (phen). All compounds present two bidentate ligands, a monoanionic 2-hydroxybenzophenone, forming a six-membered chelate ring and the diiminic ring forming a five-membered chelate ring, as well as one nitrate as counterion located at the axial position, as suggested by the crystal structure of complex 2. Complex/DNA interaction studies were also performed using spectroscopic titration (K b close to 104 M−1), viscosity, Hoechst 33258 competition, and circular dichroism, revealing a moderate interaction between them. Additionally, complexes 1 – 4 moderately interact with BSA (Bovine Serum Albumin). The compounds were evaluated against HCT116 (human colon carcinoma) and HepG2 (human hepatocellular carcinoma) cancer cells and against MRC-5 (human lung fibroblast), a noncancer cells. The cytotoxic results suggest that complexes 2 and 4 are more cytotoxic than 1 and 3 , showing that the presence of phen ligand may play an important role in increasing the biological effect of the compounds. [ABSTRACT FROM AUTHOR]

Aims The present study evaluated the carvacrol (CARV) effect on hyperalgesia and nociception induced by sarcoma 180 (S180) in mice. Main methods Carvacrol treatment (12.5–50 mg/kg s.c.) once daily for 15 days was started 24 h after injection of the sarcoma cells in the hind paw (s.c.). Mice were evaluated for mechanical sensitivity (von Frey), spontaneous and palpation-induced nociception, limb use and tumor growth on alternate days. CARV effects on the central nervous system were evaluated through immunofluorescence for Fos protein. Molecular docking studies also were performed to evaluate intermolecular interactions of the carvacrol and muscimol, as ligands of interleukin-10 and GABA A receptors. Key findings CARV was able to significantly reduce mechanical hyperalgesia and spontaneous and palpation-induced nociception, improve use paw, decrease the number of positively marked neurons in lumbar spinal cord and activate periaqueductal gray, nucleus raphe magnus and locus coeruleus . CARV also caused significant decreased tumor growth. Docking studies showed favorable interaction overlay of the CARV with IL-10 and GABA A. Significance Together, these results demonstrated that CARV may be an interesting option for the development of new analgesic drugs for the management of cancer pain. [ABSTRACT FROM AUTHOR]

This work describes a novel ent -kaurane diterpene, ent -3β-hydroxy-kaur-16-en-19-al along with five known ent -kaurane diterpenes, ent -3β,19-dihydroxy-kaur-16-eno, ent -3β-hydroxy-kaur-16-eno, ent -3β-acetoxy-kaur-16-eno, ent -3β-hydroxy-kaurenoic acid and kaurenoic acid, as well as caryophyllene oxide, humulene epoxide II, β-sitosterol, stigmasterol and campesterol from the stem bark of Annona vepretorum Mart. (Annonaceae). Cytotoxic activities towards tumor B16-F10, HepG2, K562 and HL60 and non-tumor PBMC cell lines were evaluated for ent -kaurane diterpenes. Among them, e nt -3β-hydroxy-kaur-16-en-19-al was the most active compound with higher cytotoxic effect over K562 cell line (IC 50 of 2.49 μg/mL) and lower over B16-F10 cell line (IC 50 of 21.02 μg/mL). [ABSTRACT FROM AUTHOR]

Highlights: [•] The essential oil contains (E)-caryophyllene as its major component. [•] The essential oil displays cytotoxicity to tumour cell lines. [•] The essential oil possesses in vivo antitumour action. [ABSTRACT FROM AUTHOR]

Abstract: Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Himatanthus drasticus (Mart.) Plumel – Apocynaceae is a medicinal plant popularly known as Janaguba. Its bark and latex have been used by the public for cancer treatment, among other medicinal uses. However, there is almost no scientific research report on its medicinal properties. Aim of the study: The aim of this study was to investigate the antitumor effects of Himatanthus drasticus latex proteins (HdLP) in experimental models. Materials and methods: The in vitro cytotoxic activity of the HdLP was determined on cultured tumor cells. HdLP was also tested for its ability to induce lysis of mouse erythrocytes. In vivo antitumor activity was assessed in two experimental models, Sarcoma 180 and Walker 256 carcinosarcoma. Additionally, its effects on the immunological system were also investigated. Results: HdLP did not show any significant in vitro cytotoxic effect at experimental exposure levels. When intraperitoneally administered, HdLP was active against both in vivo experimental tumors. However, it was inactive by oral administration. The histopathological analysis indicates that the liver and kidney were only weakly affected by HdLP treatment. It was also demonstrated that HdLP acts as an immunomodulatory agent, increasing the production of OVA-specific antibodies. Additionally, it increased relative spleen weight and the incidence of megakaryocyte colonies. Conclusion: In summary, HdLP has some interesting anticancer activity that could be associated with its immunostimulating properties. [ABSTRACT FROM AUTHOR]

Abstract: Ten α-santonin derivatives were synthesized in moderate to high yields. Four derivatives namely 10α-acetoxy-3-oxo-1,7αH,6,11βH-guai-4-en-6,12-olide (2), isofotosantonic acid (3), 10α-hydroxy-3-oxo-1,7αH,6,11βH-guai-4-en-6,12-olide (4), and lumisantonin (5), were prepared by different photochemical reactions using α-santonin (1) as starting material. These transformations were carried out in either anhydrous acetic acid, acetic acid/water (1:1 v/v) or acetonitrile, using different types of reactors and ultraviolet light sources. Treatment of α-santonin (1) with lithium diisopropyl amide (LDA) followed by capture of the organolithium with phenyl selenium chloride produced the compound 3-oxo-7αH,6βH,11-(phenylselenyl)-eudesma-1,4-dien-6,12-olide (6). Subsequent treatment of compound 6 with hydrogen peroxide gave 3-oxo-7αH,6βH-eudesma-1,4,11-trien-6,12-olide (7). Photochemical reaction of compound 7 led to the formation of 11,13-dehydrolumisantonin (8) and 10α-acetoxy-3-oxo-1,7αH,6βH-guai-4,11-dien-6,12-olide (9). Sodium borohydride reduction of compounds 2 and 4 afforded the derivatives 10α-acetoxy-3β-hydroxy-1,7αH,6,11βH-guai-4-en-6,12-olide (10) and 3β,10α-hydroxy-1,7αH,6,11βH-guai-4-en-6,12-olide (11). The cytotoxicity of the synthesized compounds were evaluated against the cancer cell lines HL-60 (leukemia), SF-295 (central nervous system), HCT-8 (colon), MDA-MB-435 (melanoma), UACC-257 (melanoma), A549 (lung), OVACAR-8 (ovarian), A704 (renal), and PC3 (prostate). The compounds with higher activity, possessing IC50 values in the range of 0.36–14.5μM, showed as common structural feature the presence of an α-methylidene-γ-butyrolactone moiety in their structures. The biological assays conducted with normal cells (PBMC) revealed that the compounds are selective against cancer cell lines. The modified lactones seem to be interesting lead structures towards anticancer drug development. [Copyright &y& Elsevier]

Acute myeloid leukemia (AML) is the most lethal form of leukemia. Standard anti-AML treatment remains almost unchanged for decades. Tingenone (TG) and 22-hydroxytingenone (22-HTG) are quinonemethide triterpenes found in the Amazonian plant Salacia impressifolia (Celastraceae), with cytotoxic properties in different histological types of cancer cells. In the present work, we investigated the anti-AML action mechanism of TG and 22-HTG in the AML HL-60 cell line. Both compounds exhibited potent cytotoxicity in a panel of cancer cell lines. Mechanistic studies found that TG and 22-HTG reduced cell growth and caused the externalization of phosphatidylserine, the fragmentation of internucleosomal DNA and the loss of mitochondrial transmembrane potential in HL-60 cells. In addition, pre-incubation with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, prevented TG- and 22-HTG-induced apoptosis, indicating cell death by apoptosis via a caspase-dependent pathway. The analysis of the RNA transcripts of several genes indicated the interruption of the cellular antioxidant system, including the downregulation of thioredoxin , as a target for TG and 22-HTG. The application of N -acetyl-cysteine, an antioxidant, completely prevented apoptosis induced by TG and 22-HTG, indicating activation of the apoptosis pathway mediated by oxidative stress. Moreover, TG and 22-HTG induced DNA double-strand break and phosphorylation of JNK2 (T183/Y185) and p38α (T180/Y182), and co-incubation with SP 600125 (JNK/SAPK inhibitor) and PD 169316 (p38 MAPK inhibitor) partially prevented apoptosis induced by TG and 22-HTG. Together, these data indicate that TG and 22-HTG are new candidate for anti-AML therapy targeting thioredoxin. • TG and 22-HTG induce caspase-mediated apoptotic cell death. • TG and 22-HTG target oxidative stress through downregulation of thioredoxin. • TG and 22-HTG cause DNA damage. • TG and 22-HTG cause JNK/p38-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Virola surinamensis (Rol. ex Rottb.) Warb. (Myristicaceae), popularly known in Brazil as "mucuíba", "ucuúba", "ucuúba-branca" or "ucuúba do igapó", is a medicinal plant used to treat a variety of diseases, including infections, inflammatory processes and cancer. In the present work, we investigated the chemical constituents and the in vitro and in vivo inhibition of human colon carcinoma HCT116 cells by essential oils obtained from the bark (EOB) and leaves (EOL) of V. surinamensis. EOB and EOL were obtained by hydrodistillation and analyzed via gas chromatography with flame ionization detection and gas chromatography coupled to mass spectrometry. In vitro cytotoxic activity was determined in cultured cancer cells HCT116, HepG2, HL-60, B16–F10 and MCF-7 and in a non-cancerous cell line MRC-5 by the Alamar blue assay after 72 h of treatment. Annexin V/propidium iodide staining, mitochondrial transmembrane potential and cell cycle distribution were evaluated by flow cytometry in HCT116 cells treated with essential oils after 24 and 48 h of treatment. The cells were also stained with May-Grunwald-Giemsa to analyze cell morphology. In vivo antitumor activity was evaluated in C.B-17 SCID mice with HCT116 cells. The main constituents in EOB were aristolene (28.0 ± 3.1%), α-gurjunene (15.1 ± 2.4%), valencene (14.1 ± 1.9%), germacrene D (7.5 ± 0.9%), δ-guaiene (6.8 ± 1.0%) and β-elemene (5.4 ± 0.6%). On the other hand, EOL displayed α-farnesene (14.5 ± 1.5%), β-elemene (9.6 ± 2.3%), bicyclogermacrene (8.1 ± 2.0%), germacrene D (7.4 ± 0.7%) and α-cubebene (5.6 ± 1.1%) as main constituents. EOB showed IC 50 values for cancer cells ranging from 9.41 to 29.52 μg/mL for HCT116 and B16–F10, while EOL showed IC 50 values for cancer cells ranging from 7.07 to 26.70 μg/mL for HepG2 and HCT116, respectively. The IC 50 value for a non-cancerous MRC-5 cell was 34.7 and 38.93 μg/mL for EOB and EOL, respectively. Both oils induced apoptotic-like cell death in HCT116 cells, as observed by the morphological characteristics of apoptosis, externalization of phosphatidylserine, mitochondrial depolarization and fragmentation of internucleosomal DNA. At a dose of 40 mg/kg, tumor mass inhibition rates were 57.9 and 44.8% in animals treated with EOB and EOL, respectively. These data indicate V. surinamensis as possible herbal medicine in the treatment of colon cancer. Image 1 [ABSTRACT FROM AUTHOR]

Conobea scoparioides (Cham. & Schltdl.) Benth. (syn. Sphaerotheca scoparioides Cham. & Schldtl.) (Plantaginaceae), popularly known as "pataqueira", "vassourinha-do-brejo" and/or "hierba-de-sapo", is a popular medicinal plant used to treat leishmaniasis, pain and beriberi. In addition, inhibition of cell adhesion, antioxidant, cytotoxic and leishmanicidal activities of compounds or fractions of C. scoparioides have been reported. In the present work, chemical constituents and in vitro and in vivo anti-liver cancer potential of essential oil (EO) from leaves of C. scoparioides were investigated using human hepatocellular carcinoma HepG2 cells as a cell model. EO was obtained by hydrodistillation using a Clevenger-type apparatus and characterized by GC–MS and GC–FID. The in vitro cytotoxic effect was evaluated on three human cancer cell lines (MCF-7, HepG2 and HCT116) and one human non-cancerous cell line (MRC-5) using the Alamar blue assay. Phosphatidylserine externalization and cell cycle distribution were quantified in HepG2 cells by flow cytometry after 48 h incubation. The effectiveness of EO in anti-liver cancer model was studied with HepG2 cells grafted on C.B. 17 SCID mice. The main constituents of EO were thymol methyl ether (62 %), thymol (16 %) and α -phellandrene (14 %). EO displayed an in vitro cytotoxic effect against all human cancer cell lines and caused externalization of phosphatidylserine and DNA fragmentation in HepG2 cells, suggesting induction of apoptotic-like cell death. In vivo tumor mass inhibition of 36.7 and 55.8 % was observed for treatment with EO at doses of 40 and 80 mg/kg, respectively. These results indicate in vitro and in vivo anti-liver cancer potential of EO from leaves of C. scoparioides. [ABSTRACT FROM AUTHOR]

Guatteria megalophylla Diels (Annonaceae) is an 8−10 m tall tree that grows near streams and is widely spread throughout Colombian, Ecuadorian, Peruvian, Brazilian and Guianese Amazon rainforest. Herein, we investigated for the first time the chemical composition and in vitro and in vivo anti-leukemia potential of G. megalophylla leaf essential oil (EO) using human promyelocytic leukemia HL-60 cells as model. EO was obtained by a hydrodistillation clevenger-type apparatus and characterized quali- and quantitatively by GC–MS and GC–FID, respectively. In vitro cytotoxic potential of EO was evaluated in human cancer cell lines (HL-60, MCF-7 CAL27, HSC-3, HepG2 and HCT116) and in human non-cancer cell line (MRC-5) by Alamar blue method. Annexin V/propidium iodide staining, cell cycle distribution and reactive oxygen species (ROS) were assessed by flow cytometry for HL-60 cells treated with EO. In vivo efficacy of EO (50 and 100 mg/kg) was evaluated in C.B-17 SCID mice with HL-60 cell xenografts. Chemical composition analyses showed spathulenol, γ -muurolene, bicyclogermacrene, β -elemene and δ -elemene as main constituents of assayed sample. EO displayed in vitro cytotoxicity, including anti-leukemia effect with IC 50 value of 12.51 μg/mL for HL-60 cells. EO treatment caused augment of phosphatidylserine externalization and DNA fragmentation without increasing of ROS in HL-60 cells. In vivo tumor mass inhibition rates of EO was 16.6–48.8 %. These data indicate anti-leukemia potential of G. megalophylla leaf EO. [ABSTRACT FROM AUTHOR]

We report on chemistry and cytotoxic studies of four new ruthenium (II) complexes containing uracil derivatives. All compounds are neutral, presenting the formula [Ru(PPh 3) 2 (2TU) 2 ] (1), [Ru(PPh 3) 2 (6m2TU) 2 ] (2), [Ru(dppb)(2TU) 2 ] (3) and [Ru(dppb)(6m2TU) 2 ] (4), where PPh 3 = triphenylphosphine; dppb = 1,4- bis (diphenylphosphino)butane, 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil. They were characterized using NMR, UV–vis and IR spectroscopies, microanalytical analysis and mass spectrometry. Furthermore, the crystal structures of 1 – 4 were determined by single-crystal X-ray diffraction. The coordination of 2-thiouracil derivatives with ruthenium increases regions able to carry out hydrogen bonds with the biological targets, such as DNA. We evaluated the interaction of the complexes with DNA by UV/Vis spectrophotometric titration, and as a result, the values of DNA-binding constants are in the range of 0.8–1.8 × 104 M−1. Moreover, the interaction of the complexes with BSA was investigated. In vitro , activities against B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), HL-60 (human promyelocytic leukemia) and K562 (human chronic myelocytic leukemia) and non-tumor cells: PBMC (human peripheral blood mononuclear cells activated with concanavalin A – human lymphoblast) were carried out. Cytotoxicity assays revealed that complexes (2) and (4) present biological activity against tumor cells comparable with oxaliplatin, the reference platinum drug, revealing that they are promising molecules for developing new antitumor compounds. Uracil nucleobase analogs were used as key building blocks to form new cytotoxic agents based on Ru(II). These compounds are promising for anticancer treatment. Unlabelled Image • Synthesis of four Ru(II) complexes with thiouracil • The compounds are bioactives against tumor cells. • The complexes present ability to form strong hydrogen bonds. • The internucleosomal DNA fragmentation and cell cycle distribution was studied. [ABSTRACT FROM AUTHOR]