Xanthones and Cancer: from Natural Sources to Mechanisms of Action.

Xanthones are a class of heterocyclic natural products that have been widely studied for their pharmacological potential. In fact, they have been serving as scaffolds for the design of derivatives focusing on drug development. One of the main study targets of xanthones is their anticancer activity. Several compounds belonging to this class have already demonstrated cytotoxic and antitumor effects, making it a promising group for further exploration. This review therefore focuses on recently published studies, emphasizing their natural and synthetic sources and describing the main mechanisms of action responsible for the anticancer effect of promising xanthones.

Effects of 1,3,5-triphenyl-4,5-dihydro-1H-pyrazole derivatives on cell-cycle and apoptosis in human acute leukemia cell lines.

Pyrazoline is an important 5-membered nitrogen heterocycle that has been extensively researched. Ten derivatives were synthesized and tested for antileukemic effects on 2 human acute leukemia cell lines, K562 and Jurkat. The most cytotoxic of these derivatives, compound 21, was chosen for investigation of cytotoxicity mechanisms. The results obtained with selectivity calculations revealed that compound 21 is more selective for acute leukemia (K562 and Jurkat cell lines) than for other tumor cell lines. Moreover, compound 21 was not cytotoxic to normal cell lines, indicating a potential use in clinical tests. Compound 21 caused a significant cell cycle arrest in the S-phase in Jurkat cells and increased the proportion of cells in the sub G0/G1 phase in both cell lines. Cells treated with compound 21 demonstrated morphological changes characteristic of apoptosis in the EB/AO assay, confirmed by externalization of phosphatidylserine by the annexin V - fluorescein isothiocyanate method and by DNA fragmentation. An investigation of cytotoxicity mechanisms suggests the involvement of an intrinsic apoptosis pathway due to mitochondrial damage and an increase in the ratio of mitochondrial Bax/Bcl2. Pyrazoline 21 obeyed Lipinski's "rule of five" for drug-likeness. Based on these preliminary results, the antileukemic activity of compound 21 makes it a potential anticancer agent.

Antiproliferative effect of synthetic cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) against human cancer cell lines.

This work describes the antiproliferative potential of 14 cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) against several human cancer cell lines. The antiproliferative effect was evaluated using the sulforhodamine B assay. Although some compounds from methylphtalimide and carboxylic acid phtalimide classes exhibited a selective antiproliferative activity, the itaconimides (11-14) exhibited the best results, especially compound 14, which presented a TGI (concentration that produces total growth inhibition) value of 0.0043 µM against glioma (U251), being inactive against the non-tumor cell line (HaCat). Absorption, distribution, metabolism and excretion in silico evaluations suggest that these compounds are promising candidates.

In vitro antiproliferative activity of uncommon xanthones from branches of Garcinia achachairu.

Context Garcinia achachairu Rusby (Clusiaceae) popularly known as 'achachairu' is used in folk medicine to treat rheumatism, inflammation, pain and gastric disorder. Objective The present study investigated the chemical profile and antiproliferative effects of the methanolic extract, fractions and two xanthones, against some carcinoma cell lines in vitro. Materials and methods The compounds were isolated and identified by chromatographic and spectroscopic methods. The extract, fractions and compounds were tested human tumour cell lines of U-251 (glioma), MCF-7 (breast), NCI/ADR-RES (ovary expressing multi-drug resistance phenotype), 786-0 (kidney), NCI-H460 (lung, non-small cells), PC-3 (prostate) and HT-29 (colon), non-tumour cell line HaCat (human keratinocytes) in doses of 0.25-250 µg mL (-) (1) for 48 h. The antiproliferative activity was determined by spectrophotometric quantification (at 540 nm) of the cellular protein content using sulphorhodamine B assay. The prediction of parameters involved in the molecular bioavailability was executed directly by ChemDoodle (version 5.0.1) software (iChemLabs, LLC, Somerset, NJ). Results 3-Demethyl-2-geranyl-4-prenylbellidypholine (1) and 1,5,8-trihydroxy-4',5'-dimethyl-2H-pyrane (2,3:3,2)-4-(3-methylbut-2-enyl) xanthone (2), gartanin (3) and stigmasterol (4) were identified on the basis of spectroscopic techniques. Compounds 1 and 2 exhibited cytocidal activity, especially against breast, prostate and kidney cell lines, with TGI values of 15.8, 4.9, 9.1 and 39.4, 44.7, 40.9 µg/mL, respectively. Discussion and conclusion The presence of two sets of hydrophobic and hydrophilic groups in separate domains in each molecule might play a role in the mediation of tumour-specific action. Our data show that G. achachairu have potent antiproliferative action and should be considered an important source of potent anticancer compounds.

A magnetic nanogel based on O-carboxymethylchitosan for antitumor drug delivery: synthesis, characterization and in vitro drug release.

This paper studied the synthesis, characterization and use of the magnetic chitosan nanogel for carrying meleimidic compounds. The hydrogel polymer was prepared using O-carboxymethylchitosan, which was crosslinked with epichlorohydrin for subsequent incorporation of iron oxide magnetic nanoparticles. The characterization revealed that the magnetic material comprises about 10% of the hydrogel. This material is comprised of magnetite and maghemite and exhibits ferro-ferrimagnetic behavior. The average particle size is 4.2 nm. There was high incorporation efficiency of maleimides in the magnetic nanogel. The release was of sustained character and there was a greater release when an external magnetic field was applied. The mathematical model that best explained the process of drug release by the magnetic hydrogel was that of Peppas-Sahlin. The magnetic nanogel proved to be an excellent candidate for use in drug-delivery systems.

The antihypersensitive and antiinflammatory activities of a benzofuranone derivative in different experimental models in mice: the importance of the protein kinase C pathway.

BACKGROUND: Benzofuranone (BF1) was synthesized and its effects evaluated on mechanical hypersensitivity and paw edema models induced by different agents and on neuropathic pain induced by partial ligation of the sciatic nerve. An attempt was also made to elucidate the mechanism of action. METHODS: Swiss mice were used for the tests. Hypersensitivity was induced by intraplantar injection of carrageenan, bradykinin (BK), prostaglandin E2 (PGE2), epinephrine, lipopolysaccharide, or complete Freund adjuvant or by using a neuropathic pain model (evaluated with von Frey filament 0.6 g). The antiinflammatory effects were investigated in a paw edema model induced by carrageenan, PGE2, and BK (measured with a plethysmometer). The involvement of protein kinase C (PKC) was investigated through a nociception model induced by phorbol myristate acetate. RESULTS: BF1 inhibited the hypersensitivity and paw edema induced by intraplantar injection of carrageenan, BK, and PGE2 (P < 0.001), and it was effective in reducing the hypersensitivity evoked by complete Freund adjuvant or epinephrine (P < 0.001) but not by lipopolysaccharide (P = 0.2570). BF1 inhibited the licking behavior induced by phorbol myristate acetate (P < 0.001), suggesting involvement of the PKC pathway. A reduction in hypersensitivity of mice submitted to partial ligation of the sciatic nerve (P < 0.001) was observed, with inhibition of neutrophil migration and interleukin-1ß production into the spinal cord. BF1 treatment did not interfere with locomotor activity (P = 0.0783) and thermal withdrawal threshold (P = 0.5953), which are important adverse effects of other analgesics. CONCLUSIONS: BF1 has dose-dependent antihypersensitive and antiinflammatory effects in both acute and chronic models of pain and inflammation, possibly mediated through interference with the PKC activation pathway. The easy and fast synthesis of this compound, low-cost, low-concentration-requirement, and once-daily-administration drug suggest it as a candidate for future clinical studies.

Protective Role of Rosmarinic Acid in Experimental Urolithiasis: Understanding Its Impact on Renal Parameters.

This study aimed to assess the ability of rosmarinic acid (RA) to prevent kidney stone formation in an ethylene glycol and ammonium chloride (EG/AC) model. There was an increase in diuresis in the normotensive (NTRs) and hypertensive rats (SHRs) treated with hydrochlorothiazide (HCTZ) and exposed to EG/AC, while RA restored urine volume in NTRs. The EG/AC groups exhibited lower urine pH and electrolyte imbalance; these parameters were not affected by any of the treatments. Both HCTZ+EG/AC and RA+EG/AC reduced calcium oxalate crystal formation in NTR and SHR urine. Kidney tissue analysis revealed alterations in oxidative stress and inflammation parameters in all EG/AC-receiving groups, with RA enhancing antioxidant defenses in SHRs. Additionally, crystals were found in the kidney histology of all EG/AC-exposed groups, with reduced Bowman's capsule areas in NTRs and SHRs. The NTR VEH+EG/AC group showed intense renal damage, while the others maintained their structures, where treatments with HCTZ and RA were fundamental for kidney protection in the NTRs. Docking analysis showed that RA exhibited good binding affinity with matrix metalloproteinase-9, phosphoethanolamine cytidylyltransferase, and human glycolate oxidase enzymes. The data disclosed herein underscore the importance of further research to understand the underlying mechanisms better and validate the potential of RA for clinical use.

A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

Association between sleep pattern and pharmacological treatment in children with attention deficit disorder with hyperactivity: a systematic review.

OBJECTIVE: The aim of this study was to analyze the effect of the pharmacological treatment on the sleep patterns of children with attention deficit hyperactivity disorder (ADHD). DATA SOURCE: A high-sensitivity electronic search was performed in the following databases: Cochrane Library, MEDLINE via PubMed, LILACS via the Regional Health Portal (BVS), Embase, Scopus, CINAHL, and Web of Science, as recommended by the Cochrane Handbook, and which has undergone peer review according to the PRESS Guide. DATA SYNTHESIS: The studies contemplated the use of the drugs atomoxetine, guanfacine, methylphenidate, dasotraline, L-theanine, and lisdexamfetamine. They showed efficiency in reducing the symptoms of ADHD, although all, except atomoxetine, affected sleep quality, such as by reducing total rapid eye movement (REM), non-REM phase, slow-wave sleep time, and longer sleep-onset latency. CONCLUSIONS: The drugs used in the treatment of ADHD seem to have negative repercussions on the sleep quality of children, with the drug atomoxetine showing lesser effects on this variable.

Are hospital wastewater treatment plants a source of new resistant bacterial strains?

To understand which type of hospital waste may contain the highest amount of antibiotic resistant microorganisms that could be released into the environment, the bacterial strains entering and leaving a hospital wastewater treatment plant (HWTP) were identified and tested for their antibiotic susceptibility. To achieve this goal, samples were collected from three separate sites, inlet and outlet wastewater positions, and sludge generated in a septic tank. After microbiological characterization according to APHA, AWWA, and WEF protocols, the relative susceptibility of the bacterial strains to various antibiotic agents was assessed according to the Clinical and Laboratory Standards Institute guidelines, to determine whether there were higher numbers of resistant bacterial strains in the inlet wastewater sample than in the outlet wastewater and sludge samples. The results showed more antibiotic resistant bacteria in the sludge than in the inlet wastewater, and that the Enterobacteriaceae family was the predominant species in the collected samples. The most antibiotic-resistant families were found to be Streptococcacea and non-Enterobacteriaceae. Some bacterial strains were resistant to all the tested antibiotics. We conclude that the studied HWTP can be considered a source of resistant bacterial strains. It is suggested that outlet water and sludge generated in HWTPs should be monitored, and that efficient treatment to eliminate all bacteria from the different types of hospital waste released into the environment is adopted.

Characterization of bacterial resistance in treated hospital wastewater.

This article seeks to characterize the bacterial profile of pediatric hospital wastewater samples collected at the outlet of a wastewater treatment plant, and to estimate their relative susceptibility to antimicrobial agents. A total of 64 strains were isolated in the wastewater samples, of which 49 were identified as belonging to different families: Enterobacteriaceae (e.g. Escherichia coli, Klebsiella sp., Citrobacter sp.) comprised 57.2% of the identified bacteria, non-Enterobacteriaceae (e.g. Aeromonas sp., Pseudomonas sp.) comprised 30.6%, and Streptococcaceae (e.g. Enterococcus sp.) comprised 12.2%. The tests of the susceptibility of the bacteria to the antimicrobial agents used in the hospital showed that 100% of the bacterial species found discharged in the hospital wastewater treatment system were resistant to one or more of the antimicrobial agents according to the criteria of the U.S. Clinical Laboratory Standards Institute/National Committee for Clinical Laboratory Standards. The antimicrobial agent tests showed that meropenem, norfloxacin, ciprofloxacin, levofloxacin, and cefepime were the most effective antimicrobials against bacteria of the Enterobacteriaceae family. For bacteria of the non-Enterobacteriaceae family, norfloxacin, ciprofloxacin, levofloxacin, and cefepime presented the most effective antimicrobial action, whereas for bacteria of the Streptococcaceae family, ampicillin, vancomycin, and gentamicin were the most effective antimicrobials. Hospital wastewater treatment plants could be considered as places of selection pressure for bacterial resistance because of the presence of antibiotic-resistant bacteria coming from sewers or created at the treatment plant.

Urban afforestation: using phytotoxicity endpoints to compare air pollution tolerance of two native Brazilian plants Aroeira (Schinus terebinthifolius) and Cuvatã (Cupania vernalis).

Urban afforestation can mitigate the effects of air pollution, but the suitability of plant species for this purpose needs to be determined according to pollution intensity and climate change. The goal of this study was to evaluate the sensitivity of different phytotoxicity endpoints using two native Brazilian plant species as models, Aroeira (Schinus terebinthifolius) and Cuvatã (Cupania vernalis). The sensitivity parameters evaluated could help in selecting the most air-pollution-tolerant plant species for use in urban afforestation programs. The two plant species were exposed, in a greenhouse, to the combustion gases of a diesel engine for 120 days, with daily intermittent gas exposure. Every 30 days, leaf injury (chlorosis and necrosis), biomass, and physiological/biochemical parameters (proteins, chlorophyll, and peroxidase enzyme activity) were evaluated for both plant species. For the two selected species, the endpoints studied can be ranked according to their sensitivity (or inversely the tolerance) to diesel oil combustion gases in the following order: peroxidase > biomass ≈ chlorophyll > protein > leaf injury. The endpoint responses of higher plants can be used to assess the suitability of particular plant species for use in urban afforestation areas with relatively intense vehicle traffic.

A 3D ecotoxi-topological profile: Using concentration-time-response surfaces to show peroxidase activity in Zea mays (L.) exposed to aluminium or arsenic in hydroponic conditions.

This study sought to use concentration-time-response surfaces to show the effects of exposure to toxic (semi-)metals on peroxidase activity in higher plants as a function of exposure-concentration and exposure-time. Maize (Zea mays L.) seedlings (i.e., leaves and roots) were exposed to arsenic (as As3+) or aluminium (as Al3+) under hydroponic conditions, and their biomass and peroxidase enzyme responses were assessed at different concentration-time-exposures. The 3D ecotoxi-profile generated with these data showed two distinct regions: the first region is formed by exposures (i.e., points for time-concentration pairings) that were not statistically different from the results of the control points (i.e., zero toxicant concentration and all exposure-times), whereas the second region is formed by exposure pairings with results that were statistically different to those obtained from control pairings. Overall, the data show that enzyme activity increased over a shorter exposure-time when there was an increase in the exposure-concentration of the toxicant, which can be seen on a 3-D toxicity profile. We propose that quantitative relationship ratios from different assessed endpoints (e.g., biomass and enzyme activity) and enzymatic concentration-time-response surfaces could be helpful in the field of environmental-policy management.

Usnic acid enantiomers restore cognitive deficits and neurochemical alterations induced by Aß1-42 in mice.

Alzheimer's disease (AD) is the most prevalent form of dementia with a complex pathophysiology not fully elucidated but with limited pharmacological treatment. The Usnic acid (UA) is a lichen secondary metabolite found in two enantiomeric forms: (R)-(+)-UA or (S)-(-)-UA, with antioxidant and anti-inflammatory potential. Thus, given the role of neuroinflammation and oxidative injury in the AD, this study aimed to investigate experimentally the cognitive enhancing and anti-neuroinflammatory effects of UA enantiomers. First, the interactions of UA on acetylcholinesterase (AChE) was assessed by molecular docking and its inhibitory capability on AChE was assessed in vitro. In vivo trials investigated the effects of UA enantiomers in mice exposed to Aß1-42 peptide (400 pmol/mice) intracerebroventricularly (i.c.v.). For this, mice were treated orally during 24 days with (R)-(+)-UA or (S)-(-)-UA at 25, 50, or 100 mg/kg, vehicle, or donepezil (2 mg/kg). Animals were submitted to the novel object recognized, Morris water maze, and inhibitory-avoidance task to assess the cognitive deficits. Additionally, UA antioxidant capacity and neuroinflammatory biomarkers were measured at the cortex and hippocampus from mice. Our results indicated that UA enantiomers evoked complex-receptor interaction with AChE like galantamine in silico. Also, UA enantiomers improved the learning and memory of the animals and in parallel decreased the myeloperoxidase activity and the lipid hydroperoxides (LOOH) on the cortex and hippocampus and reduced the IL-1ß levels on the hippocampus. In summary, UA restored the cognitive deficits, as well as the signs of LOOH and neuroinflammation induced by Aß1-42 administration in mice.

N-antipyrine-3, 4-dichloromaleimide, an effective cyclic imide for the treatment of chronic pain: the role of the glutamatergic system.

BACKGROUND: In recent years, cyclic imides have attracted the attention of the scientific community because of their promising therapeutic potential. Studies with the compound N-antipyrine-3,4-dichloromaleimide (NA-3,4-DCM) also demonstrated an antinociceptive effect in formalin or capsaicin models of nociception, and that it reduced acetic acid-induced abdominal writhing in mice. METHODS: In this study, we examined the effects of NA-3,4-DCM on mechanical hypernociception in persistent pain-like behavioral models in mice. We also investigated the peripheral, topical, spinal, and supraspinal antinociceptive properties of NA-3,4-DCM and evaluated the involvement of the glutamatergic system on the antinociceptive effects of NA-3,4-DCM in mice. RESULTS: NA-3,4-DCM, dosed systemically (intraperitoneally or per os), was capable of interfering with the development of mechanical hypernociception induced by intraplantar injection of carrageenan and complete Freund adjuvant in mice. Interestingly, repeated intraperitoneal or per os treatment with NA-3,4-DCM, administered after the induction of hypernociception, also reversed the mechanical sensitization induced by complete Freund adjuvant injection or partial ligation of the sciatic nerve in mice, with lower doses than gabapentin, a drug used clinically to treat chronic pain. When administered systemically, locally, spinally, or supraspinally, NA-3,4-DCM was able to inhibit the overt nociception of both phases of the formalin test. The systemic administration of NA-3,4-DCM also reduced the nociception induced by intraplantar or intrathecal injection of glutamate in mice. Furthermore, NA-3,4-DCM caused marked inhibition of the nociceptive response induced by intrathecal injection of a group I metabotropic glutamate receptors agonist (1S,3R)-aminocyclopentane-trans-1,3-dicardboxylic acid (ACPD) or N-methyl-d-aspartate (NMDA), without interfering with nociception induced by other non-NMDA receptor agonists (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid and kainate) or by substance P. Notably, in the same range of doses, the antinociception caused by the compound NA-3,4-DCM was not associated with nonspecific effects such as changes in locomotor activity or motor coordination. CONCLUSION: These results provide strong evidence that NA-3,4-DCM produces antihypernociception in mice at peripheral, spinal, and supraspinal sites, and that interaction with the group I metabotropic glutamate receptors and NMDA receptors contributes to the mechanisms underlying its effect.

Vasorelaxant action of N-p-nitrophenylmaleimide in the isolated rat mesenteric artery.

The vasorelaxant response of N-p-nitrophenylmaleimide (4-NO2-NPM) was evaluated. The mesenteric rings (1-2 mm i.d.) were suspended by cotton thread for isometric tension recordings in a Tyrode's solution at 37 degrees C and gassed with a mixture of 95% O2 and 5% CO2, under a resting tension of 0.75 g. 4-NO2-NPM induced relaxation in mesenteric rings pre-contracted with phenylephrine (Phe; 10 microM, pD2 = 6.7 +/- 0.3) or KCl (80 mM, pD2 = 3.9 +/- 0.2). This effect was significantly attenuated after removal of the vascular endothelium, N(G)-nitro L-arginine methyl ester (L-NAME; 100 microM), atropine (1 microM), indomethacin (10 microM), L-NAME + indomethacin or 1H-[1,2,3]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM). L-Arginine (1 mM) reversed the inhibitory effect of L-NAME. In endothelium-intact preparations pre-incubated with 20 mM KCl, tetraethylammonium bromide (TEA; 1 mM) or glibenclamide (Glib; 10 microM), the vasorelaxant effect was significantly attenuated when compared to controls (endothelium intact). In denuded rings, separate incubation with 20 mM KCl, TEA or Glib did not change the relaxation when compared with that obtained in denuded rings. 4-NO2-NPM inhibited in a concentration-dependent and non-competitive manner the concentration-response curves induced by CaCl2. In calcium-free medium, the transient contractions induced by Phe (10 microM) or caffeine (20 mM) were inhibited. The relaxant effect induced by 4-NO2-NPM appeared to be due to endothelial muscarinic receptors activation, NO and prostacyclin release and K(ATP) and BK(Ca) (Ca(2+)-activated K+ channels) endothelium-dependent activation. Inhibition of the Ca2+ influx and inhibition of the Ca2+ release from intracellular IP3- and caffeine-sensitive stores are also involved in the vasorelaxation.

Itaconimides derivatives induce relaxation in mesenteric artery and negative inotropism by inhibition of CA2+ influx.

BACKGROUND: The aim of this study was to evaluate the cardiovascular effects of N-phenyl-itaconimide (Imide-1), N-4-methyl-phenyl-itaconimide (Imide-2), N-4-methoxy-phenyl-itaconimide (Imide-3) and N-4-chloro-phenyl-itaconimide (Imide-4), and investigate the mechanisms of action involved in the observed responses. METHODS: The relaxant effect was investigated in rat superior mesenteric arteries by using isometric tension measurements. Additionally, in isolated atria were evaluated the heart rate and force of cardiac contraction and in vivo experiments was evaluated blood pressure and heart rate. RESULTS: Cumulative administration of itaconimides (3 × 10-8 to 3 × 10-4 M) in pre-contracted mesenteric artery rings with phenylephrine, 1 µM, induced endothelium-independent vasorelaxation. The itaconimides showed similar maximum efficacies. Additionally, Imide-3 induced vasorelaxation in rings exposed to a depolarizing-tyrode solution containing 60 mM KCl or 20 mM KCl similar to the control, suggesting the non-participation of K+ channels. Imide-3 attenuated Ca2+ influx in a concentration-dependent manner. As well, imide-3 reduced CaCl2-induced contraction in nominally calcium-free medium, in the presence of cyclopiazonic acid (20 µM), phenylephrine (1 µM) and nifedipine (1 µM), indicating a reduction of Ca2+ influx by receptor-operated channels (ROC) and store-operated channels (SOC). The presence of SKF 96365 (10-5 M), SOC blocker, did not significantly alter the vasorelaxant effect induced by imide-3. Moreover, imide-3 induced a negative inotropic effect. In vivo studies, in non-anesthetized normotensive rats, imide-3 lowered blood pressure and induced bradycardia. CONCLUSIONS: These results suggest that itaconimides have concentration-dependent vascular effects and the vasorelaxation seems to be endothelium-independent. The vasodilatory effect induced by imide-3 may be due to a possible influence on the CaV and ROC. In addition, imide-3 is able to reduce force of cardiac contraction, blood pressure and promote bradycardia.

All that glitters is not gold: Panning cytotoxic natural products and derivatives with a fused tricyclic backbone by the estimation of their leadlikeness for cancer treatment.

Tricyclic compounds call the attention because of their pharmacological properties, and are considered a preferred platform for the development of drugs. Especially, in cancer treatment, these planar compounds are known for their ability to stack with DNA base pairs, acting as intercalators. In this sense, natural products (NPs) are a prodigal source of polycyclic compounds, comprising classes, such as carbolines, anthraquinones and xanthones. However, most of these compounds lack suitable physico-chemical properties, compatible to oral bioaviability. In this perspective, this paper aims to overview the role of tricyclic cores in the development of cytotoxic compounds, focusing on the leadlikeness estimation of the most prominent NP classes and their synthetic derivatives.

Remediation efficiency of different methods for rapid-response of microbiological and/or organic matter contaminated beach sand: A laboratory study.

In this article we compare the efficiency of different methods of rapid-response remediation of beach sand contaminated with microbiological and/or organic matter. Contaminated beach sands were treated in laboratory by different treatment methods (i.e., oxidation, UV-photoexposure, or thermal methods) and the efficiency of disinfection and breakdown of organic matter were evaluated. Contaminants in raw and treated beach sands were measured by membrane filtration method, and by chemical and biochemical oxygen demand, and chromatographic analysis. All the methods tested were efficient for disinfecting beach sand with microbiological contamination, except for the UV-photoexposure method, which showed only moderate disinfection potential. Chemical degradation efficiency of beach sand contaminated by crude petroleum was higher with Fenton and Photo-Fenton (associated with the use of surfactant and ultrasound) methods. Photo-Fenton method improvement can increase the efficiency of contaminated beach sand treatment, and can also help beach managers when selecting which method to adopt for remedial actions.

Biological and Toxicological Evaluation of N-(4methyl-phenyl)-4-methylphthalimide on Bone Cancer in Mice.

BACKGROUND: It was recently demonstrated that the phthalimide N-(4-methyl-phenyl)-4- methylphthalimide (MPMPH-1) has important effects against acute and chronic pain in mice, with a mechanism of action correlated to adenylyl cyclase inhibition. Furthermore, it was also demonstrated that phthalimide derivatives presented antiproliferative and anti-tumor effects. Considering the literature data, the present study evaluated the effects of MPMPH-1 on breast cancer bone metastasis and correlated painful symptom, and provided additional toxicological information about the compound and its possible metabolites. METHODS: In silico toxicological analysis was supported by in vitro and in vivo experiments to demonstrate the anti-tumor and anti-hypersensitivity effects of the compound. RESULTS: The data obtained with the in silico toxicological analysis demonstrated that MPMPH-1 has mutagenic potential, with a low to moderate level of confidence. The mutagenicity potential was in vivo confirmed by micronucleus assay. MPMPH-1 treatments in the breast cancer bone metastasis model were able to prevent the osteoclastic resorption of bone matrix. Regarding cartilage, degradation was considerably reduced within the zoledronic acid group, while in MPMPH-1, chondrocyte multiplication was observed in random areas, suggesting bone regeneration. Additionally, the repeated treatment of mice with MPMPH-1 (10 mg/kg, i.p.), once a day for up to 36 days, significantly reduces the hypersensitivity in animals with breast cancer bone metastasis. CONCLUSION: Together, the data herein obtained show that MPMPH-1 is relatively safe, and significantly control the cancer growth, allied to the reduction in bone reabsorption and stimulation of bone and cartilage regeneration. MPMPH-1 effects may be linked, at least in part, to the ability of the compound to interfere with adenylylcyclase pathway activation.