Search

Three new polyprenylated benzophenone derivatives named burlemarxiones G-I (1-3) were isolated from C. burle-marxii trunks (compound 1) and leaves (compounds 2 and 3), along with the known compound burlemarxione F. Burlemarxione G (1) was isolated after methylation with diazomethane and it is the keto-enol tautomeric pair of burlemarxione F. Burlemarxione H (2) derives from burlemarxiones F and G, but it has additional rings due to cyclization of the prenyl group attached to C-5 that establishes new single bonds between C-1 and C-23, as well as, between C-24 and C-29. Burlemarxione I (3) has two additional cyclizations: the first encompasses the cyclization of the former isopentenyl group into an 11,11-dimethyl-six-membered ring, whereas the second produces additional rings due to the cyclization of the prenyl group attached to C-5 that establishes new single bonds between C-1 and C-23, as well as, between C-24 and C-29. All three compounds showed moderate anti-glioma activity. These results show that C. burle-marxii is an important source of sophisticated polyprenylated benzophenone derivatives., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Parkinson's Disease (PD) is a progressive neurodegenerative disease characterized by loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). Iron (Fe)-dependent programmed cell death known as ferroptosis, plays a crucial role in the etiology and progression of PD. Since SNpc is particularly vulnerable to Fe toxicity, a central role for ferroptosis in the etiology and progression of PD is envisioned. Ferroptosis, characterized by reactive oxygen species (ROS)-dependent accumulation of lipid peroxides, is tightly regulated by a variety of intracellular metabolic processes. Moreover, the recently characterized bi-directional interactions between ferroptosis and the gut microbiota, not only provides another window into the mechanistic underpinnings of PD but could also suggest novel interventions in this devastating disease. Here, following a brief discussion of PD, we focus on how our expanding knowledge of Fe-induced ferroptosis and its interaction with the gut microbiota may contribute to the pathophysiology of PD and how this knowledge may be exploited to provide novel interventions in PD.

Unsuccessful anesthesia often occurs under an inflammatory tissue environment, making dentistry treatment extremely painful and challenging. Articaine (ATC) is a local anesthetic used at high (4%) concentrations. Since nanopharmaceutical formulations may improve the pharmacokinetics and pharmacodynamics of drugs, we encapsulated ATC in nanostructured lipid carriers (NLCs) aiming to increase the anesthetic effect on the inflamed tissue. Moreover, the lipid nanoparticles were prepared with natural lipids (copaiba ( Copaifera langsdorffii ) oil and avocado ( Persia gratissima ) butter) that added functional activity to the nanosystem. NLC-CO-A particles (~217 nm) showed an amorphous lipid core structure according to DSC and XDR. In an inflammatory pain model induced by λ-carrageenan in rats, NLC-CO-A improved (30%) the anesthetic efficacy and prolonged anesthesia (3 h) in relation to free ATC. In a PGE2-induced pain model, the natural lipid formulation significantly reduced (~20%) the mechanical pain when compared to synthetic lipid NLC. Opioid receptors were involved in the detected analgesia effect since their blockage resulted in pain restoration. The pharmacokinetic evaluation of the inflamed tissue showed that NLC-CO-A decreased tissue ATC elimination rate (ke) by half and doubled ATC's half-life. These results present NLC-CO-A as an innovative system to break the impasse of anesthesia failure in inflamed tissue by preventing ATC accelerated systemic removal by the inflammatory process and improving anesthesia by its association with copaiba oil.

Breast cancer is the neoplasia of highest incidence in women worldwide. Docetaxel (DTX), a taxoid used to treat breast cancer, is a BCS-class-IV compound (low oral bioavailability, solubility and intestinal permeability). Nanotechnological strategies can improve chemotherapy effectiveness by promoting sustained release and reducing systemic toxicity. Nanostructured lipid carriers (NLC) encapsulate hydrophobic drugs in their blend-of-lipids matrix, and imperfections prevent drug expulsion during storage. This work describes the preparation, by design of experiments (2 3 factorial design) of a novel NLC formulation containing copaiba oil (CO) as a functional excipient. The optimized formulation (NLC DTX ) showed approximately 100% DTX encapsulation efficiency and was characterized by different techniques (DLS, NTA, TEM/FE-SEM, DSC and XRD) and was stable for 12 months of storage, at 25 °C. Incorporation into the NLC prolonged drug release for 54 h, compared to commercial DTX (10 h). In vitro cytotoxicity tests revealed the antiproliferative effect of CO and NLC DTX , by reducing the cell viability of breast cancer (4T1/MCF-7) and healthy (NIH-3T3) cells more than commercial DTX. NLC DTX thus emerges as a promising drug delivery system of remarkable anticancer effect, (strengthened by CO) and sustained release that, in clinics, may decrease systemic toxicity at lower DTX doses.

Articaine (ATC) and lidocaine (LDC) are the local anesthetics (LAs) currently most employed in dentistry. Cases of paresthesia, reported more frequently for ATC, have raised concerns about their potential neurotoxicity, calling for further investigation of their biological effects in neuronal cells. In this work, the impact of ATC and LDC on the metabolism of SH-SY5Y cells was investigated through 1 H NMR metabolomics. For each LA, in vitro cultured cells were exposed to concentrations causing 10 and 50% reductions in cell viability, and their metabolic intracellular and extracellular profiles were characterized. Most effects were common to ATC and LDC, although with varying magnitudes. The metabolic variations elicited by the two LAs suggested (i) downregulation of glycolysis and of glucose-dependent pathways (e.g., one-carbon metabolism and hexosamine biosynthetic pathway), (ii) disturbance of branched chain amino acids (BCAA) catabolism, (iii) downregulation of TCA cycle anaplerotic fueling and activation of alternative energy producing pathways, (iv) interference with choline metabolism and (v) lipid droplet build-up. Interestingly, LDC had a greater impact on membrane phospholipid turnover, as suggested by higher phosphatidylcholine to phosphocholine conversion. Moreover, LDC elicited an increase in triglycerides, whereas cholesteryl esters accumulated in ATC-exposed cells, suggesting a different composition and handling of lipid droplets.

Lepidium meyenii is an edible plant that has been used as a nutritional supplement worldwide due to its medicinal properties. However, most of the studies have focused on the pharmacological activities of the extracts rather than their chemical composition. Herein, we used a combination of a multiplatform metabolite profiling approach and chemometrics to identify bioactive metabolites in L. meyenii. Extracts obtained with ethyl acetate and ethanol showed the promising antioxidant, anti-glioma and antibacterial activities. Sixty metabolites were identified by HPLC-MS, whereas fifteen were identified by GC-MS. Partial least squares discriminant analysis (PLS-DA), hierarchical cluster analysis (HCA), and Variable Importance in Projection (VIP) successfully discriminated extracts obtained in different organic solvents from in natura dry roots and commercial product samples of L. meyenii. Additionally, correlation analysis allowed us to pinpoint potential candidates responsible for each biological activity tested for the extracts, which could be extrapolate for other food-related species., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Ideally, antineoplastic treatment aims to selectively eradicate cancer cells without causing systemic toxicity. A great number of antineoplastic agents (AAs) are available nowadays, with well-defined therapeutic protocols. The poor bioavailability, non-selective action, high systemic toxicity, and lack of effectiveness of most AAs have stimulated the search for novel chemotherapy protocols, including technological approaches that provide drug delivery systems (DDS) for gold standard medicines. Nanostructured lipid carriers (NLC) are DDS that contain a core of solid and lipid liquids stabilised by surfactants. NLC have high upload capacity for lipophilic drugs, such as the majority of AAs. These nanoparticles can be prepared with a diversity of biocompatible (synthetic or natural) lipid blends, administered by different routes and functionalised for targeting purposes. This review focused on the research carried out from 2000 to now, regarding NLC formulations for AAs (antimetabolites, antimitotics, alkylating agents, and antibiotics) encapsulation, with special emphasis on studies carried out in vivo. NLC systems for codelivery of AAs were also considered, as well as those for non-classical drugs and therapies (natural products and photosensitisers). NLC have emerged as powerful DDS to improve the bioavailability, targeting and efficacy of antineoplastics, while decreasing their toxic effect in the treatment of different types of cancer.

Melanoma is the most aggressive skin carcinoma and nanotechnology can bring new options for its pharmacological treatment. Nanostructured lipid carriers (NLC) are ideal drug-delivery carriers for hydrophobic drugs, such as the antineoplastic docetaxel (DTX), and hybrid (NLC-in-hydrogel) systems are suitable for topical application. This work describes a formulation of NLC DTX in xanthan-chitosan hydrogel containing lidocaine (LDC) with anticancer and analgesia effects. The optimized nanoparticles encapsulated 96% DTX and rheological analysis revealed inherent viscoelastic properties of the hydrogel. In vitro assays over murine fibroblasts (NIH/3T3) and melanoma cells (B16-F10), human keratinocytes (HaCaT) and melanoma cells (SK-MEL-103) showed reduction of docetaxel cytotoxicity after encapsulation in NLC DTX and HGel-NLC DTX . Addition of LDC to the hybrid system (HGel-NLC DTX -LDC) increased cell death in tumor and normal cells. In vivo tests on C57BL/6J mice with B16-F10-induced melanoma indicated that LDC, NLC DTX , HGel-NLC DTX -LDC and NLC DTX + HGel-LDC significantly inhibited tumor growth while microPET/SPECT/CT data suggest better prognosis with the hybrid treatment. No adverse effects were observed in cell survival, weight/feed-consumption or serum biochemical markers (ALT, AST, creatinine, urea) of animals treated with NLC DTX or the hybrid system. These results confirm the adjuvant antitumor effect of lidocaine and endorse HGel-NLC DTX -LDC as a promising formulation for the topical treatment of melanoma.

Lepidium meyenii is widely used as a food supplement because of its medicinal properties and nutritional value. Several studies have described the identification of its metabolites and LC-HRMS analysis is one of the most frequently used analytical tool to assess plant extract metabolome. Nevertheless, proper and reliable metabolite identification is essential for such metabolomics studies. Although HRMS distinguishes even minor changes in the metabolites structures, highly specialized secondary metabolites might not be present on available databases imposing serious obstacles for metabolite identification This review discusses the structural diversity and biosynthetic aspects of 101 compounds previously identified in L. meyenii. More importantly, we have compiled the available information on expected and experimental high-resolution masses of L. meyenii compounds. This will help upcoming metabolomics studies not only of L. meyenii but also other plant species by providing the necessary tools to perform proper and reliable identification of their bioactive compounds., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A survey of drug use carried out from April 1984 to May 1985 at the University of São Paulo, Brazil, showed that of 2,475 undergraduate students surveyed, 588 respondents, or 23.8 per cent, abused drugs at some time in their lives. Drug use was somewhat more common among males (25.3 per cent) than among females (21.5 per cent). Among the drug users, the use of cannabis ranked first (41.2 per cent), followed by amphetamines (27.4 per cent), cocaine (12.2 per cent), tranquillizers (12.2 per cent), barbiturates (5.6 per cent), morphine and heroin (0.8 per cent) and lysergic acid diethylamide (0.5 per cent). Of the total number of respondents, 10 per cent were current habitual drug users, while 13.8 per cent had at some time been drug users but were no longer using drugs at the time of the survey. Of 23 postgraduate students surveyed, 10 respondents, or 43.5 per cent, used either cannabis, amphetamines or tranquillizers.

Both the learning of brightness discrimination, discrimination reversal and a simple oddity problem, and the pain-sensitivity to electric shock were studied in rats treated with 100 mg/kg of D, L-parachlorophenylalanine (PCPA), 100 mg/kg of D, L-tryptophan (TP) or 2.0 ml/kg of control solution (CS). At the end of the last behavioral session all animals were killed and the levels and rate of 5-hydroxytryptamine (5-HT) synthesis were measured. PCPA treatments produce rats which are more effective in coping with a problem; these animals were similar in that both the levels and turnover rate of brain 5-HT and the pain-sensitivity were lower. Results are tentatively explained suggesting that these differences in learning ability could be a result of the drug's action in pain-sensitivity. The possibility that 5-HT might be responsible for these differences is discussed.

Ovariectomized rats, chronically treated with cannabis extract or control solution, were given different hormonal treatments. Results indicated that both cannabis-treated and estrogen-treated animals were more aggressive than controls. Furthermore, aggressiveness was virtually abolished when cannabis-treated females were made sexually receptive by estrogen and progesterone treatments. After 25 days of cannabis or control solution treatment, all subjects were sacrificed. The levels and turnover rate of brain 5-HT and peripheral plasma corticosterone were then assayed. Data indicated both a significant inverse relationship between plasma corticosterone and whole brain levels of 5-HT(r = -0.742 to -0.985) for all groups and a significant positive relationship between aggressive behavior and plasma corticosterone (r = +0.675 to +0.946) in all groups that were fighting prior to decapitation. Results are tentatively explained, suggesting that the variability of the female response to stress during the different phases of the estrus cycle, permitted them to perform differently after chronic cannabis treatment. 5-HT is apparently involved, either directly in its effects on aggressive behavior or indirectly through the pituitary-adrenocortical axis activation.