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Green Synthesis of Silver Nanoparticles Using A. eupatoria extract in certain conditions
Published: 01 November 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General

Green synthesis of silver nanoparticles represents the great interest in pharmacology due to their wide range of applications. Silver nanoparticles have characteristic physical, chemical, and biological properties, which have potential applications in nanobiotechnological research. Green synthesis involves the synthesis of non-toxic nanoparticles, with cheap and ecological acceptable synthesis technology, and implies the use of plant extracts as a reducing agent of selected metal salts.

In our research, we used the cosmopolitan plant species A. eupatoria, which is known to be used for medicinal purposes, as well as silver nitrate with known antimicrobial properties. Different reaction conditions were applied for the synthesis of nanoparticles using the extracts of A. eupatoria. Silver nitrate was dissolved in different concentrations (5, 10, and 20mM). The reaction mixtures were stirred on a magnetic stirrer and heated at different temperatures (25 0C and 50 0C) until metal nanoparticles were formed. To modify the pH of the reaction mixture (pH 2, 4, and 6) 0,1M HNO3 or 0,1M NaOH were used. Visual color change (from light yellow to dark brown) and UV-Vis spectrophotometry were used to observe the production of AgNPs throughout the synthesis.

The UV-Vis absorption spectra of formed nanoparticles were recorded (300–800 nm) and the highest peaks were positioned within 300–375 nm (characteristic peak for AgNPs), suggesting the formation of AgNPs. The best conditions for the highest AgNPs yield production were a 5 mM concentration of AgNO3, a reaction temperature of 25 0C, pH=4, and a reaction time of 3h for synthesis

  • Open access
  • 44 Reads
Uncovering of bioactives and mechanisms of garlic (Allium sativum L.) husk for the amelioration of type 2 diabetes mellitus via network pharmacology

Allium sativum L. husk (ASLH) extracts have been used as a reliever against type 2 diabetes mellitus (T2DM). Currently, its significant mechanisms against T2DM remain unclear. Thus, the aim of this study is to investigate the characteristics of its key signaling pathways, targets, and compounds. The compounds in ASLH were analyzed by gas chromatography-mass spectrum (GC–MS) and confirmed drug-like compounds (DLCs) in silico. Then, protein-protein interaction (PPI) networks and signaling pathways, targets, and compounds are constructed, and visualized by using RStudio. Finally, we performed a molecular docking test (MDT) to identify the key mechanism(s), target(s), and compound(s) of ASLH on T2DM. A total of 23 compounds in ASLH were identified by GC–MS, and all compounds were accepted by Lipinski’s rule. The 23 compounds were associated with 521 targets and retrieved 4,736 T2DM-related targets by Online Mendelian Inheritance in Man (OMIM) and DisGeNET. The final overlapping 87 targets were obtained between compounds–targets and T2DM-related targets. The number of 13 signaling pathways, 33 targets, and 19 compounds of ASLH were associated with T2DM. In parallel, MDT revealed four potential compounds: (1) 9-hexacosene, (2) 2-(([2-ethylhexyl]oxy)carbonyl)benzoic acid, (3) clionasterol, (4) 4-methyl-2-phenylpyrimidine on PPAR signaling pathway. Overall, the four compounds from ASLH might show an anti-T2DM synergistic effect by activating the PPAR signaling pathway or inactivating the phospholipase D signaling pathway. In this study, we suggest that ASLH might be considered a health-promising resource from both nutraceutical and pharmaceutical perspectives.

  • Open access
  • 29 Reads
Hepatoprotective effect of the N-alkylated isobornylamine against CCl4-induced chronic liver damage in mice

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by impaired lipid and carbohydrate metabolism and characterized by fatty degeneration, necrosis, inflammation and fibrosis of hepatocytes. There are currently no approved drugs for the treatment of NAFLD, so their search remains an urgent task for present pharmacology. Previously, N-alkylated isobornylamine (compound 1), a GPR40 agonist, at a dose of 30 mg/kg was shown to resolve of fatty liver degeneration of C57Bl/6Ay mice improving glucose tolerance. Based on this, we continued to study the hepatoprotective effect of compound 1 on CCl4 - induced chronic hepatotoxicity model in CD-1 mice. The compound 1 was administered per os at doses of 60, 90, 120, 150 mg/kg daily for 3 weeks as well as the reference drug Silymarin at a dose of 100 mg/kg. At the end of the experiment, a biochemical blood assay was carried out, which showed that compound 1 dose-dependently reduces ALT, AST and ALKP. According to the results of a histological and morphometry liver examination, the compound 1 was found to reduce the severity of degenerative-necrotic changes in hepatocytes. More pronounced improvements in doses of 120 and 150 mg/kg were noted. Thus, isobornylamine derivative exhibit a hepatoprotective effect not only in metabolic liver injury, but also in CCl4 - induced chronic liver damage.

  • Open access
  • 93 Reads
Virtual screening and drug repurposing: together against worm-borne diseases
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Worm-borne diseases cause a huge impact on human health and economics since they can also affect livestock animals. For these reasons, our research group has been employing simple rational-designed approaches to fight them. Here we present the results of combining the Virtual Screening approach and drug repurposing to find, among the drugs on the market, fast and cheap therapeutic alternatives. Starting from the top 10 pharmacophore models, validated through the ROC curve, we screened the FDA-approved drugs library to find any compound that fulfils the pharmacophore requirements. We were able to select a vitamin which was submitted to molecular dynamics simulations and in vitro experimental assays. We found out that the compound really seems to keep stable in the enzyme's active site, but it first needed to accommodate to perform a higher number of interactions inside the site. Once accommodated, the vitamin seems to be able to close the active site denying access to the original substrate. Experimental in vitro data corroborate that the vitamin is able to inhibit worm growth and induces 100% of females' death after 72 h when used at 12.5 micromolar. In vitro tests with digestive extract of the worms, prepared to predominantly measure CatB1 activity, showed that the vitamin was able to inhibit the substrate consumption closer to 10 micromolar when using the specific CatB1 substrate but when the experiment employed a non-specific substrate, the vitamin was effective only at higher doses (up to 2000 micromolar) suggesting the potential selectivity of it toward cathepsins B1.

  • Open access
  • 32 Reads
Identification of novel ERβ ligands

Estrogen receptor (ER) is a major therapeutic target in the treatment of estrogen-related diseases, such as breast cancer. There is a need to develop potent ER ligands capable of selective targeting of cancer cells without affecting normal cells. Blocking ERα action by antagonists and inhibition of steroidogenic enzymes is standard therapy in the treatment of breast cancer for many years. On the other hand, ERβ isoform usually has anti-proliferative and tumor-suppressive functions, so targeting ERβ with specific agonists represents new promising approach not only in breast cancer therapy, but also prostate. Beside anticancer activity of ERβ agonists, their application is considered in the treatment of depression, anxiety and inflammation. In order to obtain potent antiproliferative agents, triazole ring is often incorporated as pharmacophore into the steroid skeleton. This study provides evaluation of binding affinity of novel N(2)-substituted D-condensed steroidal triazoles for ligand-binding domains (LBDs) of ERβ and androgen receptor using yeast-based fluorescent assay. LBD of steroid receptor was expressed in-frame with yellow fluorescent protein (YFP) in Saccharomyces cerevisiae. Upon ligand-binding induced dimerization, fluorescence resonance energy transfer (FRET) between YFP molecules was analyzed by fluorescence spectroscopy and microscopy. We have identified new selective ERβ ligands without androgenic properties, but further experiments are required to determine whether their mechanism of action is agonistic or antagonistic. Having in mind the broad therapeutic potential of specific ERβ ligands, our findings indicate that steroid derivatives containing triazole are promising bioactive compounds in the field of anticancer agents.

  • Open access
  • 42 Reads
Pentacyclic triterpenoids as potential inhibitors of aldo-keto reductase 1C: virtual screening of a natural product library

Aldo-keto reductase (AKR) 1C isoforms (AKR1C1-C4) are involved in metabolism of steroid hormones, and are targets for treatment of hormone-dependent cancers, such as breast and prostate cancers; as well as hormone-independent leukemias. AKR1C enzymes also metabolize several chemotherapeutics, reducing their effectiveness. Natural products provide a potent source of compounds with anticancer activities. Over 50% of small-molecule anticancer drugs approved by the U.S. FDA are derived from natural products. Previous studies suggest that AKR1C homologs are inhibited by triterpenoids; and we have shown that a pentacyclic steroid derivative is an inhibitor of human AKR1C3. In the present study, a virtual library of 1228 natural products was screened in silico, for relative binding affinity for AKR1C2. Virtual screening was conducted using MTiOpenScreen. The structure of AKR1C2 in complex with ursodeoxycholate was used as ‘receptor’. Results from virtual screening were analyzed in PyMol and validated by comparison with X-ray crystallographic and experimental data. Pentacyclic triterpenoid derivatives with similarities to maslinic, oleaonic, ursolic and betulinic acid were identified among the top 1% of compounds. Several compounds are predicted to form hydrogen bonds with catalytic residues in AKR1C. Oleaonic acid derivatives were shown to inhibit another member of the AKR superfamily, AKR1B10, in vitro. Compounds with similarities to AKR1C inhibitors, such as naringenin and apigenin were ranked among the top 10%. Pentacyclic triterpenoid derivatives have potential anticancer properties, and based on the present study represent a new class of compounds for testing as AKR1C inhibitors.

  • Open access
  • 34 Reads
Selected biomarkers of oxidative stress in ischemic stroke.

Stroke is a serious health problem all over the world and the second, after the heart attack, cause of death and permanent disability in people. Oxidative stress plays an important role in the pathogenesis of ischemic stroke (AIS).

The aim of our study was to evaluate the temporal profile of the melatonin metabolite 6-hydroxymelatonin sulphate (6-SM) in the urine and carbonyl groups in the serum of patients with acute ischemic stroke treated with intravenous thrombolysis.

There were statistically significant differences between the values of 6-SM and carbonyls compared to the control group. Statistical differences were also found in the concentrations of the examined parameters depending on the type of stroke. The studies revealed the correlations between the concentrations of 6-SM and the carbonyl groups measured in various time intervals and between the concentration of biomarkers and mortality was also evaluated.

The obtained results may indicate an increased oxidative stress, and the intense increase in the concentration of carbonyl groups in patients with AIS may be considered a potential marker of protein damage in thrombolytic patients. Melatonin supplementation in AIS patients can also be considered, as it can effectively prevent both behavioral and neurophysiological defects caused by cerebral hypoxia and ischemia.

  • Open access
  • 56 Reads
In the heart of cardio-oncology: the targets and biomarkers of anticancer drugs cardiotoxicity

The cardiotoxicity of anticancer drugs is the second leading cause of death in cancer patients. Among other adverse effects, left ventricular ejection fraction decrease or heart failure emerge after anticancer treatments comprising old or new targeted therapies. In the last few years, our group has been trying to unveil the cardiac adverse outcome pathways of classic chemotherapeutic agents, mainly focusing on two topoisomerase inhibitors, mitoxantrone and doxorubicin.

Mitoxantrone and doxorubicin both cause cumulative dose cardiotoxicity and were tested in in vitro and in pre-clinical models. Results obtained in mice and rats, following a clinical relevant dosing scheme, were mimicked in vitro and demonstrated that those drugs change cellular redox homeostasis and promote inflammation, although in different biomarkers. Moreover, autophagy and energetic pathways were affected, the first mainly after mitoxantrone treatments and the latter when doxorubicin was used. Thus, distinct cardiac fingerprints for these two drugs exist.

In conclusion, although their clinical cardiac effects are similar in humans, mitoxantrone and doxorubicin have different initiating cardiotoxic events. These were revealed taking into account the use of proper experimental models, clinical relevant concentrations and Omics methods. These data are of the essence to promote drug specific cardioprotective measures in the future, for patients treated with these drugs.

VMC acknowledges funding of Fundação para a Ciência e Tecnologia (FCT), IP, under Norma Transitória DL57/2016/CP1334/CT0006. This work is funded by project UIDP/04378/2020 of UCIBIO and project LA/P/0140/2020 of i4HB.

  • Open access
  • 66 Reads
Resveratrol-loaded glycosylated liposomes for targeting bacteria

Biofilm-associated bacterial diseases are a major health problem due to the high antibiotic resistance of biofilm infections. In recent years, several methods, some of which relying on nanotechnology, have been developed to tackle this problem. The search for non-antibiotic strategies has renewed interest in natural molecules that exploit alternative bacterial-fighting mechanisms and, above all, do not induce resistance. In this context, we have developed two sets of cationic glycosylated liposomes for the targeted delivery of trans-resveratrol (RSV), a secondary plant metabolite with antimicrobial properties, to bacteria that express carbohydrate-specific proteins able to recognize monosaccharides, namely Staphylococcus epidermidis and Methicillin Resistant Staphylococcus Aureus (MRSA). Liposome physico-chemical properties (diameter, PDI, charge, RSV entrapment efficiency) were measured by DLS, electrophoretic mobility, and HPLC.

Liposomes used in the experiments on MRSA were composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine, cholesterol (Chol) and glycoamphiphiles featuring a galactosyl, mannosyl or glucosyl moiety. The objective was to identify the best sugar moiety to target MRSA biofilm. Microbiological tests carried out to monitor the demolition effect of RSV-loaded liposome on MRSA mature biofilm showed that RSV-galactosylated liposomes are the most effective at a RSV concentration sixty times below the MIC.

Liposomes used in the experiments on S. epidermidis were formulated with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, Chol, and the glycoamphiphile featuring the glucose residue. The ability of RSV-loaded liposomes to inhibit the growth of a slime positive and a slime negative strain of S. epidermidis was evaluated. Glucosylated liposomes, non-toxic in itself, kill bacteria at concentration tenfold under the MIC of RSV.

  • Open access
  • 45 Reads
Phytochemical and pharmacological profile of four Malagasy medicinal plants used in different chronic diseases: strategies for the sustainable use of natural resources in the Malagasy health system
Published: 01 November 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General

Traditional medicine plays important role in the Malagasy health system. In Madagascar, medicinal plants are the main remedies for several diseases, especially chronic diseases. Scientific studies are performed to valorize the use of Imperata cylindrica (Ic), Uapaca bojeri (Ub), Vaccinium secondiflorum (Vs), and Ravenala madagascariensis (Rm). Ic and Ub are used to treat some inflammatory-related diseases, Vs has an anti-diabetic value and Rm is known as an antihypertensive. Phytochemical and pharmacological studies were carried out using standard scientific models to justify their properties. Firstly, the antioxidant, analgesic, anti-inflammatory, and/or vasorelaxant activities of their crude methanol extracts (ME) were evaluated according to ethnomedicinal information. The ME of Ic, Ub, and Vs showed potent antioxidant activities on DPPH and FRAP methods. These species are rich in phenolics, flavonoids, and organic acids, known for their antioxidant activities. They also possess significant analgesic and anti-inflammatory activities respectively assessed on the pain model caused by acetic acid (1%) and on inflammatory edema induced by carrageenan in mice. Sitostenone was isolated as an analgesic and anti-inflammatory compound from Ic. Ub and Vs ME significantly reduced the glycemia level after 30 min of glucose loading in mice compared to glibenclamide. Androsta-1,4-dien-3,16-dione was isolated as the vasorelaxant molecule from Rm responsible for its antihypertensive activity. These results showed that there are some scientific reasons justifying the therapeutic properties of these plants. It is very important to investigate the local use of biodiversity to identify new bioactive compounds, for supporting biodiversity conservation and sustainable development projects in Madagascar.