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  • Open access
  • 79 Reads
Effects of Protein Hydrophobicity on Protein Corona Formation Modes on Soluplus® Nanomicelles

Soluplus® nanomicelles have been rising as excellent drug carriers for their great drug loading capacity. Nevertheless, the protein corona would formed when subjected to biological fluids, but few efforts have been made in elucidating that. Here, the effects of protein hydrophilicity on protein corona formation modes were investigated based on three model proteins, Bovine serum albumin (BSA, hydrophilic), Lysozyme (Lyso, hydrophilic) and Bovine hemoglobin (BHb, more hydrophobic). Protein corona formation was proved by the size and zeta potential measurements, while the size increments of BHb group were the most significant. We hypothesized that the hydrophilic protein might be dominated by the surface adsorption mode, where the proteins were cross-linked by the out-layer PEG chains. However, the hydrophobic protein may show insertion mode, where the nonpolar part was inserted into the hydrophobic core of nanomicelles and the polar part distributed on the surface. To justify this hypothesis, the microenvironment polarity of hydrophobic tryptophan (Trp) acid amino residue was analyzed. The most obvious peak wavelength changes and the minute absorbance change were exhibited in ultraviolet-visible spectra of the BHb group, indicating the hydrophobic Trp was distributed in the nonpolarity core of nanomicelles. This conclusion was further proved by the similar results in fluorescence emission wavelength. In addition, the circular dichroism results confirmed the obvious arresting conformational change induced by insertion mode protein corona formation. In summary, the hydrophilic proteins follow the surface adsorption mode while the hydrophobic proteins follow the insertion mode in the protein corona formation of Soluplus® nanomicelles.

  • Open access
  • 108 Reads
An ethnoveterinary investigation into medicinal and aromatic plants used to treat livestock diseases by the local communities of the Rif, north of Morocco.

Ethnopharmacological relevance: Phytotherapy has been playing a significant role in the livestock health care system for a long, especially in remote areas. This study aimed to document the therapeutic uses of plant species practised by the Rif's indigenous people to treat various veterinary health diseases.

Methods: Semi-structured questionnaires, field walks, and group discussions were conducted from June 2016 - to October 2019 to collect the data. Quantitative indices include Plant Part Value (PPV), Use value (UV), Fidelity Level (FL), Relative Popularity Level (RPL), Rank Order Priority (ROP), Jaccard Index (JI), and Informant Consensus Factor (ICF) were used for the data analysis.

Results: A total of 300 medicinal plants belonging to 205 genera and 67 families have been recorded with ethnoveterinary uses. Dominant families are Asteraceae (33 species), Lamiaceae (28 species), and Fabaceae (24 species). The reported illness was classified into 4 disease categories based on ICF values, and the highest number of plants was reported to treat internal parasites (ICF=0.967). Leaves were the most consistently used parts (PPV=48.4%). Aloysia citrodora Palau. (RPL=) had the highest RPL level (1.15).

Conclusions: It can be concluded that the local people of Rif hold rich ethnoveterinary knowledge to cure livestock diseases. Plant species with high FL, RPL, and UV values should be screened for comprehensive phytochemical and pharmacological studies to validate the ethnomedicinal knowledge.

  • Open access
  • 46 Reads
Stochastic dynamics mass spectrometric 3D structural analysis of N-glycans of fetal bovine serum – an experimental and theoretical study

The contribution addresses the problem of mass spectrometric (MS) 3D molecular and electronic structural analysis of mixtures of glycans of fetal bovine serum. The research task is unexpectedly difficult, due to random variation of non-template-driven glycosylation and fucosylation processes; a lack of regioselective derivatization, causing for mixtures of polydisperse glycans toward length and skeletal modifications; isomers of oligomers and polymers, including linear and branches molecular structures, respectively. That fact difficult significantly their structural analysis, mass spectromerically. Furthermore, MS phenomena of carbohydrates include reactions of intramolecular rearrangement and cylization, proton and charge transfer effects, noncovalent binded self-associates, alkali metal ion aducts, and multiply charged species under tandem MS/MS operation mode. Despite, the study presents a new line of plausible solution to the problem. It employs our innovative stochastic dynamic MS model formula DSD = 2.6388.10-17.(<I2>–<I>2) capable of exactly quantifying fluctuations and temporal behaviour of measurable variable intensity (I) of analyte peaks. It has been shown, that it exactly and directly quantifies analyte concentration in solution and determines 3D molecular and electronic structures. The later task is less straightforward. It employs Arrhenius’s model equation within the framework of his transition state theory and the power capability of quantum chemical methods. The validity of the latter statements is examined, herein. The study, first, comes to grips MS collision-induced dissociation phenomena of mixtures of 2-aminobenzamide derivatized glycans. It utilizes ab initio and DFT static and molecular dynamics, molecular mechanics, and chemometrics, as well.

  • Open access
  • 84 Reads
In vitro inhibitory effects on pancreatic lipase and α-glucosidase activity by extracts and fractions of Lavandula angustifolia L. from Southern Italy

Lavandula angustifolia is one of the most popular medicinal plants, rich source of bioactive compounds. Most of the studies on lavender had focused on its essential oil and its use as a sleep aid, calmative, fragrant, insect repellant and flavoring agent. This work is aimed at investigating, for the first time, the potential role of L. angustifolia in the management of metabolic syndrome (MetS), one of the major and escalating public-health and clinical challenge worldwide. Herein, the aerial parts of L. angustifolia, collected in June 2021 in the “Parco Nazionale del Pollino”, Southern Italy, were subjected to extraction by maceration with ethanol. Then, the total extract was partitioned with solvents at different polarity such as n-hexane, dichloromethane and ethyl acetate. Extract and fractions were evaluated for their ability to inhibit alpha-glucosidase as well as lipase. The ethanol extract remarkably inhibited a-glucosidase and lipase (IC50 of 2.55 and 30.50 microg/ml, respectively) better than the positive control acarbose and orlistat (IC50 of 35.51 and 37.12 microg/ml, respectively). The most active fraction was dichloromethane with IC50 of 14.67 and 17.64 mg/ml, against alpha-glucosidase and lipase, respectively. Taking into account obtained results, L. angustifolia could be used for formulation of new products; however, further preclinical studies will be needed to confirm its in vivo efficacy, as well as to prove the safety of the tested extracts and fractions.

  • Open access
  • 36 Reads
Prodrugs activated by vascular ectopeptidases: proof of concept
Published: 19 September 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General

Several vascular ectopeptidases reside in blood vessels and efficiently regulate peptide hormones. For instance, bradykinin (BK) is inactivated by angiotensin converting enzyme (ACE) or arginine-carboxypeptidases (Arg-CPs) and aminopeptidase N (APN) cleaves several substrates. Whether such peptidases may activate latent prodrugs of vasoactive agents has been tested. The contractility of the isolated human umbilical vein, radioligand binding assays, immunolocalization of peptidases, the internalization cycle of fluorescent receptors (microscopy), blood pressure measurements in anesthetized rats and specific inhibitors of peptidases have been exploited to show the feasibility of prodrug activation by vascular peptidases. L-Alanyl-histamine has virtually no affinity for the human histamine H1 receptor, but releases histamine and contracts the vein following cleavage by endogenous APN. Prolonged sequences of BK, such as BK-Arg, Arg0-BK-Arg-Arg and BK-His-Leu have little affinity for the BK B2 receptor but are contractile in the umbilical vein and hypotensive in anesthetized rats via their action on this receptor type following cleavage of the C-terminal extensions by Arg-CPs for the first two peptides, also by ACE for the last two. Vascular ectopeptidases were shown to activate latent agonists of the H1 and B2 receptors, a concept that could be extended to various classes of drugs for a local action on the vasculature.

  • Open access
  • 241 Reads
Discovery of Novel HIV Protease Inhibitors using Modern Computational Techniques

The human immunodeficiency virus type 1 (HIV-1) has continued to be a global concern. With the new HIV incidence, the emergence of multi-drug resistance and the untoward side effects of currently used HIV protease inhibitors (PIs), there is an urgent need to discover more efficient HIV PIs. Modern computational tools have played vital roles in facilitating drug discovery process. This research focuses on pharmacophore-based similarity search to screen 111,566,735 unique compounds in the PubChem database to discover novel HIV-1 PIs. We used in-silico approach involving 3D-similarity search, physicochemical and ADMET evaluations, HIV protease-inhibitor prediction (IC50/percent inhibition), rigid receptor-molecular docking studies and free-binding energy calculations. The 10 FDA approved HIV PIs (saquinavir, lopinavir, ritonavir, amprenavir, fosamprenavir, atazanavir, nelfinavir, darunavir, tipranavir and indinavir) were used as reference. The in-silico analysis revealed that fourteen out of the twenty-eight selected optimized hit molecules were within the acceptable range of all the parameters investigated. The hit molecules demonstrated significant binding affinity to the HIV protease (PR) when compared to the reference drugs with the residues ASP25, GLY27, ASP29, ASP30, ILE50 involved in essential hydrogen bonding and п-п stacked interactions, which stabilize the optimized hit molecules in the active binding site of the HIV-1 PR (PDB:2Q5K). HPS/002 and HPS004 are most promising in terms of IC50/percent inhibition (90.15%) of HIV-1 PR, in addition to their drug metabolism and safety profile. These hit candidates should be investigated further as possible HIV-1 PIs with improved efficacy and low toxicity through in-vitro experiments and clinical trial investigation.

  • Open access
  • 39 Reads
Bibliometric Profile of Metered Dose Inhalers

Pulmonary drug delivery systems (PDDS) have gained particular attention by pharmaceutical scientists due to its potent in the therapy of both pulmonary diseases and systemic diseases. Metered dose inhalers (MDI) as a delivery approach of PDDS have ample advantages over other approaches. No drying process is associated with MDI, which avoids the chemical and physical instability. MDI are cost-effective, portable and can be self-administered. It was recently reported that MDI had occupied a large proportion of the respiratory drug market since the last century. To facilitate the future studies on MDI, this work was aimed to conduct bibliometric analysis of the publications of MDI in Science Citation Index Expanded database of Web of Science from 2000 to 2020 (2,858 in total). The documents were processed by Clarivate Analytic tool equipped by Web of Science, VOSviewer, Statistical Analysis Toolkit for Informetric (SATI) and bibliometric online platform, and the data were visualized. After describing the detailed bibliometric profile of MDI publications, which included publication years, countries/regions, organizations, research areas, publication media, authorship and funding agencies, we assessed the publication tendencies by virtue of analysis of co-citation, bibliographic coupling, keywords and co-occurrence. Based on the results, we put forward three promising topics for future studies of MDI. Taken together, we believed that MDI had become a topic under investigation across the world, and will still be an emphasis for fundamental and translational researches.

  • Open access
  • 39 Reads
Larger Particle Size Resulted in Longer Lung Retention Time of Inhaled Solid Lipid Nanoparticles

Aims: Particle size-lung retention time correlation is a vital guiding principle in developing pulmonary nanoparticle drug delivery systems (PNDDS). Fluorescence probes with accurate water-quenching attributes, which are emissive under PNDDS encapsulation while quenched after release in psysiological environments, reflex fluorescence signals of intact PNDDS and thus unambigously clarify the lung retention profile of PNDDS. Herein, water-quenching probe P2 was used to investigate the particle size-lung retention time correlation.

Methods: P2 was donated by Prof. Wei Wu (Fudan University). P2-loaded PNDDS, viz. solid lipid nanoparticles (SLN) with different sizes, were prepared by high-pressure homogenization, encoded as P2-SLN1~P2-SLN4. Particle sizes of P2-SLN1~P2-SLN4 were measured, and then endotracheally aerosolized to male BALB/c mice (22~26 g), and P2 fluorescence signals were detected by living imaging. Half-life (T1/2) and mean retention time (MRT0-∞) were computed by WinNonlin to describe lung retention time. T1/2 or MRT0-∞ was plotted versus particle size, and linear regression was performed.

Results: P2-SLN1~P2-SLN4 possessed average sizes of circa 120, 240, 360 and 480 nm, respectively, with good size distribution homogeneity. After inhalation, P2 fluorescence intensity continuously decreased in the pulmonary region. Noticeably, T1/2 or MRT0-∞ were positively correlated to particle size, with great model-fitness (R2 > 0.99, p < 0.05). Therefore, larger particle size (within the range of 120~480 nm) caused longer retention time.

Conclusion: A positive particle size-lung retention time correlation in SLN was demonstrated. For the development of PNDDS, appropriately increase the particle size would enhance lung retention, vice versa.

  • Open access
  • 59 Reads
Testing the suitability of preserved insect collections for biodiscovery using liquid chromatography mass spectrometry

Small metabolites and venom metabolites produced by insects are known to exhibit biological activity. These metabolites could be used to develop natural product-based therapeutics. To screen for these metabolites, insects must be collected and accurately identified. Natural history collections consist of identified insects and provide a source of raw material for metabolomic screening. The objective of this research was to understand whether preservation significantly altered the insect metabolomic profiles. Insects from the family Sphecidae: Podalonia tydei (Le Guillou), which were preserved in ethanol and flash frozen, were homogenized with methanol. The resulting metabolomic extracts and storage ethanol were analysed using untargeted liquid chromatography-mass spectrometry. Mass spectral data were processed with MZmine2. The data were analysed using multivariate statistical analysis. In the Principal Component Analysis, ethanol stored samples and their storage solvents clustered close together and this was verified by Analysis of Similarity (ANOSIM). Based on ANOSIM (p = 0.003, R2= 0.48) there was significant overlap between chemical profiles of treatments (ethanol only, ethanol stored tissue, flash frozen tissue). A group of acyl-carnitines were putatively identified from the extracts. The flash frozen samples have a high relative abundance for acyl-carnitines, however the Kruskal Wallis (p > 0.05) showed no significant difference between the median of abundance. Therefore, preserved insects from natural history collections and their ethanol storage solvents could be used for metabolomic screening. However, it would be best to use specimens from the same species preserved under various conditions to capture metabolites that may degrade or leach during preservation.

  • Open access
  • 59 Reads
In vivo antigenotoxic properties of Hericium erinaceus ethanolic extract
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Published: 26 September 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General

Hericium erinaceus (Bull.) Pers., also known as lion’s mane or monkey’s head, is a well-established culinary and medicinal mushroom used traditionally against dementia, depression, anxiety, ulcers, heart disease, cancer, and diabetes in animals. This mushroom with a variety of health benefits has strong anti-inflammatory, antioxidant and immune-boosting abilities. Ethanolic extract of the cultured fruiting bodies of H. erinaceus were investigated for antigenotoxic activity against ethyl methanesulphonate (EMS)-induced genotoxicity in third instar larvae of Drosophila melanogaster using alkaline comet assay. A simultaneous 24-h treatment with seven different concentrations of the extract (1.25, 2.5, 5, 10, 20, 40, and 80 mg/mL standard Drosophila food) and 1 mM EMS, show decreased in total comet score compared to positive control. The results showed that the ethanolic extracts of H. erinaceus have a remarkable DNA protective activity against EMS-induced DNA damage, suggesting that this mushroom has potential to be used as a natural preventive compound against DNA damage caused by monofunctional alkylating agents such as EMS.