Milk is a rich source of miRNA packaged in exosomes. Evidence for the systemic uptake and tissue distribution of milk exosomes was reported in newborn and adult humans and animals. Breastfeeding in infants was associated with a reduced risk of obesity. Numerous adipogenesis-related miRNAs have been detected in human milk exosomes. It has been demonstrated that ingested exosomal milk miRNAs may alter gene expression in offspring to regulate their metabolism and growth. In humans, consumption of other species' milk, such as cows and goats, is continued through adulthood. Since miRNAs are conserved, the concern of cross-species transfer of adipogenic miRNA has been raised in recent years, and the increase in obesity worldwide was attributed partially to dairy milk consumption by humans. However, evidence is still weak. Research emphasizes the need for an adequate number of exosomal milk's miRNAs to reach the target cell for biological action to be achieved. It was reported that obese women's milk had less miRNA-148a and miRNA-30b, which may affect the fat acquisition of their babies. Some exosomal milk miRNAs, such as miRNA-29, miRNA-148, miRNA-30b and miRNA-125b, may have epigenetic effects on milk recipients. Moreover, the ability of milk exosomes to cross the gastrointestinal barrier makes them a promising oral drug delivery tool. Yet, exosomes may also be tagged with specific ligands which target certain tissues. Thus, milk exosomes can be engineered and loaded with certain miRNAs responsible for adipocyte differentiation, conversion, or browning. Modifications in the miRNA cargo of exosomes can benefit human health and be an alternative to traditional drugs.
Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA-FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.
Lung cancer (LC) is the leading cause of cancer-related deaths, responsible for approximately 18.4% of all cancer mortalities in both sexes combined. The use of systemic therapeutics remains one of the primary treatments for LC. However, the therapeutic efficacy of these agents is limited due to their associated severe adverse effects, systemic toxicity and poor selectivity. In contrast, pulmonary delivery of anticancer drugs can provide many advantages over conventional routes. The inhalation route allows the direct delivery of chemotherapeutic agents to the target LC cells with high local concertation that may enhance the antitumor activity and lead to lower dosing and fewer systemic toxicities. Nevertheless, this route faces by many physiological barriers and technological challenges that may significantly affect the lung deposition, retention, and efficacy of anticancer drugs. The use of lipid-based nanocarriers could potentially overcome these problems owing to their unique characteristics, such as the ability to entrap drugs with various physicochemical properties, and their enhanced permeability and retention (EPR) effect for passive targeting. Besides, they can be functionalized with different targeting moieties for active targeting. This article highlights the physiological, physicochemical, and technological considerations for efficient inhalable anticancer delivery using lipid-based nanocarriers and their cutting-edge role in LC treatment.
P2Y12 is a platelet surface protein which is responsible for the amplification of P2Y1 response. It plays a crucial role in platelet aggregation and thrombus formation through an ADP-induced platelet activation mechanism. Despite that P2Y12 platelets' receptor is an excellent target for developing antiplatelet agents, only five approved medications are currently in clinical use which are classified into thienopyridines and nucleoside-nucleotide derivatives. In the past years, many attempts for developing new candidates as P2Y12 inhibitors have been made. This review highlights the importance and the role of P2Y12 receptor as part of the coagulation cascade, its reported congenital defects, and the type of assays which are used to verify and measure its activity. Furthermore, an overview is given of the clinically approved medications, the potential naturally isolated inhibitors, and the synthesised candidates which were tested either in-vitro, in-vivo and/or clinically. Finally, we outline the in-silico attempts which were carried out using virtual screening, molecular docking and dynamics simulations in efforts of designing novel P2Y12 antagonists. Various phytochemical classes might be considered as a corner stone for the discovery of novel P2Y12 inhibitors, whereas a wide range of ring systems can be deliberated as leading scaffolds in that area synthetically and theoretically.
P2Y12 has a key role in platelet aggregation and thrombus formation via an ADP-induced platelet activation mechanism. Recently, P2Y12 antagonists have become of great interest in the clinical management of antithrombotic therapy. In light of this, we explored the pharmacophoric space of P2Y12 using structure-based pharmacophore modelling. Subsequently, genetic algorithm and multiple linear regression analyses were conducted to select the best combination of physicochemical descriptors and pharmacophoric models to create useful predictive quantitative structure-activity relationship (QSAR) equation (r 2 = 0.9135, r (adj) 2 = 0.9147, r (PRESS) 2 = 0.9129, LOF = 0.3553). One pharmacophoric model emerged in the QSAR equation and was validated by analysing receiver operating characteristic (ROC) curves. The model was then used to screen 200 000 compounds from the National Cancer Institute (NCI) database. The top-ranked hits were in vitro tested, where their IC50's range between 4.20 to 35.00 μM when measured via the electrode aggregometry assay. Whilst, the VASP phosphorylation assay showed 29.70% platelet reactivity index for NSC618159, which is superior to that of ticagrelor.
Extensive attention has been focused on herbal medicine for the treatment of different endocrine disorders. In fact, compelling scientific evidence indicates that natural compounds might act as endocrine modulators by mimicking, stimulating, or inhibiting the actions of different hormones, such as thyroid, sex, steroidal, and glucose regulating hormones. These potentials might be effectively employed for therapeutic purposes related to the endocrine system as novel complementary choices. Nevertheless, despite the remarkable therapeutic effects, inadequate targeting efficiency and low aqueous solubility of the bioactive components are still essential challenges in their clinical accreditation. On the other hand, nanotechnology has pushed the wheels of combining inorganic nanoparticles with biological structures of medicinal bioactive compounds as one of the utmost exciting fields of research. Nanoparticle conjugations create an inclusive array of applications that provide greater compliance, higher bioavailability, and lower dosage. This can safeguard the global availability of these wealthy natural sources, regardless of their biological occurrence. This review inspects future challenges of medicinal plants in various endocrine disorders for safe and alternative treatments with examples of their nanoparticle formulations.
According to the World Health Organisation (WHO), as of week 23 of 2022, there were more than 1,311 cases of dengue in Malaysia, with 13 deaths reported. Furthermore, there was an increase of 65.7% during the same period in 2021. Despite the increase in cumulative dengue incidence, there is no effective antiviral drug available for dengue treatment. This work aimed to evaluate several nitro-benzylidene phenazine compounds, especially those that contain 4-hydroxy-3,5-bis((2-(4-nitrophenyl)hydrazinylidene)-methyl)benzoate through pharmacophore queries selection method as potential dengue virus 2 (DENV2) NS2B-NS3 protease inhibitors. Herein, molecular docking was employed to correlate the energies of selected hits' free binding and their binding affinities. Pan assay interference compounds (PAINS) filter was also adopted to identify and assess the drug-likeness, toxicity, mutagenicity potentials, and pharmacokinetic profiles to select hit compounds that can be considered as lead DENV2 NS2B-NS3 protease inhibitors. Molecular dynamics assessment of two nitro-benzylidene phenazine derivatives bearing dinitro and hydroxy groups at the benzylidene ring showed their stability at the main binding pocket of DENV2 protease, where their MM-PBSA binding energies were between -22.53 and -17.01 kcal/mol. This work reports those two nitro-benzylidene phenazine derivatives as hits with 52-55% efficiency as antiviral candidates. Therefore, further optimisation is required to minimise the lead compounds' toxicity and mutagenicity.