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  • Open access
  • 72 Reads
A Potential Role of Hypoxia-Inducible Factor (Hif-1) Alpha in Taravana Syndrome

The number of subjects who practice recreational breath-hold diving is increasing; therefore there is a growing need to know the adaptations that this sport could have on the health of the participants. They are exposed to an increased hyperbaric pressure and low temperature that cause change in arterial blood gases and induced a human diving response which includes increased arterial blood pressure, reduced cardiac output, bradycardia and peripheral vasoconstriction. Start on the matter that these adaptations are still not fully understood, we decided to investigate some biomarkers that should be involved in this disorders starting to analyse Hypoxia-inducible factor 1 alpha (HIF-1a). We enrolled in our study 31 healthy free divers from different part of Sicily, aged 41,86 ± 11,41, weight 77,52 ± 11,30 kg, height 175,19 ± 6,13 cm, who practiced this activity for more than 5 years. We asked them to perform 5 consecutive dives at 20 meters, without permanence on the bottom, with free recovery between the different dives. A baseline venous blood sample was taken immediately after surfacing from the 5th dive (less than 3 minutes). The samples were stored to -80 until the analysis were done using ELISA method. The results showed that comparing HIF-1a value before and after the dives, there were an increase in the concentration that started from 158,43 pg/ml and be at end 246,06 pg/ml. In conclusion, the Hypoxia-inducible factor 1 alpha can be considered co-responsible for various phenomena, certainly not with pathological destinies, but rather working with "adaptation" phenomena to this type of activity. These are just the preliminary results that need further investigations to be confirmed.

  • Open access
  • 88 Reads
Lignocellulosic-based nanoparticles loaded with essential oils against Staphylococcus aureus and Pseudomonas aeruginosa – mediated infections

Infected diabetic foot ulcers (DFUs) are a frequent and costly complication of diabetes, with limb amputation being highly prevalent worldwide. Even if treated, recurrence is frequent, with pathogen clearance and degenerated tissue recovery being increasingly more difficult each time. Persistent pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa are the main microbial inhabitants of infected DFUs, often gaining antimicrobial-resistance to treatment [1]. Nanoparticle (NP)-mediated therapies may overcome this problem, as they are able to carry and protect loads from biodegradation, be internalized by the cell, and release the load(s) in a controlled manner [2, 3]. As payloads, plant-derived essential oils (EOs) exert quick and strong bactericidal action. This work proposes EO-encapsulation into polyelectrolyte complexed (PEC) NPs fabricated with natural, renewable, and bactericidal polymers [quaternized cellulose (QC) and carboxymethyl lignin (CML)] [4]. The antimicrobial activity of laurel, oregano and dill EOs was screened for the first time against reference strains of S. aureus and P. aeruginosa, by minimum inhibitory concentration (MIC) and time-kill kinetics, up to 24 h of incubation [1, 5]. Glycidyltrimethylammonium chloride was added to microcrystalline cellulose to obtain QC. CML was obtained through reaction with monochloroacetic acid to softwood kraft lignin and served as anionic counterpart. At optimized pH and ionic strength, EOs were added to the anionic polyion before complexation, then added to polycation and ultrasonicated to form EO-loaded QC/CML PEC NPs. Dialysis and condensation purified NP dispersions, and the release profile of loaded EOs was monitored by UV-Visible spectroscopy. Antimicrobial activity of loaded PEC NPs was confirmed through the determination of agar diffusion and time-kill kinetics assays, similarly to Antunes et al. [1]. Preliminary data pointed out the potential of EO-loaded PECs to work as a therapeutic alternative to conventional strategies, or treatment adjuvant, to fight some of the pathogens colonizing DFUs.

[1] Antunes JC, Tavares TD, Teixeira MA, et al (2021) Eugenol-Containing Essential Oils Loaded onto Chitosan/Polyvinyl Alcohol Blended Films and Their Ability to Eradicate Staphylococcus aureus or Pseudomonas aeruginosa from Infected Microenvironments. Pharmaceutics 13:195.

[2] Antunes JC, Pereira CL, Teixeira GQ, et al (2017) Poly(γ-glutamic acid) and poly(γ-glutamic acid)-based nanocomplexes enhance type II collagen production in intervertebral disc. J Mater Sci Mater Med 28:.

[3] Antunes JC, Benarroch L, Moraes FC, et al (2019) Core-Shell Polymer-Based Nanoparticles Deliver miR-155-5p to Endothelial Cells. Mol Ther - Nucleic Acids 17:210–222.

[4] Barhoum A, Jeevanandam J, Rastogi A, et al (2020) Plant celluloses, hemicelluloses, lignins, and volatile oils for the synthesis of nanoparticles and nanostructured materials. Nanoscale 12:22845–22890.

[5] Felgueiras HP, Homem NC, Teixeira MA, et al (2020) Physical, thermal, and antibacterial effects of active essential oils with potential for biomedical applications loaded onto cellulose acetate/polycaprolactone wet-spun microfibers. Biomolecules 10:1–20.

  • Open access
  • 69 Reads
Protective Roles of Thymoquinone Nanoformulations: Potential Nanonutraceuticals in Human Diseases

Nanotechnology has the potential to improve bioavailability and drug delivery for bioactive compounds derived black seed (Thymoquinone, TQ) for the effective management of different human diseases. Therefore, numerous Nanoformulations have been developed improved oral bioavailability of Thymoquinone. The current study gives a review of the applications of Nanomedicine to enhance the biological activities of TQ to control different diseases in several in vivo studies as preliminary investigation for human diseases treatment by Nano-TQ. Nano-TQ effectively augments the anticancer roles of doxorubicin by upregulation of P53, downregulation of Bcl2 and potentiated paclitaxel’s apoptosis in MCF-7, breast cancer cell. Moreover, Nano-TQ protects against diabetes, inflammation, CNS, and hepatotoxicity mainly by enhancement of organs’ antioxidant status. From the current studies, we can conclude that Nano-TQ is a promising nutraceutical for human health in the prevention and treatment of various disorders.

  • Open access
  • 73 Reads
Impact of Nanotechnology on the future of pharmaceuticals and Nutraceuticals: The Road toward precision Medicines –Case Studies

Over the past decade, evidence from the scientific and medical communities has demonstrated that nanobiotechnology and nanomedicine have tremendous potential to affect numerous aspects of cancer and other disorders in term of early diagnosis and targeted therapy. The utilization of nanotechnology for the development of new Nano-carrier systems has the potential to offer improved targeted delivery through increased solubility and sustained retention and more importantly active targeting. One of the major advantages of this innovative technology is its unique multifunctional characteristics. Targeted delivery of drug incorporated nanoparticles, through conjugation of site-specific cell surface markers, such as tumor-specific antibodies or ligands, which can enhance the efficacy of the anticancer drug and reduce the side effects. Additionally, multifunctional characteristics of the Nano-carrier system would allow for simultaneous imaging of tumor mass, targeted drug delivery and monitoring (Theranostics).

A summary of recent progress in nanotechnology as it relates to nanoparticles and drug delivery will be reviewed. Nano Nutraceuticals using combination of various natural products provide a great potential in diseases prevention. Additionally, various Nanomedicine approaches for the detection and treatment of various types of organ specific delivery, vascular targeting, and vaccine will be briefly discussed.

Reference: Mousa SA, Bawa R, and Audette GF (Editors): The Road from Nanomedicine to Precision Medicine, Jenny Stanford Publishing (2020) – 1200+ pages, 36 chapters [ISBN 978-981-4800-59-4 (Hardcover), 978-0-429-29501-0 (eBook)].

  • Open access
  • 131 Reads
Proteomics based precision medicine for diagnosis of Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is an autoimmune disease which presents clinical manifestations in different organs and presenting autoantibodies targeting its own body. The pathogenesis of SLE is not yet fully understood. However, there is no proper biomarker to diagnose SLE and to measure disease activity. Proteomics based precision medicine approaches aims to improve diagnostics and prognostics of SLE. Components of the complement system have been associated with improved diagnosis of SLE patients.

We present a proteomics driven study to address and identify potential proteomic markers for patient subtyping. Plasma samples from the four different SLE patient groups (low vs. high SLEDAI; low vs. high C3gd) were selected based on clinical scores from the SLE patients (n=40). Plasma samples were analyzed by quantitative proteome analysis tandem mass spectrometry and low-abundance regulatory proteins using multiplex analysis. Autoantigen profiles were determined by 1536plex Immunome array. Our findings identify patients with the high SLEDAI scores were diagnosed with SLE at an earlier age of, while the patients with the low SLEDAI score were diagnosed at a later age. Proteomics analysis enabled quantitative assessment of patient group specific changes enabling subtyping of the four patient groups by principle component analysis. When compared between C3dghigh – C3dglow groups, 7 proteins were found to be upregulated and 43 proteins were downregulated. There were 16 upregulated proteins and 10 downregulated proteins in SLEDAIhigh – SLEDAIlow protein comparison.

From our experiments, we found the differences in key parameters of the blood test such as age of diagnosis, anti-dsDNA concentration, lymphocyte count of C1q concentration. The list of upregulated and downregulated proteins was obtained in the proteome analysis of these patient groups. These proteins can be valuable to understand subtypes of SLE patients as well as serve as potential diagnostic biomarkers for SLE.

  • Open access
  • 591 Reads
Self-Nano Emulsifying Drug-Delivery Systems: From the Development to The Current Applications and Update of the Biopharmaceutical Aspect

Approximately one-third of newly discovered drug molecules show insufficient water solubility and therefore low oral bioavailability. Different lipid-based formulations have been explored in the past few decades to improve the oral delivery of such compounds. Self-nano-emulsifying drug-delivery systems (SNEDDSs) are one of the emerging strategies developed to tackle the issues associated with their oral delivery.

Self-Nano-emulsifying drug delivery systems (SNEDDS), which are isotropic mixtures of oils, surfactants, solvents, and co-solvents/surfactants, can be used for the design of formulations in order to improve the oral absorption of highly lipophilic drug compounds. The efficiency of oral absorption of the said drug from such type of formulation depends on many formulation-related parameters, such as surfactant concentration, oil/surfactant ratio, the polarity of the emulsion, droplet size, and charge, all of which in essence determine the self-emulsification ability. With the growing interest in this field, there is an increasing need for the selection of excipients guidelines to obtain an effective and safe delivery system with improved bioavailability. The aim of this review is to present the mechanism of self-emulsification, composition, the role of various excipients, formulation approaches, different techniques, evaluation parameters, factors affecting SNEDDS, advantages, drawbacks, applications, and future trends. This review also offers an updated overview of SNEDDS application from the biopharmaceutical point of view, various techniques used for the transformation of liquid SNEDDS into solid dosage forms, and regulatory status of SNEDDS. The present review gives an insight into SNEDDS for the oral administration of both lipophilic and hydrophilic compounds.

  • Open access
  • 337 Reads
Antidepressant-like Effects of Kynurenic Acid Analogues

Kynurenic acid (KYNA) is a metabolite of the L-tryptophan (TRP)-kynurenine (KYN) pathway which has been shown to possess neuroprotective and antidepressant-like properties. The intracerebroventricular (i.c.v.) administration of kynurenic acid (KYNA) triggered antidepressant-like effects at least in part through the serotonin 5-hydroxytryptamine (5-HT) type 2 receptors, D2, D3, D4 dopamine receptors, and gamma-aminobutyric acid subunit A (GABAA) receptors in modified forced swimming test (FST) of mouse. However, KYNA is impermeable to the blood-brain-barrier (BBB) and thus it is probably a cause that the peripheral administration of KYNA did not exhibit an antidepressant-like effect.

New KYNA analogues were designed to overcome the BBB in attempt to deliver neuroprotective KYNA molecules to the central nervous system (CNS). The antidepressant-like effects of KYNA analogues SZR-72, SZR-81, and SZR-104 were studied i.c.v. and intraperitoneally (i.p.) with a modified FST.

The FST revealed that i.c.v. administration of SZR-81 significantly decreased immobility and significantly increased swimming time, which suggested that its antidepressant-like effects were triggered through the serotonin 5-HT nervous system. SZR-72 and SZR-104 did not significantly change either immobility, climbing, or swimming time, suggesting SZR-72and SZR-104 did not have antidepressant-like effects. Furthermore, i.p. administration of SZR-81 did not change either immobility, climbing, or swimming time like i.c.v. administration.

Two of the KYNA analogues SZR-72and SZR-104 may not have the antidepressant-like properties and SZR-81 may not cross the BBB or be modified on the way to the CNS. Novel KYNA analogues are expected to be designed in search of potent antidepressants which reserve antidepressant properties, cross the BBB, and target in the CNS.

  • Open access
  • 262 Reads
Antibacterial assessment of sodium alginate/gelatin films loaded with propolis extract

Antimicrobial resistance has been increasing owing to the excessive use of antibiotics, contributing thus to the exploration of plant extracts as potential alternatives. Propolis extract (PE) for instance, has been applied as antimicrobial agent against the most prevalent bacteria found in infected wounds (e.g. Staphylococcus aureus and Pseudomonas aeruginosa). Moreover, PE can induce tissue regeneration; however, to increase its effectiveness, delivery platforms such as polymeric films composed of biocompatible materials must be applied. In this scenario, the goal of this work was to produce PE-loaded biodegradable/biocompatible polymeric films, composed of sodium alginate (SA)/gelatin (GN) (2wt% SA concentration, polymer ratio 70/30 v/v), via the solvent casting/phase inversion technique, followed by cross-linking with CaCl2 at 2wt% in dH2O. First, PE’s minimum inhibitory concentration (MIC) was obtained (0.338 mg/mL for S. aureus and 1.353 mg/mL for P. aeruginosa). Subsequently, SA/GN films were fabricated and functionalized with PE (at P. aeruginosa MIC) before (blended within polymeric solution) and after (via adsorption) its production. Successful incorporation of PE was confirmed via Fourier-transformed infrared spectroscopy (FTIR). The antibacterial activity of the films was evaluated via agar diffusion (qualitative) and killing-time kinetics (quantitative) assays. Results showed that PE-loaded SA/GN films were capable of efficiently inhibit the growth of by S. aureus and P. aeruginosa, and thus, SA/GN/PE films can be considered as potential delivery platforms of PE for applications in wound healing.

  • Open access
  • 74 Reads
Co-entrapment of sorafenib and cisplatin in poly[ε-caprolactone-co-(12-hydroxystearate)] copolymer for dual drug delivery application

Drug-loaded nanocarriers have overcome various challenges compared with the bare chemo-drug, such as limited bioavailability, multiple drug resistance, poor patient compliance, adverse drug reactions, particularly side effects of chemotherapy and offer advantages such as protection from degradation in the blood stream, better drug solubility and improved drug stability. One promising group of controlled and targeted drug delivery systems is the polymer-based nanoparticles which can sustain release of active agent by diffusion and their degradation.

Sorafenib is the only drug which is capable to prolong the life of patients suffered from Hepatocellular carcinoma. Cisplatin remains one of the most widely used broad spectrum anticancer drug for the treatment of a variety of solid tumors. Nanoformulations can exert synergistic effect by entrapping two drugs with different mode of action, such as sorafenib and cisplatin.

In our study, we prepared polymeric nanoparticles by optimised double emulsion solvent evaporation method with a good production yield by a novel biocatalytically synthetized 12-hydroxystearic acid ε-caprolactone copolymer (12CL) which is biocompatible and biodegradable carrier by co-entrapment of sorafenib and cisplatin in nanotherapeutics in order to investigate the synergistic effect of sorafenib in combination with cisplatin. The active agents were encapsulated and also cross-linked with carbodiimide to increase the encapsulation efficiency. To improve the drug encapsulation efficiency, bovine serum albumin (BSA) was also incorporated as a protein capable of complexation with the cisplatin.

  • Open access
  • 150 Reads
Neuroprotective Therapies in Spinal Cord Injury, the First and Necessary Step towards the Cure.

A trauma to the spinal cord involves the massive injury to the white matter and initiates a severe, destructive and extraordinarily protracted inflammation characterized by heavy infiltration by CD68+/CD163-, inflammatory macrophages. Post-traumatic destruction of the spinal cord by phagocytic macrophages along with a marked elevation of pro-inflammatory cytokines, including IFN-γ, IL-1α, IL-1β, IL-6 and of chemokines indicates the need for anti-inflammatory therapies to inhibit and eliminate these damaging processes and to result in neuroprotection. In a rat model of the balloon crush over the mid-thoracic spinal cord from the 3Fogarty catheter placed epidurally a deep area of necrosis and hemorrhage resulting from the trauma is converted into a cavity of injury (COI) filled by necrotic debris and hemorrhage and filling up with excess edema fluid. The COI is defined by progressively severe astrogliosis forming a wall whose thickness grows with a progressive lowering of the numbers of phagocytic macrophages beyond 16 weeks post-SCI. An area of necrosis that is superficial with disruption of a wide area of the surface of the spinal cord, it becomes invaded by granulomatous inflammation from the sub-arachnoid space including macrophages, fibroblasts and blood vessels. The expansion of this type of inflammation, called arachnoiditis, is counteracted by a progressively severe astrogliosis and in time it is often separated from the spinal cord by liquid-containing cystic spaces not unlike the COI. A macrophage count in the COI test has been developed to measure the severity of inflammation and also, to measure the anti-inflammatory effect of a candidate treatment. It involves counting phagocytic macrophages in a standardized fashion at the margin of the COI in consecutive sections of the spinal cord stained with luxol fast blue and haematoxylin and eosin (LFB+H&E). This new analytic method allowed for detection of a powerful anti-inflammatory effect of dexamethasone and two Myxomavirus-derived proteins, Serp-1, with anti-thrombotic/anti-thrombolytic action, and M-T7, a chemokine inhibitor. Each of these 3 agents were administered by a continuous subdural infusion in the vicinity of the SCI for one week and resulted in lowering of the numbers of macrophages by 50-80% with remarkable slowing down of the phagocytosis of myelin-rich necrotic debris and hemorrhages in the COI, indicating the need for much longer administration to eliminate the debris by drug-reduced phagocytosis. While administration of dexamethasone has proven to result in severe toxicity leading to shock, both viral proteins were well tolerated. Continuous subdural administration of Serp-1 for 8 weeks resulted in elimination of phagocytic macrophages from the COI. This is the first pre-clinical study demonstrating that an anti-inflammatory treatment can effectively shorten the inflammatory disease and result in neuroprotection. The inhibition and elimination of severe, destructive inflammation post-SCI is the first and necessary step in a multistep therapy leading to the cure of severe spinal cord trauma. Once inflammation is eliminated, implantation of a bridge into the COI that will support axonal regeneration in neuroregenerative therapies can be contemplated.