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.

In December 2019, a novel strain of coronavirus, SARS-CoV-2, was identified. Infected patients revealed symptoms of fever, cough (dry), sore throat, and fatigue, which began manifesting after 5 days of incubation. Hoping to prevent transmission, many countries adopted a mandatory mask use in closed public spaces. However, most mask options display a passive action against COVID-19. To overcome such restrictions, this work proposes the incorporation of anti-viral essential oils (EOs) loaded onto a nanofibrous layer that can be adapted to both community and commercial masks.

Twenty EOs selected based on their antimicrobial nature were examined for the first time against the Escherichia virus MS2. The most effective were the lemongrass (LO), Niaouli (NO) and eucalyptus (ELO) with a minimum inhibitory concentration (MIC) of 356.0 mg/mL, 365.2 mg/mL and 586.0 mg/mL, respectively. Polycaprolactone (PCL) and cellulose acetate (CA) were prepared individually at 14 wt% in chloroform/dimethylformamide (DMF) and 10 wt% in acetone/DMF, respectively, and combined at 3:1 ratio. Polymeric solutions were then processed via eletrospinning with processing parameters being optimized to 24.7 kV, 3.2 mL/h and 21 cm. Uniform, beadless nanofibers were obtained. Mats were characterized as mechanically resilient, to endure movements arising from mask positioning, and hydrophobic in nature, to repel droplets coming from the exterior. Loading of the nanofibrous mats was accomplished via physisorption using the free -OH groups of the CA as linkers. Mats were loaded with the EOs at MIC concentration for 72 h (saturation). Presence of the EOs was confirmed along the mats. Antimicrobial testing via halo determination, verified their diffusion abilities. More importantly, time-kill kinetics testing of the loaded mats attested to the EOs capability to fight the virus MS2 even when bonded to the nanofibers. Data demonstrated the potential of these EOs-loaded PCL/CA nanofibers mats to work as COVID-19 active barriers for individual protection masks.

Supramolecular protein assembly, such as cages, rings, and tubes can be used as reaction vessels and molecular templates for applications in catalysis, imaging and drug delivery.¹ Ferritin (Ft) is a member of ferroxidase family of enzymes that forms a spherical nanocage. It sequesters iron by concentrating it in its internal cavity for storage and detoxification.² Ft is very promising as a drug loading and releasing system since it is non-immunogenic, bio-compatible, highly stable, soluble in the bloodstream. It can be internalized via Ft-binding receptors (like transferrin receptor 1³ or Scara5⁴) that are over-expressed in a variety of malignant cells. Well established metallodrugs like cisplatin,⁵ carboplatin,⁶ a Pt-terpyridine compound,⁷ three different gold-based anticancer compounds (Auoxo3, Au2phen, Auoxo4),^8-9 a bimetallic Pt-Au compound¹⁰, a bimetallic Pt-As compound and a di-ruthenium complex¹¹ have been trapped within the Ft nanocages, taking advantage of the alkaline pH disassembly/reassembly protocol. The drug-loaded nanocomposites have been characterized by circular dichroism, to evaluate the protein secondary structure content upon drug encapsulation, and by UV-vis absorption spectroscopy, to assess the drug loading within the protein cage. ICP-MS allowed to quantify the amount of drug trapped inside the nanocage and to define metal/Ft stoichiometry, while X-ray crystallography unveiled the metallodrugs binding sites on the proteins structure and the nature of the interaction of the different compounds with Ft. The compounds often degrade upon encapsulation within the protein cage; metal-containing fragments coordinate Cys or His side chains. However, the coordination does not affect the overall cytotoxicity of the encapsulated anticancer agents, since many molecules of the metallodrugs remain trapped in the bulk within the inner core of the cage. Biological activity studies show that, even though the presence of the cage reduces the overall toxicity of the metallodrugs, the adducts of the selected compounds with Ft are generally more selective towards cancer cells than to non-malignant cells. Altogether these data indicate that encapsulation of metal-based drugs within Ft nanocages is a promising strategy to deliver these molecules to their final targets.¹²

1. Maity, B.et al. Curr. Opin. Chem. Biol. (2015) 25, 88.
2. Uchida M. et al. Am. Chem. Soc. (2006) 128, 16626.
3. Hogemann-Savellano, D. Neoplasia (2003) 5, 495.
4. Mendes-Jorge, L. PLoS One (2014) 9, 106974.
5. Pontillo, N. Commun. (Camb) (2016) 52, 4136.
6. Pontillo, N. ACS Med. Chem. Lett. (2017) 8, 433.
7. Ferraro, G. Nanomedicine (Lond.) (2018) 13, 2995.
8. Ferraro, G. Chem. Commun. (Camb) (2016) 52, 9518.
9. Monti, D.M. Dalt. Trans. (2017) 46, 15454.
10. Ferraro, G. Int J Biol Macromol. (2018) 115, 1116.
11. Petruk, G. Chem. Med. Chem. (2019) 14, 594.
12. Monti, D.M. Nanomedicine: N.B.M. (2019) 20 ,101997.

According to the World Health Organization, the neuropsychiatric disorders pose an increasingly greater burden on health, society and economy of countries. Currently there are strategies to prevent some of these disorders and there are treatments or means to alleviate their symptoms. In the case of depression, the medication consists of antidepressant drugs. Such drugs can also be used in other conditions like anxiety, pain or insomnia. A shortcoming of the currently used antidepressants is the occurrence of side effects that sometimes are unbearable for the patient. In this respect, a promising direction is the usage of medicinal plants. Plant parts are rich in phytochemicals that could be beneficial in mental disorders by acting on various targets. Here we investigated the antidepressant effect of ten natural compounds from sage, mint and citrus. The biological activity of these compounds was investigated by calculating ki values and affinities for dopamine receptor D2, serotonin transporter (SERT) and 5-hydroxytryptamine receptor 1A (5HT1A) using Almond-Pentacle software. Our results showed that resveratrol and rutin could be efficient antidepressants.

Acknowledgments. The study was supported by UEFISCDI through the projects PN-III-P2-2.1-PED2019-1471 “New biocompatible shagaol and curcuminoid-like products used as adjuvantes in cancer radiotherapy” and PN-III-P1-1.2-PCCDI-2017-0728 “Integrated project for the development of technologies dedicated to advanced medical treatments”.

G-protein-coupled receptors (GPCR), a seven-transmembrane α-helical domain protein, contribute to many physiologic functions including vision, olfaction and taste and also to several pathologic processes including hypersensitivity to angiotensin II, inflammatory and vascular diseases [1, 2]. GPCRs in binding with agonistic ligands adopt a proton-transport dependent conformational change and activate cytoplasmic heterotrimeric G proteins (Gα/Gβγ subunits) through dissociation of Gα from Gβγ complex and exchange of GTP for GDP in Gα subunit [3, 4]. This activates a second messenger including cAMP, Ca2+, diacylglycerol which induces some intracellular pathways such as MAPK, PI3K-Akt and Ras and Rho GTPases [5]. Moreover, GPCR activation promotes receptor phosphorylation by GPCR-kinase with subsequent binding of β-arrestin which induces G-protein independent signaling cascades [6, 7].

COVID-19-induced inflammatory cascade has been attributed to ACE2 downregulation and imbalance of proinflammatory ACE/AngII/AT1R and anti-inflammatory ACE2/Angiotensin(1-7)/Mas axes in favor of the former [8]. AT1R, AT2R and Mas receptors belong to GPCR family [9, 10]. While sustained AngII activation of AT1R induces inflammatory responses through G-proteins, angiotensin(1-7) promotes anti-inflammatory effects both via Mas/GPCR receptors and AT1R/GPCR mediated β-arrestin pathway [11]. SARS-CoV2 has been suggested to induce lung edema via activation of GPCRs or modulating G-proteins involved in adenosine-CFTR regulation system and epithelial Na channel function [12]. Complement 5a receptor1 (C5aR1), a member of GPCR family, has recently been proposed to be involved in COVID-19 pathogenesis [13]. GPCR4, which regulates vascular permeability and leukocyte recruitment, has been hypothesized to play a part in SARS-CoV2 infection [14].
In this article the role of GPCRs in the body and in COVID-19 are discussed.

References:
1. Quitterer, U. and S. AbdAlla, Discovery of pathologic GPCR aggregation. Frontiers in medicine, 2019. 6: p. 9.
2. Zalewska, M., M. Siara, and W. Sajewicz, G protein-coupled receptors: abnormalities in signal transmission, disease states and pharmacotherapy. Acta Pol Pharm, 2014. 71(2): p. 229-243.
3. Rajagopal, S., K. Rajagopal, and R.J. Lefkowitz, Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nature reviews Drug discovery, 2010. 9(5): p. 373-386.
4. Zhang, X.C., et al., Proton transfer-mediated GPCR activation. Protein & cell, 2015. 6(1): p. 12-17.
5. Walsh, C.T., D. Stupack, and J.H. Brown, G Protein–Coupled Receptors Go Extracellular: RhoA Integrates the Integrins. Molecular interventions, 2008. 8(4): p. 165.
6. Tilley, D.G., G protein–dependent and G protein–independent signaling pathways and their impact on cardiac function. Circulation research, 2011. 109(2): p. 217-230.
7. Peterson, Y.K. and L.M. Luttrell, The diverse roles of arrestin scaffolds in G protein–coupled receptor signaling. Pharmacological reviews, 2017. 69(3): p. 256-297.
8. Nejat, R. and A.S. Sadr, Are losartan and imatinib effective against SARS-CoV2 pathogenesis? A pathophysiologic-based in silico study. In silico pharmacology, 2021. 9(1): p. 1-22.
9. Magnani, F., et al., Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. ACS chemical biology, 2014. 9(7): p. 1420-1425.
10. Santos, R.A., et al., Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proceedings of the National Academy of Sciences, 2003. 100(14): p. 8258-8263.
11. Manglik, A., et al., β-Arrestin–Biased Angiotensin II Receptor Agonists for COVID-19. Circulation, 2020. 142(4): p. 318-320.
12. Hameid, R.A., et al., SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport. American Physiological Society Rockville, MD.
13. Carvelli, J., et al., Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis. Nature, 2020: p. 1-5.
14. Yang, L.V., et al., Can GPR4 Be a Potential Therapeutic Target for COVID-19? Frontiers in medicine, 2021. 7: p. 1150.