Graphene-based materials as nanoplatforms for antiviral therapy and prophylaxis.

INTRODUCTION: The dramatic effects caused by viral diseases have prompted the search for effective therapeutic and preventive agents. In this context, 2D graphene-based nanomaterials (GBNs) have shown great potential for antiviral therapy, enabling the functionalization and/or decoration with biomolecules, metals and polymers, able to improve their interaction with viral nanoparticles. AREAS COVERED: This review summarizes the most recent advances of the antiviral research related to 2D GBNs, based on their antiviral mechanism of action. Their ability to inactivate viruses by inhibiting the entry inside cells, or through drug/gene delivery, or by stimulating the host immune response are here discussed. As reported, biological studies performed in vitro and/or in vivo allowed to demonstrate the antiviral activity of the developed GBNs, at different stages of the virus life cycle and the evaluation of their long-term toxicity. Other mechanisms closely related to the physicochemical properties of GBNs are also reported, demonstrating the potential of these materials for antiviral prophylaxis. EXPERT OPINION: GBNs represent valuable tools to fight emerging or reemerging viral infections. However, their translation into the clinic requires standardized scale-up procedures leading to the reliable and reproducible synthesis of these nanomaterials with suitable physicochemical properties, as well as more in-depth pharmacological and toxicological investigations. We believe that multidisciplinary approaches will give valuable solutions to overcome the encountered limitations in the application of GBNs in biomedical and clinical field.

Design of New Schiff Bases and Their Heavy Metal Ion Complexes for Environmental Applications: A Molecular Dynamics and Density Function Theory Study.

Schiff bases (SBs) are important ligands in coordination chemistry due to their unique structural properties. Their ability to form complexes with metal ions has been exploited for the environmental detection of emerging water contaminants. In this work, we evaluated the complexation ability of three newly proposed SBs, 1-3, by complete conformational analysis, using a combination of Molecular Dynamics and Density Functional Theory studies, to understand their ability to coordinate toxic heavy metal (HMs) ions. From this study, it emerges that all the ligands present geometries that make them suitable to complex HMs through the N-imino moieties or, in the case of 3, with the support of the oxygen atoms of the ethylene diether chain. In particular, this ligand shows the most promising coordination behavior, particularly with Pb2+.

Antiviral Compounds to Address Influenza Pandemics: An Update from 2016-2022.

In recent decades, the world has gained experience of the dangerous effects of pandemic events caused by emerging respiratory viruses. In particular, annual epidemics of influenza are responsible for severe illness and deaths. Even if conventional influenza vaccines represent the most effective tool for preventing virus infections, they are not completely effective in patients with severe chronic disease and immunocompromised and new small molecules have emerged to prevent and control the influenza viruses. Thus, the attention of chemists is continuously focused on the synthesis of new antiviral drugs able to interact with the different molecular targets involved in the virus replication cycle. To date, different classes of influenza viruses inhibitors able to target neuraminidase enzyme, hemagglutinin protein, Matrix-2 (M2) protein ion channel, nucleoprotein or RNA-dependent RNA polymerase have been synthesized using several synthetic strategies comprising the chemical modification of currently used drugs. The best results, in terms of inhibitory activity, are in the nanomolar range and have been obtained from the chemical modification of clinically used drugs such as Peramivir, Zanamivir, Oseltamir, Rimantadine, as well as sialylated molecules, and hydroxypyridinone derivatives. The aim of this review is to report, covering the period 2016-2022, the most recent routes related to the synthesis of effective influenza virus inhibitors.

Theranostic Applications of 2D Graphene-Based Materials for Solid Tumors Treatment.

Solid tumors are a leading cause of cancer-related deaths globally, being characterized by rapid tumor growth and local and distant metastases. The failures encountered in cancer treatment are mainly related to the complicated biology of the tumor microenvironment. Nanoparticles-based (NPs) approaches have shown the potential to overcome the limitations caused by the pathophysiological features of solid cancers, enabling the development of multifunctional systems for cancer diagnosis and therapy and allowing effective inhibition of tumor growth. Among the different classes of NPs, 2D graphene-based nanomaterials (GBNs), due to their outstanding chemical and physical properties, easy surface multi-functionalization, near-infrared (NIR) light absorption and tunable biocompatibility, represent ideal nanoplatforms for the development of theranostic tools for the treatment of solid tumors. Here, we reviewed the most recent advances related to the synthesis of nano-systems based on graphene, graphene oxide (GO), reduced graphene oxide (rGO), and graphene quantum dots (GQDs), for the development of theranostic NPs to be used for photoacoustic imaging-guided photothermal-chemotherapy, photothermal (PTT) and photodynamic therapy (PDT), applied to solid tumors destruction. The advantages in using these nano-systems are here discussed for each class of GBNs, taking into consideration the different chemical properties and possibility of multi-functionalization, as well as biodistribution and toxicity aspects that represent a key challenge for their translation into clinical use.

An antibody that targets cell-surface glucose-regulated protein-78 inhibits expression of inflammatory cytokines and plasminogen activator inhibitors by macrophages.

Glucose-regulated protein-78 (Grp78) is an endoplasmic reticulum chaperone, which is secreted by cells and associates with cell surfaces, where it functions as a receptor for activated α2 -macroglobulin (α2 M) and tissue-type plasminogen activator (tPA). In macrophages, α2 M and tPA also bind to the transmembrane receptor, LDL receptor-related protein-1 (LRP1), activating a cell-signaling receptor assembly that includes the NMDA receptor (NMDA-R) to suppress innate immunity. Herein, we demonstrate that an antibody targeting Grp78 (N88) inhibits NFκB activation and expression of proinflammatory cytokines in bone marrow-derived macrophages (BMDMs) treated with the toll-like receptor-4 (TLR4) ligand, lipopolysaccharide, or with agonists that activate TLR2, TLR7, or TLR9. Pharmacologic inhibition of the NMDA-R or deletion of the gene encoding LRP1 (Lrp1) in BMDMs neutralizes the activity of N88. The fibrinolysis protease inhibitor, plasminogen activator inhibitor-1 (PAI1), has been implicated in diverse diseases including metabolic syndrome, cardiovascular disease, and type 2 diabetes. Deletion of Lrp1 independently increased expression of PAI1 and PAI2 in BMDMs, as did treatment of wild-type BMDMs with TLR agonists. tPA, α2 M, and N88 inhibited expression of PAI1 and PAI2 in BMDMs treated with TLR-activating agents. Inhibiting Src family kinases blocked the ability of both N88 and tPA to function as anti-inflammatory agents, suggesting that the cell-signaling pathway activated by tPA and N88, downstream of LRP1 and the NMDA-R, may be equivalent. We conclude that targeting cell-surface Grp78 may be effective in suppressing innate immunity by a mechanism that requires LRP1 and the NMDA-R.

Orange-Peel-Derived Nanobiochar for Targeted Cancer Therapy.

Cancer-targeted drug delivery systems (DDS) based on carbon nanostructures have shown great promise in cancer therapy due to their ability to selectively recognize specific receptors overexpressed in cancer cells. In this paper, we have explored a green route to synthesize nanobiochar (NBC) endowed with graphene structure from the hydrothermal carbonization (HTC) of orange peels and evaluated the suitability of this nanomaterial as a nanoplatform for cancer therapy. In order to compare the cancer-targeting ability of different widely used targeting ligands (TL), we have conjugated NBC with biotin, riboflavin, folic acid and hyaluronic acid and have tested, in vitro, their biocompatibility and uptake ability towards a human alveolar cancer cell line (A549 cells). The nanosystems which showed the best biological performances-namely, the biotin- and riboflavin- conjugated systems-have been loaded with the poorly water-soluble drug DHF (5,5-dimethyl-6a-phenyl-3-(trimethylsilyl)-6,6a-dihydrofuro[3,2-b]furan-2(5H)-one) and tested for their anticancer activity. The in vitro biological tests demonstrated the ability of both systems to internalize the drug in A549 cells. In particular, the biotin-functionalized NBC caused cell death percentages to more than double with respect to the drug alone. The reported results also highlight the positive effect of the presence of oxygen-containing functional groups, present on the NBC surface, to improve the water dispersion stability of the DDS and thus make the approach of using this nanomaterial as nanocarrier for poorly water-soluble drugs effective.

Chemoselective Oxidation of Isoxazolidines with Ruthenium Tetroxide: A Successful Intertwining of Combined Theoretical and Experimental Data.

The direct oxidation reaction of isoxazolidines plays an important role in organic chemistry, leading to the synthesis of biologically active compounds. In this paper, we report a computational mechanistic study of RuO4-catalyzed oxidation of differently N-substituted isoxazolidines 1a-c. Attention was focused on the endo/exo oxidation selectivity. For all the investigated compounds, the exo attack is preferred to the endo one, showing exo percentages growing in parallel with the stability order of transient carbocations found along the reaction pathway. The study has been supported by experimental data that nicely confirm the modeling results.

Nanoscale Technologies in the Fight against COVID-19: From Innovative Nanomaterials to Computer-Aided Discovery of Potential Antiviral Plant-Derived Drugs.

The last few years have increasingly emphasized the need to develop new active antiviral products obtained from artificial synthesis processes using nanomaterials, but also derived from natural matrices. At the same time, advanced computational approaches have found themselves fundamental in the repurposing of active therapeutics or for reducing the very long developing phases of new drugs discovery, which represents a real limitation, especially in the case of pandemics. The first part of the review is focused on the most innovative nanomaterials promising both in the field of therapeutic agents, as well as measures to control virus spread (i.e., innovative antiviral textiles). The second part of the review aims to show how computer-aided technologies can allow us to identify, in a rapid and therefore constantly updated way, plant-derived molecules (i.e., those included in terpenoids) potentially able to efficiently interact with SARS-CoV-2 cell penetration pathways.

Neoadjuvant Systemic Therapy (NAST) in Patients with Melanoma: Surgical Considerations by the International Neoadjuvant Melanoma Consortium (INMC).

Exciting advances in melanoma systemic therapies have presented the opportunity for surgical oncologists and their multidisciplinary colleagues to test the neoadjuvant systemic treatment approach in high-risk, resectable metastatic melanomas. Here we describe the state of the science of neoadjuvant systemic therapy (NAST) for melanoma, focusing on the surgical aspects and the key role of the surgical oncologist in this treatment paradigm. This paper summarizes the past decade of developments in melanoma treatment and the current evidence for NAST in stage III melanoma specifically. Issues of surgical relevance are discussed, including the risk of progression on NAST prior to surgery. Technical aspects, such as the definition of resectability for melanoma and the extent and scope of routine surgery are presented. Other important issues, such as the utility of radiographic response evaluation and method of pathologic response evaluation, are addressed. Surgical complications and perioperative management of NAST related adverse events are considered. The International Neoadjuvant Melanoma Consortium has the goal of harmonizing NAST trials in melanoma to facilitate rapid advances with new approaches, and facilitating the comparison of results across trials evaluating different treatment regimens. Our ultimate goals are to provide definitive proof of the safety and efficacy of NAST in melanoma, sufficient for NAST to become an acceptable standard of care, and to leverage this platform to allow more personalized, biomarker-driven, tailored approaches to subsequent treatment and surveillance.

Activated Alpha 2-Macroglobulin Is a Novel Mediator of Mesangial Cell Profibrotic Signaling in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is caused by the overproduction of extracellular matrix proteins (ECM) by glomerular mesangial cells (MCs). We previously showed that high glucose (HG) induces cell surface translocation of GRP78 (csGRP78), mediating PI3K/Akt activation and downstream ECM production. Activated alpha 2-macroglobulin (α2M*) is a ligand known to initiate this signaling cascade. Importantly, increased α2M was observed in diabetic patients' serum, saliva, and glomeruli. Primary MCs were used to assess HG responses. The role of α2M* was assessed using siRNA, a neutralizing antibody and inhibitory peptide. Kidneys from type 1 diabetic Akita and CD1 mice and human DKD patients were stained for α2M/α2M*. α2M transcript and protein were significantly increased with HG in vitro and in vivo in diabetic kidneys. A similar increase in α2M* was seen in media and kidneys, where it localized to the mesangium. No appreciable α2M* was seen in normal kidneys. Knockdown or neutralization of α2M/α2M* inhibited HG-induced profibrotic signaling (Akt activation) and matrix/cytokine upregulation (collagen IV, fibronectin, CTGF, and TGFß1). In patients with established DKD, urinary α2M* and TGFß1 levels were correlated. These data reveal an important role for α2M* in the pathogenesis of DKD and support further investigation as a potential novel therapeutic target.

Glucose-regulated protein (GRP78) is an important cell surface receptor for viral invasion, cancers, and neurological disorders.

The 78 kDa glucose-regulated protein (GRP78) is an endoplasmic reticulum (ER)-resident molecular chaperone. GRP78 is a member of the 70 kDa heat shock family of proteins involved in correcting and clearing misfolded proteins in the ER. In response to cellular stress, GRP78 escapes from the ER and moves to the plasma membrane where it (a) functions as a receptor for many ligands, and (b) behaves as an autoantigen for autoantibodies that contribute to human disease and cancer. Cell surface GRP78 (csGRP78) associates with the major histocompatibility complex class I (MHC-I), and is the port of entry for several viruses, including the predictive binding of the novel SARS-CoV-2. Furthermore, csGRP78 is found in association with partners as diverse as the teratocarcinoma-derived growth factor 1 (Cripto), the melanocortin-4 receptor (MC4R) and the DnaJ-like protein MTJ-1. CsGRP78 also serves as a receptor for a large variety of ligands including activated α2 -macroglobulin (α2 M*), plasminogen kringle 5 (K5), microplasminogen, the voltage-dependent anion channel (VDAC), tissue factor (TF), and the prostate apoptosis response-4 protein (Par-4). In this review, we discuss the mechanisms involved in the translocation of GRP78 from the ER to the cell surface, and the role of secreted GRP78 and its autoantibodies in cancer and neurological disorders.

Synthesis and Biological Evaluation of 2,3,4-Triaryl-1,2,4-oxadiazol-5-ones as p38 MAPK Inhibitors.

A series of azastilbene derivatives, characterized by the presence of the 1,2,4-oxadiazole-5-one system as a linker of the two aromatic rings of stilbenes, have been prepared as novel potential inhibitors of p38 MAPK. Biological assays indicated that some of the synthesized compounds are endowed with good inhibitory activity towards the kinase. Molecular modeling data support the biological results showing that the designed compounds possess a reasonable binding mode in the ATP binding pocket of p38α kinase with a good binding affinity.

Antiretroviral treatment leading to secondary trimethylaminuria: Genetic associations and successful management with riboflavin.

WHAT IS KNOWN AND OBJECTIVE: Trimethylaminuria is a metabolic disorder characterized by excessive excretion of trimethylamine in body fluids following FMO3 gene mutations. Secondary forms of the disease may be due to consumption of trimethylamine precursor-rich foods or metabolism of some xenobiotics. CASE SUMMARY: A HIV patient developed secondary trimethylaminuria following antiretroviral treatment. Riboflavin supplementation ameliorated his phenotype. 1 H-NMR confirmed increased urine level of TMA. Several genes involved in choline catabolism harboured missense mutations. Riboflavin supplement improved enzymatic activity of mutated enzymes promoting TMA clearance. WHAT IS NEW AND CONCLUSION: Antiretrovirals may increase the concentration of TMA precursors. The present study reports antiretroviral treatment as risk factor for such secondary trimethylaminuria. Riboflavin is an effective treatment.

Cell surface GRP78 signaling: An emerging role as a transcriptional modulator in cancer.

Cancer cells acquire dysregulated gene expression to establish specific transcriptional dependencies and their underlying mechanisms that are ultimately responsible for this addictions have not been fully elucidated. Glucose-regulated protein 78 (GRP78) is a stress-inducible, multifunctional, prosurvival, endoplasmic reticulum chaperone in the heat shock protein 70 family. Expression of cell surface GRP78 (CS-GRP78) is associated with increased malignant behavior and resistance to chemotherapy and radiotherapy by endowing various cancer cells with increased proliferative ability, altered metabolism, improved survival, and augmented invasive and metastatic potential. Emerging evidence has highlighted an unusual role of CS-GRP78 in regulating transcription factors (TFs) by mediating various signaling pathways involved in malignant transformation, metabolic reprogramming, and tumor progression. During the last decade, we targeted CS-GRP78 with C38 monoclonal antibody (C38 Mab) in numerous studies, which have highlighted the epigenetic interplay between CS-GRP78 and various TFs including c-MYC, Yes-associated protein/transcriptional coactivator with PDZ-binding motif, c-Fos, and histone acetylation to potentiate subsequent modulation of tumorigenesis, invasion, and metastasis. Here, we summarize the current state of knowledge about the role of CS-GRP78 in cancer development and progression, including epigenetic regulation and sheds light on CS-GRP78 as vulnerable target for cancer therapy. Overall, this review focuses on the mechanisms of TFs that are behind the transcriptional dysregulation in cancer and lays the groundwork for rational therapeutic use of C38 Mab based on CS-GRP78 biology.

Eco-Friendly 1,3-Dipolar Cycloaddition Reactions on Graphene Quantum Dots in Natural Deep Eutectic Solvent.

Due to their outstanding physicochemical properties, the next generation of the graphene family-graphene quantum dots (GQDs)-are at the cutting edge of nanotechnology development. GQDs generally possess many hydrophilic functionalities which allow their dispersibility in water but, on the other hand, could interfere with reactions that are mainly performed in organic solvents, as for cycloaddition reactions. We investigated the 1,3-dipolar cycloaddition (1,3-DCA) reactions of the C-ethoxycarbonyl N-methyl nitrone 1a and the newly synthesized C-diethoxyphosphorylpropilidene N-benzyl nitrone 1b with the surface of GQDs, affording the isoxazolidine cycloadducts isox-GQDs 2a and isox-GQDs 2b. Reactions were performed in mild and eco-friendly conditions, through the use of a natural deep eutectic solvent (NADES), free of chloride or any metal ions in its composition, and formed by the zwitterionic trimethylglycine as the -bond acceptor, and glycolic acid as the hydrogen-bond donor. The results reported in this study have for the first time proved the possibility of performing cycloaddition reactions directly to the p-cloud of the GQDs surface. The use of DES for the cycloaddition reactions on GQDs, other than to improve the solubility of reactants, has been shown to bring additional advantages because of the great affinity of these green solvents with aromatic systems.

STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes.

Epstein-Barr virus (EBV) causes lymphomas and epithelial cell cancers. Though generally silent in B lymphocytes, this widely prevalent virus can cause endemic Burkitt lymphoma and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. By learning how EBV breaches barriers to cell proliferation, we hope to undermine those strategies to treat EBV lymphomas and potentially other cancers. We had previously found that EBV, through activation of cellular STAT3 prevents phosphorylation of Chk1, and thereby, suppresses activation of the intra-S phase cell-cycle checkpoint, a potent barrier to oncogene-driven proliferation. This observation prompted us to examine the consequences on DNA repair since homologous recombination repair, the most error-free form, requires phosphoChk1. We now report that the defect in Chk1 phosphorylation also curtails RAD51 nucleation, and thereby, homologous recombination repair of DNA double strand breaks. The resulting reliance on error-prone microhomology-mediated end-joining (MMEJ) repair makes EBV-transformed cells susceptible to PARP inhibition and simultaneous accrual of genome-wide deletions and insertions resulting from synthesis-dependent MMEJ. Analysis of transcriptomic and drug susceptibility data from hundreds of cancer lines reveals a STAT3-dependent gene-set predictive of susceptibility of cancers to synthetic lethal PARP inhibition. These findings i) demonstrate how the tumor virus EBV re-shapes cellular DNA repair, ii) provide the first genome-wide evidence for insertions resulting from MMEJ in human cells, and iii) expand the range of cancers (EBV-related and -unrelated) that are likely to respond to synthetic lethal inhibitors given the high prevalence of cancers with constitutively active STAT3.

Chitosan/PAMAM/Hydroxyapatite Engineered Drug Release Hydrogels with Tunable Rheological Properties.

In this paper, a new formulation of biodegradable and bioresorbable chitosan-based hydrogel for controlled drug release was investigated. A chitosan-dendrimer-hydroxyapatite hydrogel, obtained by covalently grafting chitosan powder with an hyperbranched PAMAM dendrimer followed by in-situ precipitation of hydroxyapatite and gelification, was synthesized and characterized by FTIR, NMR, TGA, XRD and rheological studies. The hydrogels have been also doped with an anti-inflammatory drug (ketoprofen) in order to investigate their drug release properties. Chemical and chemical-physical characterizations confirmed the successful covalent functionalization of chitosan with PAMAM and the synthesis of nanostructured hydroxyapatite. The developed hydrogel made it possible to obtain an innovative system with tunable rheological and drug-releasing properties relative to the well-known formulation containing chitosan and hydroxyapatite powder. The developed hydrogel showed different rheological and drug-releasing properties of chitosan matrix mixed with hydroxyapatite as a function of dendrimer molecular weight; therefore, the chitosan-dendrimer-hydroxyapatite hydrogel can couple the well-known osteoconductive properties of hydroxyapatite with the drug-release behavior and good processability of chitosan-dendrimer hydrogels, opening new approaches in the field of tissue engineering based on biopolymeric scaffolds.

Transverse myelitis associated with yellow fever vaccination.

Yellow fever is a mosquito-borne viral hemorrhagic fever endemic to sub-Saharan Africa and South America associated with significant morbidity and mortality. The use of a live attenuated vaccine can prevent yellow fever, but vaccine-associated neurologic disease has been reported and is a safety concern. We present the case of a previously healthy 35-year-old active-duty man who received the yellow fever vaccine prior to deployment and subsequently developed progressive neurologic dysfunction consistent with transverse myelitis.

Pyrimidine 2,4-Diones in the Design of New HIV RT Inhibitors.

The pyrimidine nucleus is a versatile core in the development of antiretroviral agents. On this basis, a series of pyrimidine-2,4-diones linked to an isoxazolidine nucleus have been synthesized and tested as nucleoside analogs, endowed with potential anti-HIV (human immunodeficiency virus) activity. Compounds 6a-c, characterized by the presence of an ethereal group at C-3, show HIV reverse transcriptase (RT) inhibitor activity in the nanomolar range as well as HIV-infection inhibitor activity in the low micromolar with no toxicity. In the same context, compound 7b shows only a negligible inhibition of RT HIV.