Dendritic Cells/Natural Killer Cross-Talk: A Novel Target for Human Immunodeficiency Virus Type-1 Protease Inhibitors

BACKGROUND: HIV-1 Protease Inhibitors, namely PIs, originally designed to inhibit HIV-1 aspartic protease, can modulate the immune response by mechanisms largely unknown, and independent from their activity on viral replication. Here, we analyzed the ability of PIs to interfere with differentiation program of monocytes toward dendritic cell (DCs) lineage, a key process in the inflammatory response. METHODOLOGY/PRINCIPAL FINDINGS: Monocytes from healthy donors were isolated and induced to differentiate in vitro in the presence or absence of saquinavir, ritonavir, nelfinavir, indinavir or amprenavir (sqv, rtv, nlfv, idv, apv, respectively). These drugs demonstrated a differential ability to sustain the generation of immature DCs (iDCs) with an altered phenotype, including low levels of CD1a, CD86, CD36 and CD209. DCs generated in the presence of rtv also failed to acquire the typical phenotype of mature DCs (mDCs), and secreted lower amounts of IL-12 and IL-15. Accordingly, these aberrant mDCs failed to support activation of autologous Natural Killer (NK) cells, and resulted highly susceptible to NK cell-mediated cytotoxicity. CONCLUSIONS/SIGNIFICANCE: Our findings uncover novel functional properties of PIs within the DC-NK cell cross-talk, unveiling the heterogeneous ability of members of this class drugs to drive the generation of atypical monocyte-derived DCs (MDDCs) showing an aberrant phenotype, a failure to respond appropriately to bacterial endotoxin, a weak ability to prime autologous NK cells, and a high susceptibility to NK cell killing. These unexpected properties might contribute to limit inflammation and viral spreading in HIV-1 infected patients under PIs treatment, and open novel therapeutical perspectives for this class drugs as immunomodulators in autoimmunity and cancer

A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality

The coronavirus disease 19 (COVID-19) pandemic is currently the most acute healthcare challenge in the world. Despite growing knowledge of the nature of Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), treatment options are still poorly defined. The safety of non-steroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofen, has been openly questioned without any supporting evidence or clarity over dose, duration, or temporality of administration. This has been further conflicted by the initiation of studies to assess the efficacy of ibuprofen in improving outcomes in severe COVID-19 patients. To clarify the scientific reality, a literature search was conducted alongside considerations of the pharmacological properties of ibuprofen in order to construct this narrative review. The literature suggests that double-blind, placebo-controlled study results must be reported and carefully analysed for safety and efficacy in patients with COVID-19 before any recommendations can be made regarding the use of ibuprofen in such patients. Limited studies have suggested: (i) no direct interactions between ibuprofen and SARS-CoV-2 and (ii) there is no evidence to suggest ibuprofen affects the regulation of angiotensin-converting-enzyme 2 (ACE2), the receptor for COVID-19, in human studies. Furthermore, in vitro studies suggest ibuprofen may facilitate cleavage of ACE2 from the membrane, preventing membrane-dependent viral entry into the cell, the clinical significance of which is uncertain. Additionally, in vitro evidence suggests that inhibition of the transcription factor nuclear factor-κB (NF-kB) by ibuprofen may have a role in reducing excess inflammation or cytokine release in COVID-19 patients. Finally, there is no evidence that ibuprofen will aggravate or increase the chance of infection of COVID-19

On the modulation of TRPM channels: Current perspectives and anticancer therapeutic implications

: The transient melastatin receptor potential (TRPM) ion channel subfamily functions as cellular sensors and transducers of critical biological signal pathways by regulating ion homeostasis. Some members of TRPM have been cloned from cancerous tissues, and their abnormal expressions in various solid malignancies have been correlated with cancer cell growth, survival, or death. Recent evidence also highlights the mechanisms underlying the role of TRPMs in tumor epithelial-mesenchymal transition (EMT), autophagy, and cancer metabolic reprogramming. These implications support TRPM channels as potential molecular targets and their modulation as an innovative therapeutic approach against cancer. Here, we discuss the general characteristics of the different TRPMs, focusing on current knowledge about the connection between TRPM channels and critical features of cancer. We also cover TRPM modulators used as pharmaceutical tools in biological trials and an indication of the only clinical trial with a TRPM modulator about cancer. To conclude, the authors describe the prospects for TRPM channels in oncology

High level verification of the VFAT3 ASIC for CMS GEM detectors

A front-end readout chip VFAT3 was designed for the muon detector gas electron multipliers (GEM). GEMs were installed at the Compact Muon Solenoid (CMS) experiment of the Large Hadron Collider (LHC) at CERN for the high luminosity upgrade. The design of the VFAT3 uses 790 analog and 172 digital blocks which are highly integrated, thus it is crucial to ensure that the different blocks work together and the chip works as a whole. Mixed signal simulation methods were used to verify the high level functionality. Trigger latencies of 125, 150, 175 and 225 ns were found for front-end peaking times of 25, 50, 75 and 100 ns, respectively. The maximum trigger rate for reading out standard data packets was found to be 1.7 MHz. Results of the VFAT3 high level verification are presented and the simulation methods described

Optimization of microwave-assisted extraction of antioxidant compounds from spring onion leaves using Box–Behnken design

Many studies have explored the extraction of bioactive compounds from different onion solid wastes, such as bulb, skin, and peel. However, onion leaves have received limited attention despite their potential as a valuable source of nutraceutical compounds. This study aimed to valorise, for the first time, the agricultural waste in the form of spring onion leaves (CN, Cipollotto Nocerino) to obtain antioxidant-rich polyphenolic extracts. A Box–Behnken design (BBD) was used to assess the impact of microwave-assisted extraction (MAE) variables (temperature, time, extraction volume, and ethanol concentration) on total polyphenol content (TPC) measured by Folin–Ciocalteu method and the antioxidant power determined by FRAP assay. Response surface methodology (RSM) was applied, and regression equations, analysis of variance, and 3D response curves were developed. Our results highlighted that the TPC values range from 0.76 to 1.43 mg GAE g−1 dw, while the FRAP values range from 8.25 to 14.80 mmol Fe(II)E g−1 dw. The optimal extraction conditions predicted by the model were 60 °C, 22 min, ethanol concentration 51% (v/v), and solvent volume 11 mL. These conditions resulted in TPC and FRAP values of 1.35 mg GAE g−1 dw and 14.02 mmol Fe(II)E g−1 dw, respectively. Furthermore, the extract obtained under optimized conditions was characterized by UHPLC-ESI-Orbitrap-MS analysis. LC/MS–MS platform allowed us to tentatively identify various compounds belonging to the class of flavonoids, saponins, fatty acids, and lipids. Finally, the ability of CN optimal extract to inhibit the intracellular reactive oxygen species (ROS) release in a hepatocarcinoma cell line using an H2O2-induced oxidative stress model, was evaluated. The results highlighted the potential of CN extract as a valuable source of polyphenols with significant antioxidant properties, suitable for various applications in the food and pharmaceutical industries

Immune-Modulation and Properties of Absorption and Blood Brain Barrier Permeability of 1,8-Naphthyridine Derivatives

Considering the high selectivity at the cannabinoid CB2 receptor of recently designed 1,8-naphthyridine derivatives and the protective role of this receptor in neurological disorders, in this study we investigated the immune-modulatory and anti-inflammatory effects of these compounds as well as their potential properties of intestinal absorption and blood-brain barrier (BBB) permeability. We used peripheral blood mononuclear cells (PBMC) known to express the CB2 receptor. We observed that test compounds, CB13, CB82 and CB91 reduced PBMC proliferation. The anti-proliferative effect of CB13 and CB91 was partially mediated by the CB2 receptor. These compounds blocked the cells cycle and CB91 reduced T cell activation. CB82 and CB91 down-regulated the expression of phosphorylated proteins like NF-κB, ERK, Akt and the enzyme Cox-2, CB91 blocked the expression of the CB2 receptor and its inhibitory effect was CB2 receptor mediated. We also investigated CB91 properties of intestinal absorption and BBB permeability in order to suggest its potential efficacy on the infiltrating auto-reactive lymphocytes at the level of the central nervous system. For this purpose, CB91 was tested in drug-permeability assays on Caco-2 cells to evaluate its oral bioavailability and on MDCKII-hMDR1 cells to estimate its BBB permeability. The results indicated that this compound possesses medium level of intestinal absorption and BBB permeability. Our data suggest that CB91, modulating the immune response by CB2 receptor mediated mechanism and showing medium level of intestinal absorption and BBB permeability, might be developed as a potential orally delivered drug and might find potential application in pathologies like multiple sclerosi

Immune-Modulation and Properties of Absorption and Blood Brain Barrier Permeability of 1,8-Naphthyridine Derivatives.

Considering the high selectivity at the cannabinoid CB2 receptor of recently designed 1,8-naphthyridine derivatives and the protective role of this receptor in neurological disorders, in this study we investigated the immune-modulatory and anti-inflammatory effects of these compounds as well as their potential properties of intestinal absorption and blood-brain barrier (BBB) permeability. We used peripheral blood mononuclear cells (PBMC) known to express the CB2 receptor. We observed that test compounds, CB13, CB82 and CB91 reduced PBMC proliferation. The anti-proliferative effect of CB13 and CB91 was partially mediated by the CB2 receptor. These compounds blocked the cells cycle and CB91 reduced T cell activation. CB82 and CB91 down-regulated the expression of phosphorylated proteins like NF-κB, ERK, Akt and the enzyme Cox-2, CB91 blocked the expression of the CB2 receptor and its inhibitory effect was CB2 receptor mediated. We also investigated CB91 properties of intestinal absorption and BBB permeability in order to suggest its potential efficacy on the infiltrating auto-reactive lymphocytes at the level of the central nervous system. For this purpose, CB91 was tested in drug-permeability assays on Caco-2 cells to evaluate its oral bioavailability and on MDCKII-hMDR1 cells to estimate its BBB permeability. The results indicated that this compound possesses medium level of intestinal absorption and BBB permeability. Our data suggest that CB91, modulating the immune response by CB2 receptor mediated mechanism and showing medium level of intestinal absorption and BBB permeability, might be developed as a potential orally delivered drug and might find potential application in pathologies like multiple sclerosi