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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an RNA virus belonging to the coronavirus family responsible for coronavirus disease 2019 (COVID-19). It primarily affects the pulmonary system, which is the target of chronic obstructive pulmonary disease (COPD), for which many new compounds have been developed. In this study, phosphodiesterase 4 (PDE4) inhibitors are being investigated. The inhibition of PDE4 enzyme produces anti-inflammatory and bronchodilator effects in the lung by inducing an increase in cAMP concentrations. Piclamilast and rolipram are known selective inhibitors of PDE4, which are unfortunately endowed with common side effects, such as nausea and emesis. The selective inhibition of the phosphodiesterase 4B (PDE4B) subtype may represent an intriguing technique for combating this highly contagious disease with fewer side effects. In this article, molecular docking studies for the selective inhibition of the PDE4B enzyme have been carried out on 21 in-house compounds. The compounds were docked into the pocket of the PDE4B catalytic site, and in most cases, they were almost completely superimposed onto piclamilast. Then, in order to enlarge our study, drug-likeness prediction studies were performed on the compounds under study.

Abstract Background Oxidative stress plays a key role in the neuropathogenesis of Human Immunodeficiency Virus-1 (HIV-1) infection causing apoptosis of astroglia cells and neurons. Recent data have shown that oxidative stress is also responsible for the acceleration of human fibroblast telomere shortening in vitro. In the present study we analyzed the potential relations occurring between free radicals formation and telomere length during HIV-1 mediated astroglial death. Results To this end, U373 human astrocytoma cells have been directly exposed to X4-using HIV-1IIIB strain, for 1, 3 or 5 days and treated (where requested) with N-acetylcysteine (NAC), a cysteine donor involved in the synthesis of glutathione (GSH, a cellular antioxidant) and apoptosis has been evaluated by FACS analysis. Quantitative-FISH (Q-FISH) has been employed for studying the telomere length while intracellular reduced/oxidized glutathione (GSH/GSSG) ratio has been determined by High-Performance Liquid Chromatography (HPLC). Incubation of U373 with HIV-1IIIB led to significant induction of cellular apoptosis that was reduced in the presence of 1 mM NAC. Moreover, NAC improved the GSH/GSSG, a sensitive indicator of oxidative stress, that significantly decreased after HIV-1IIIB exposure in U373. Analysis of telomere length in HIV-1 exposed U373 showed a statistically significant telomere shortening, that was completely reverted in NAC-treated U373. Conclusion Our results support the role of HIV-1-mediated oxidative stress in astrocytic death and the importance of antioxidant compounds in preventing these cellular damages. Moreover, these data indicate that the telomere structure, target for oxidative damage, could be the key sensor of cell apoptosis induced by oxidative stress after HIV infection.

Abstract Background Monocytes/Macrophages (M/M) play a pivotal role as a source of virus during the whole course of HIV-1 infection. Enhanced oxidative stress is involved in the pathogenesis of HIV-1 infection. HIV-1 regulatory proteins induce a reduction of the expression and the activity of MnSOD, the mitochondrial isoform leading to a sustained generation of superoxide anions and peroxynitrite that represent important mediators of HIV-1 replication in M/M. MnTBAP (Mn(III)tetrakis(4-benzoic acid)porphrin chloride), a synthetic peroxynitrite decomposition catalyst, reduced oxidative stress subsequent to peroxynitrite generation. Results Virus production was assessed by p24 ELISA, western blot, and electron microscopy during treatment with MnTBAP. MnTBAP treatment showed a reduction of HIV-1 replication in both acutely and chronically infected M/M: 99% and 90% inhibition of p24 released in supernatants compared to controls, respectively. Maturation of p55 and p24 was strongly inhibited by MnTBAP in both acutely and chronically infected M/M. EC50 and EC90 are 3.7 (± 0.05) μM and 19.5 (± 0.5) μM, in acutely infected M/M; 6.3 (± 0.003) μM and 30 (± 0.6) μM, in chronically infected M/M. In acutely infected peripheral blood limphocytes (PBL), EC50 and EC90 are 7.4 (± 0.06) μM and of 21.3 (± 0.6) μM, respectively. Treatment of acutely-infected M/M with MnTBAP inhibited the elevated levels of malonildialdehyde (MDA) together with the nitrotyrosine staining observed during HIV-1 replication. MnTBAP strongly reduced HIV-1 particles in infected M/M, as shown by electron microscopy. Moreover, in presence of MnTBAP, HIV-1 infectivity was reduced of about 1 log compared to control. Conclusion Results support the role of superoxide anions in HIV-1 replication in M/M and suggest that MnTBAP may counteract HIV-1 replication in combination with other antiretroviral treatments.

Abstract Background Oxidative stress has shown to contribute in the mechanisms underlying apoptotic cell death occuring in AIDS-dementia complex. Here we investigated the role of peroxynitrite in apoptosis occurring in astroglial cells incubated with supernatants of HIV-infected human primary macrophages (M/M). Results Flow cytometric analysis (FACS) of human cultured astrocytes shortly incubated with HIV-1-infected M/M supernatants showed apoptotic cell death, an effect accompanied by pronounced staining for nitrotyrosine (footprint of peroxynitrite) and by abnormal formation of malondialdehyde (MDA). Pretreatment of astrocytes with the peroxynitrite decomposition catalyst FeTMPS antagonized HIV-related astrocytic apoptosis, MDA formation and nitrotyrosine staining. Conclusions Taken together, our results suggest that inibition of peroxynitrite leads to protection against peroxidative stress accompanying HIV-related apoptosis of astrocytes. Overall results support the role of peroxynitrite in HIV-related programmed death of astrocytes and suggest the use of peroxynitrite decomposition catalyst to counteract HIV-1-related neurological disorders.

The scientific interest in the chemical modification of chitosan to increase its solubility and application has led to its conjugation with Schiff bases, which are interesting scaffolds endowed with diverse biological properties. The resultant chitosan-based Schiff bases (CSBs) are widely studied in scientific literature due to the myriad of activities exerted, both catalytic and biological, including anticancer, anti-inflammatory, antioxidant, and especially antimicrobial ones. Antimicrobial resistance (AMR) is one of the major public health challenges of the twenty-first century because it represents a threat to the prevention and treatment of a growing number of bacterial, parasitic, viral, and fungal infections that are no longer treatable with the available drugs. Thus, in this review, we present a brief outline of the biological activities of CSBs as well as their complexes with metals, with a particular focus on the recent literature regarding the antimicrobial effect of these captivating derivatives. [ABSTRACT FROM AUTHOR]

Background/Objectives: Infectious diseases represent a serious threat due to rising antimicrobial resistance, particularly among multidrug-resistant bacteria and influenza viruses. Metal-based complexes, such as N-heterocyclic carbene–gold (NHC–gold) complexes, show promising therapeutic potential due to their ability to inhibit various pathogens. Methods: Eight NHC–gold complexes were synthesized and tested for antibacterial activity against Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, and for anti-influenza activity in lung and bronchial epithelial cells infected with influenza virus A/H1N1. Antibacterial activity was assessed through the determination of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC), while the viral load was quantified using qRT-PCR. Results: Complexes 3, 4, and 6 showed significant antibacterial activity at concentrations of 10–20 µg/mL. Additionally, these complexes significantly reduced viral load, with complexes 3 and 4 markedly inhibiting replication. Conclusions: These findings support the potential use of NHC–gold complexes in combined antimicrobial and antiviral therapies, representing an attractive option for fighting resistant infections. [ABSTRACT FROM AUTHOR]

N-heterocyclic carbene (NHC)–gold and –silver complexes have attracted the interest of the scientific community because of their multiple applications and their versatility in being chemically modified in order to improve their biological properties. However, most of these complexes contain one or more chiral centers, and have been obtained and studied as racemic mixture. In particular, concerning the interesting biological and medicinal properties, many questions about how the chirality may influence these properties still remain unanswered. Aiming at a better understanding, herein a series of enantiopure NHC–gold and –silver complexes was synthesized, characterized and biologically evaluated in different in vitro systems. The individuated complexes exerted different properties based on the complexed metal and the specific configuration, with the (R)-gold–NHC complexes being the most active, particularly as anti-inflammatory molecules. Docking simulations indicated a different binding mode for each enantiomer. Moreover, anticancer and antibacterial activities were also evaluated for the considered enantiomers. Overall, the reported data may contribute to a better understanding of the different biological properties exerted by the enantiopure gold and silver complexes. [ABSTRACT FROM AUTHOR]

More than 80 million people worldwide have been infected with the human immunodeficiency virus (HIV). There are now approximately 39 million individuals living with HIV/acquired immunodeficiency syndrome (AIDS). Although treatments against HIV infection are available, AIDS remains a serious disease. Combination antiretroviral therapy (cART), also known as highly active antiretroviral therapy (HAART), consists of treatment with a combination of several antiretroviral drugs that block multiple stages in the virus replication cycle. However, the increasing usage of cART is inevitably associated with the emergence of HIV drug resistance. In addition, the development of persistent cellular reservoirs of latent HIV is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted. Thus, several efforts are being applied to new generations of drugs, vaccines and new types of cART. In this review, we summarize the antiviral therapies used for the treatment of HIV/AIDS, both as individual agents and as combination therapies, and highlight the role of both macrophages and HIV cellular reservoirs and the most recent clinical studies related to this disease. [ABSTRACT FROM AUTHOR]

Infection by HIV-1 causes persistent, long-term high virus production in macrophages. Major evidence, both in humans and in primate models, shows the crucial role of macrophages in sustaining virus production and in mediating a cytopathic effect on bystander [CD4.sup.+] T lymphocytes and neuronal cells. In the present study, we used severe combined immunodeficient (SCID) mice engrafted with human peripheral blood lymphocytes (hu-PBL-SCID mice) to investigate the in vivo effect of HIV-1-infected macrophages on virus spread and [CD4.sup.+] T lymphocyte depletion, and the ability of a mAb against nerve growth factor (NGF, a neurokine essential for the survival of HIV-1-infected macrophages) to suppress the pathogenetic events mediated by infected macrophages. Injection of mice with as few as 500 HIV-exposed macrophages causes (i) complete depletion of several millions of autologous [CD4.sup.+] T lymphocytes, (ii) sustained HIV viremia, and (iii) spreading of HIV-1 DNA in mouse lymphoid organs. In contrast, in vivo treatment with an anti-NGF Ab completely abrogates all effects mediated by HIV-infected macrophages. Taken together, the results demonstrate the remarkable power of macrophages in sustaining in vivo HIV-1 infection, and that such a phenomenon can be specifically abrogated by an anti-NGF Ab. This may open new perspectives of experimental approaches aimed at selectively eliminating persistently infected macrophages from the bodies of HIV-infected patients.