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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.

Abstract: Carbohydrate-binding agents (CBAs) have been proposed as innovative anti-HIV compounds selectively targeting the glycans of the HIV-1 envelope glycoprotein gp120 and preventing DC-SIGN-directed HIV capture by dendritic cells (DCs) and transmission to CD4+ T-lymphocytes. We now show that CBAs efficiently prevent R5 HIV-1 infection of human primary monocyte-derived macrophage (MDM) cell cultures in the nanomolar range. Both R5 and X4 HIV-1 strains were efficiently captured by the macrophage mannose-binding receptor (MMR) present on MDM. HIV-1 capture by MMR-expressing MDM was inhibited by soluble mannose-binding lectin and MMR antibody. Short pre-exposure of these HIV-1 strains to CBAs is able to prevent virus capture by MDM and subsequent syncytia formation in cocultures of the CBA-exposed HIV-1-captured MDM and uninfected CD4+ T-lymphocytes. The potential of CBAs to impair MDM in their capacity to capture and to transmit HIV to T-lymphocytes might be an important property to be taken into consideration in the eventual choice to select microbicide candidate drugs for clinical investigation. [Copyright &y& Elsevier]

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.

In Western industrialized countries, prostate cancer (PCa) is the second most common malignant disease and prevalent cause of death for men. Epidemiological studies have shown that curcumin (CUR) either prevents PCa initiation or delays its progression to a more aggressive and treatment-refractory form, thus reducing related mortality. Our previous studies have proven the anticancer, antioxidant, and anti-inflammatory properties of CUR on PCa cells. However, there are few reports of the effect of CUR on energy and lipid pathways in PCa. Herein, we show that CUR can modulate the two metabolic energy pathways, increasing glycolytic reserve and reducing oxidative phosphorylation. Moreover, through the regulation of key enzymes and proteins, CUR affected the lipid pathway in PC-3 to a greater extent compared to the healthy PNT-2 cells. According to molecular docking investigations, the CUR activity in PCa may be mediated by the direct binding to the pyruvate dehydrogenase (PDHA1) enzyme, which is essential for regulating the appropriate mitochondrial activity. Taken together, our results shed light on the mechanism of action of CUR in the PCa cell metabolism and provide evidence of its potential value as an anticancer metabolic modulator, paving opportunities for novel therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The biological activity of structural HIV-1 proteins is not limited to ensuring a productive viral infection but also interferes with cellular homeostasis through intra- and extracellular signaling activation. This interference induces genomic instability, increases the lifespan of the infected cell by inhibiting apoptosis, and subverts cell senescence, resulting in unrestricted cell proliferation. HIV structural proteins are present in a soluble form in the lymphoid tissues and blood of infected individuals, even without active viral replication. The HIV matrix protein p17, the envelope glycoprotein gp120, the transenvelope protein gp41, and the capsid protein p24 interact with immune cells and deregulate the biological activity of the immune system. The biological activity of HIV structural proteins is also demonstrated in endothelial cells and some tumor cell lines, confirming the ability of viral proteins to promote cell proliferation and cancer progression, even in the absence of active viral replication. This review corroborates the hypothesis that HIV structural proteins, by interacting with different cell types, contribute to creating a microenvironment that is favorable to the evolution of cancerous pathologies not classically related to AIDS.

N -heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A 3 -coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated.

In the developed world, pediatric obesity (PO) has been a major health concern since the last century, and this condition may lead to detrimental life-long physical and mental comorbidities. Currently, its prevalence has increased in low- and middle-income countries and in many high-income countries. Thus, the provision of effective and tailored care for children and their families has become vital. The social consequences of the COVID-19 pandemic are known everywhere, and among these, it has been argued that the COVID-19 pandemic has had a major impact on PO. Overall, the growth of PO over the last decade has been enhanced by the pandemic. During the COVID-19 pandemic, children, adolescents and young adults gained weight as the pediatric population dealt with sedentary lifestyles and changes in food habits. In this review, we want to highlight the impact that the COVID-19 pandemic had on PO.

Antibacterial resistance is a renewed public health plague in modern times, and the COVID-19 pandemic has rekindled this problem. Changes in antibiotic prescribing behavior, misinformation, financial hardship, environmental impact, and governance gaps have generally enhanced the misuse and improper access to antibiotics during the COVID-19 pandemic. These determinants, intersected with antibacterial resistance in the current pandemic, may amplify the potential for a future antibacterial resistance pandemic. The occurrence of infections with multidrug-resistant (MDR), extensively drug-resistant (XDR), difficult-to-treat drug-resistant (DTR), carbapenem-resistant (CR), and pan-drug-resistant (PDR) bacteria is still increasing. The aim of this review is to highlight the state of the art of antibacterial resistance worldwide, focusing on the most important pathogens, namely Enterobacterales , Acinetobacter baumannii , and Klebsiella pneumoniae , and their resistance to the most common antibiotics.

Prostate cancer is the second most common cancer in men. Although epidemiologic studies show that a higher intake of polyphenols, curcumin (CUR), and quercetin (QRT), in particular, result in lower prostate cancer risk, the chemopreventive mechanisms underlying the effects of CUR and QRT have not been fully understood yet, and most investigations were conducted with individual compounds. Here, we investigated the anticancer and anti-inflammatory effects of CUR in combination with QRT, respectively, in a human prostate cancer cell line, PC-3, and in LPS-stimulated RAW 264.7 cells, and found that their combination significantly inhibited proliferation and arrested the cell cycle, inducing apoptosis, so exhibiting synergic activities stronger than single drug use. Moreover, via their antioxidant effects, the combination of CUR and QRT modulated several inflammation-mediated signaling pathways (ROS, nitric oxide, and pro-inflammatory cytokines) thus helping protect cells from undergoing molecular changes that trigger carcinogenesis. Although additional studies, including in vivo experiments and translational studies, are required, this study raises the possibility of their use as a safe, effective, and affordable therapeutic approach to prostate cancer.

Stilbenoids, a group of phytoalexin polyphenols produced by plants as a defence mechanism in response to stress conditions, are known for their anti-inflammatory potential. Pinosylvin, a naturally occurring molecule traditionally found in pinus trees, was here identified in Pinus nigra subsp. laricio var. calabrica from Southern Italy through HPLC analysis. Both this molecule and its well-known analogue resveratrol, the most famous wine polyphenol, were compared for their in vitro potential anti-inflammatory activity. Pinosylvin significantly inhibited the release of pro-inflammatory cytokines (TNF-α and IL-6) and NO mediator in LPS-stimulated RAW 264.7 cells. Moreover, its ability to inhibit the JAK/STAT signaling pathway was assessed: Western blot analyses showed a downregulation of both phosphorylated JAK2 and STAT3 proteins. Finally, in order to verify whether this biological activity could be attributed to a direct interaction of pinosylvin with JAK2, a molecular docking study was performed, confirming the capability of pinosylvin to bind the active site of the protein.

The effects of clinical symptoms, laboratory indicators, and comorbidity status of SARS-CoV-2-infected patients on the severity of disease and the risk of death were investigated. Questionnaires and electronic medical records of 371 hospitalized COVID-19 patients were used for data collection (demographics, clinical manifestation, comorbidities, laboratory data). Association among categorical variables was determined using Kolmogorov-Smirnov test (P-value ≤0.05). Median age of study population (249 males, 122 females) was 65 years. Roc curves analysis found that age ≥64 years and age ≥67 years are significant cut-offs identifying patients with more severe disease and mortality at 30 days. CRP values at cut-off ≥80.7 and ≥95.8 significantly identify patients with more severe disease and mortality. Patients with more severe disease and risk of death were significantly identified with platelet value at the cut-off ≤160,000, hemoglobin value at the cut-off ≤11.7, D-Dimer values ≥1383 and ≥1270, and with values of neutrophil granulocytes (≥8.2 and ≤2) and lymphocytes (≤2 and ≤2.4). Detailed clinical investigation suggests granulocytes together with lymphopenia may be a potential indicator for diagnosis. Older age, several comorbidities (cancer, cardiovascular diseases, hypertension) and more laboratory abnormalities (CRP, D-Dimer, platelets, hemoglobin) were associated with development of more severity and mortality among COVID-19 patients.

Ruthenium N -heterocyclic carbene (Ru-NHC) complexes show interesting physico-chemical properties as catalysts and potential in medicinal chemistry, exhibiting multiple biological activities, among them anticancer, antimicrobial, antioxidant, and anti-inflammatory. Herein, we designed and synthesized a new series of Ru-NHC complexes and evaluated their biological activities as anticancer, antibacterial, and antioxidant agents. Among the newly synthesized complexes, RANHC-V and RANHC-VI are the most active against triple-negative human breast cancer cell lines MDA-MB-231. These compounds were selective in vitro inhibitors of the human topoisomerase I activity and triggered cell death by apoptosis. Furthermore, the Ru-NHC complexes' antimicrobial activity was studied against Gram-positive and -negative bacteria, revealing that all the complexes possessed the best antibacterial activity against the Gram-positive Staphylococcus aureus , at a concentration of 25 µg/mL. Finally, the antioxidant effect was assessed by DPPH and ABTS radicals scavenging assays, resulting in a higher ability for inhibiting the ABTS •+ , with respect to the well-known antioxidant Trolox. Thus, this work provides encouraging insights for further development of novel Ru-NHC complexes as potent chemotherapeutic agents endowed with multiple biological properties.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the seventh known human coronavirus, and it was identified in Wuhan, Hubei province, China, in 2020. It caused the highly contagious disease called coronavirus disease 2019 (COVID-19), declared a global pandemic by the World Health Organization (WHO) on 11 March 2020. A great number of studies in the search of new therapies and vaccines have been carried out in these three long years, producing a series of successes; however, the need for more effective vaccines, therapies and other solutions is still being pursued. This review represents a tracking shot of the current pharmacological therapies used for the treatment of COVID-19.

Different phytochemical compounds have been demonstrated to modulate the JAK/STAT signaling pathway. Here, three Cachrys species from Southern Italy were investigated for both the phytochemical profile and the potential anti-inflammatory properties. The aerial parts were extracted with methanol through Naviglio Extractor ® , an innovative solid-liquid extraction technique that allows to obtain high quality extracts by working with gradient pressure. Extracts were analyzed with GC-MS and standardized in furanocoumarin content, resulting rich in xanthotoxin, bergapten and isopimpinellin. Given the known ability of bergapten to inhibit the JAK/STAT signaling pathway by decreasing the levels of pro-inflammatory cytokines (TNF-α, IL-6) and inflammatory mediators (NO) in RAW 264.7 cells activated by LPS, Cachrys extracts were investigated for their biological properties. The results obtained in this study showed that Cachrys pungens extract, presenting the highest content in furanocoumarins (7.48 ± 0.48 and 2.94 ± 0.16 mg/50 mg of extract for xanthotoxin and bergapten, respectively), significantly decreased STAT3 protein levels, pro-inflammatory cytokines (TNF-α, IL-6) and increased IL-10 anti-inflammatory cytokine. Cachrys ferulacea significantly decreased JAK2 phosphorylation, being even more effective than bergapten. In conclusion, investigated extracts could be potential candidates for the search of novel anti-inflammatory agents acting via inhibiting the JAK/STAT signaling pathway.

The beginning of the end or the end of the beginning? After two years mastered by coronavirus disease 19 (COVID-19) pandemic, we are now witnessing a turnaround. The reduction of severe cases and deaths from COVID-19 led to increasing importance of a new disease called post-COVID syndrome. The term post-COVID is used to indicate permanency of symptoms in patients who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immune, antiviral, antimicrobial therapies, as well as ozone therapy have been used to treat COVID-19 disease. Vaccines have then become available and administered worldwide to prevent the insurgence of the disease. However, the pandemic is not over yet at all given the emergence of new omicron variants. New therapeutic strategies are urgently needed. In this view, great interest was found in nutraceutical products, including vitamins (C, D, and E), minerals (zinc), melatonin, probiotics, flavonoids (quercetin), and curcumin. This review summarizes the role of nutraceuticals in the prevention and/or treatment of COVID-19 disease and post-COVID syndrome.

In recent years, the number of people suffering from cancer has risen rapidly and the World Health Organization and U.S. and European governments have identified this pathology as a priority issue. It is known that most bioactive anticancer molecules do not target a single protein but exert pleiotropic effects, simultaneously affecting multiple pathways. In our study, we designed and synthesized a new series of silver N-heterocyclic carbene (NHC) complexes [(NHC) 2 Ag] + [AgX 2 ] - (X=iodide or acetate). The new complexes were active against two human breast cancer cell lines, MCF-7 and MDA-MB-231. These compounds showed multiple target actions as anticancer, by inhibiting in vitro the activity of the human topoisomerases I and II and interfering with the cytoskeleton dynamic, as also confirmed by in silico studies. Moreover, the antimicrobial activity of these silver complexes was studied against Gram-positive/negative bacteria. These dual properties provide a two-tiered approach, making these compounds of interest to be further deepened for the development of new chemotherapeutic agents., (© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

These days, most of our attention has been focused on the COVID-19 pandemic, and we have often neglected what is happening in the environment. For instance, the bacterium Xylella fastidiosa re-emerged as a plant pathogen of global importance in 2013 when it was first associated with an olive tree disease epidemic in Italy, called Olive Quick Decline Syndrome (OQDS), specifically caused by X. fastidiosa subspecies pauca ST53, which affects the Salento olive trees (Apulia, South-East Italy). This bacterium, transmitted by the insect Philaenus spumarius, is negatively reshaping the Salento landscape and has had a very high impact in the production of olives, leading to an increase of olive oil prices, thus new studies to curb this bacterium are urgently needed. Thidiazuron (TDZ), a diphenylurea ( N -phenyl-1,2,3-thiadiazol-5-yl urea), has gained considerable attention in recent decades due to its efficient role in plant cell and tissue culture, being the most suitable growth regulator for rapid and effective plant production in vitro. Its biological activity against bacteria, fungi and biofilms has also been described, and the use of this low-cost compound to fight OQDS may be an intriguing idea.

Triclosan (TCS), a broad-spectrum antimicrobial agent, has been widely used in personal care products, medical products, plastic cutting boards, and food storage containers. Colgate Total ® toothpaste, containing 10 mM TCS, is effective in controlling biofilm formation and maintaining gingival health. Given its broad usage, TCS is present ubiquitously in the environment. Given its strong lipophilicity and accumulation ability in organisms, it is potentially harmful to biohealth. Several reports suggest the toxicity of this compound, which is inserted in the class of endocrine disrupting chemicals (EDCs). In September 2016, TCS was banned by the U.S. Food and Drug Administration (FDA) and the European Union in soap products. Despite these problems, its application in personal care products within certain limits is still allowed. Today, it is still unclear whether TCS is truly toxic to mammals and the adverse effects of continuous, long-term, and low concentration exposure remain unknown. Indeed, some recent reports suggest the use of TCS as a repositioned drug for cancer treatment and cutaneous leishmaniasis. In this scenario it is necessary to investigate the advantages and disadvantages of TCS, to understand whether its use is advisable or not. This review intends to highlight the pros and cons that are associated with the use of TCS in humans.

A strategy adopted to combat human immunodeficiency virus type-1 (HIV-1) infection is based on interfering with virus entry into target cells. In this study, we found that phosphatidylcholine (PC) liposomes reduced the expression of the CD4 receptor in human primary type-1 macrophages but not in CD4 + T cells. The down-regulation was specific to CD4, as any effect was not observed in CCR5 membrane expression. Moreover, the reduction of membrane CD4 expression required the Ca 2+ -independent protein kinase C (PKC), which in turn mediated serine phosphorylation in the intracytoplasmic tail of the CD4 receptor. Serine phosphorylation of CD4 was also associated with its internalization and degradation in acidic compartments. Finally, the observed CD4 downregulation induced by PC liposomes in human primary macrophages reduced the entry of both single-cycle replication and replication competent R5 tropic HIV-1. Altogether, these results show that PC liposomes reduce HIV entry in human macrophages and may impact HIV pathogenesis by lowering the viral reservoir., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 De Santis, Lopez, Virtuoso, Poerio, Saccomandi, Olimpieri, Duca, Henrici De Angelis, Aquilano, D’Andrea, Aquaro, Borsetti, Ceccherini-Silberstein and Fraziano.)

(1) Background: The production of anti-SARS-CoV-2 antibodies should help minimize the severity of COVID-19 disease. Our focus was to investigate and compare different vaccination schedules, monitoring circulating S-RBD Ab (antibodies anti-Spike protein-Receptor Binding Domain) levels after administering two doses in naïve patients. Likewise, vaccine-stimulated immunity in naïve and previously infected patients was compared. (2) Methods: We included 392 patients. Sera were evaluated by Elecsys anti-SARS-CoV-2 S. Statistical analyses were conducted by MedCalc and JASP. (3) Results: In COVID-19 patients, the median value of Ab levels was 154 BAU/mL, stable up to 9 months after the infection. From the data observed in vaccinated patients, higher median values were recorded in COVID-19/Pfizer BioNTech (18913 BAU/mL) than in other groups (Pfizer BioNTech: 1841; ChadOx1 961; heterologous vaccination: 2687) BAU/mL. (4) Conclusions: In conclusion, a single booster dose given to previously infected patients raised an antibody response much higher than two doses given to naïve individuals and heterologous vaccination generated a robust persistent antibody response at high levels, steady up to three months after administration.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a member of the Coronavirus family which caused the worldwide pandemic of human respiratory illness coronavirus disease 2019 (COVID-19). Presumably emerging at the end of 2019, it poses a severe threat to public health and safety, with a high incidence of transmission, predominately through aerosols and/or direct contact with infected surfaces. In 2020, the search for vaccines began, leading to the obtaining of, to date, about twenty COVID-19 vaccines approved for use in at least one country. However, COVID-19 continues to spread and new genetic mutations and variants have been discovered, requiring pharmacological treatments. The most common therapies for COVID-19 are represented by antiviral and antimalarial agents, antibiotics, immunomodulators, angiotensin II receptor blockers, bradykinin B2 receptor antagonists and corticosteroids. In addition, nutraceuticals, vitamins D and C, omega-3 fatty acids and probiotics are under study. Finally, drug repositioning, which concerns the investigation of existing drugs for new therapeutic target indications, has been widely proposed in the literature for COVID-19 therapies. Considering the importance of this ongoing global public health emergency, this review aims to offer a synthetic up-to-date overview regarding diagnoses, variants and vaccines for COVID-19, with particular attention paid to the adopted treatments.

Multidrug resistance is a leading concern in public health. It describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. Multidrug resistance may be also related to antimicrobial drugs, and is known to be one of the most serious global public health threats of this century. Indeed, this phenomenon has increased both mortality and morbidity as a consequence of treatment failures and its incidence in healthcare costs. The large amounts of antibiotics used in human therapies, as well as for farm animals and even for fishes in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. It is not negligible that the ongoing COVID-19 pandemic may further contribute to antimicrobial resistance. In this paper, multidrug resistance and antimicrobial resistance are underlined, focusing on the therapeutic options to overcome these obstacles in drug treatments. Lastly, some recent studies on nanodrug delivery systems have been reviewed since they may represent a significant approach for overcoming resistance.

The chronic infection established by the human immunodeficiency virus 1 (HIV-1) produces serious CD4+ T cell immunodeficiency despite the decrease in HIV-1 ribonucleic acid (RNA) levels and the raised life expectancy of people living with HIV-1 (PLWH) through treatment with combined antiretroviral therapies (cART). HIV-1 enters the central nervous system (CNS), where perivascular macrophages and microglia are infected. Serious neurodegenerative symptoms related to HIV-associated neurocognitive disorders (HAND) are produced by infection of the CNS. Despite advances in the treatment of this infection, HAND significantly contribute to morbidity and mortality globally. The pathogenesis and the role of inflammation in HAND are still incompletely understood. Principally, growing evidence shows that the CNS is an anatomical reservoir for viral infection and replication, and that its compartmentalization can trigger the evolution of neurological damage and thus make virus eradication more difficult. In this review, important concepts for understanding HAND and neuropathogenesis as well as the viral proteins involved in the CNS as an anatomical reservoir for HIV infection are discussed. In addition, an overview of the recent advancements towards therapeutic strategies for the treatment of HAND is presented. Further neurological research is needed to address neurodegenerative difficulties in people living with HIV, specifically regarding CNS viral reservoirs and their effects on eradication.

Antimicrobials have allowed medical advancements over several decades. However, the continuous emergence of antimicrobial resistance restricts efficacy in treating infectious diseases. In this context, the drug repositioning of already known biological active compounds to antimicrobials could represent a useful strategy. In 2002 and 2003, the SARS-CoV pandemic immobilized the Far East regions. However, the drug discovery attempts to study the virus have stopped after the crisis declined. Today's COVID-19 pandemic could probably have been avoided if those efforts against SARS-CoV had continued. Recently, a new coronavirus variant was identified in the UK. Because of this, the search for safe and potent antimicrobials and antivirals is urgent. Apart from antiviral treatment for severe cases of COVID-19, many patients with mild disease without pneumonia or moderate disease with pneumonia have received different classes of antibiotics. Diarylureas are tyrosine kinase inhibitors well known in the art as anticancer agents, which might be useful tools for a reposition as antimicrobials. The first to come onto the market as anticancer was sorafenib, followed by some other active molecules. For this interesting class of organic compounds antimicrobial, antiviral, antithrombotic, antimalarial, and anti-inflammatory properties have been reported in the literature. These numerous properties make these compounds interesting for a new possible pandemic considering that, as well as for other viral infections also for CoVID-19, a multitarget therapeutic strategy could be favorable. This review is meant to be an overview on diarylureas, focusing on their biological activities, not dwelling on the already known antitumor activity. Quite a lot of papers present in the literature underline and highlight the importance of these molecules as versatile scaffolds for the development of new and promising antimicrobials and multitarget agents against new pandemic events.

Human immunodeficiency virus (HIV) is a pathogen that infects blood cells, using CD4 molecule and two cell receptors CCR5 and CXCR4. The other major actor is gp120/gp41 viral protein complex, which interacts with receptors. Here, the presence of synonymous mutations associated with HIV-1 tropism and the related RNA secondary-structure in HIV-1 infected patients was evaluated. The analysis includes gp120-sequences from 340 HIV-1 subtype-B infected patients, all retrieved from Los Alamos database and with phenotypic HIV tropism determination based on recombinant-virus entry-assay. Frequencies of all nucleotide substitutions were calculated. Mfold and RNAfold algorithms were used to predict RNA secondary-structure of HIV-1. Nineteen codons in V2/C2, V3 and C3 domains were found to be closely related to CCR5 and CXCR4. Additionally, in X4-sequences, gp120 gca303gcu and gua222guc synonymous mutations are positively related to the gp120 S11R and T8A/I codons in V3 protein domain. Furthermore, gua222guc increases stability of the viral RNA secondary-structure. Probably, it would not be surprising if a novel escape viral strategy therapy will be related to the gp120 synonymous mutations. Moreover, in relation to the pivotal role played by gp120 in polyvalent vaccine approaches, the impact of gp120 synonymous mutations may play an important role in HIV entry into the cell. Keywords: gp120; tropism; v3; s11r; evolution; vaccine.

Increasing evidences suggest that HBsAg-production varies across HBV-genotypes. HBsAg C-terminus plays a crucial role for HBsAg-secretion. Here, we evaluate HBsAg-levels in different HBV-genotypes in HBeAg-negative chronic infection, the correlation of specific mutations in HBsAg C-terminus with HBsAg-levels in-vivo, their impact on HBsAg-secretion in-vitro and on structural stability in-silico .HBsAg-levels were investigated in 323 drug-naïve HBeAg-negative patients chronically infected with HBV genotype-D( N  = 228), -A( N  = 65) and -E( N  = 30). Genotype-D was characterized by HBsAg-levels lower than genotype-A and -E (3.3[2.7-3.8]IU/ml; 3.8[3.5-4.2]IU/ml and 3.9[3.7-4.2]IU/ml, P  < 0.001). Results confirmed by multivariable analysis correcting for patients'demographics, HBV-DNA, ALT and infection-status.In genotype-D, specific C-terminus mutations (V190A-S204N-Y206C-Y206F-S210N) significantly correlate with HBsAg<1000IU/ml( P -value from <0.001 to 0.04). These mutations lie in divergent pathways involving other HBsAg C-terminus mutations: V190A + F220L (Phi = 0.41, P  = 0.003), S204N + L205P (Phi = 0.36, P  = 0.005), Y206F + S210R (Phi = 0.47, P  < 0.001) and S210N + F220L (Phi = 0.40, P  = 0.006). Notably, patients with these mutational pairs present HBsAg-levels 1log lower than patients without them( P -value from 0.003 to 0.02). In-vitro , the above-mentioned mutational pairs determined a significant decrease in HBsAg secretion-efficiency compared to wt( P -value from <0.001 to 0.02). Structurally, these mutational pairs reduced HBsAg C-terminus stability and determined a rearrangement of this domain.In conclusion, HBsAg-levels in genotype-D are significantly lower than in genotype-A and -E in HBeAg-negative patients. In genotype-D, specific mutational clusters in HBsAg C-terminus correlate with lower HBsAg-levels in-vivo , hamper HBsAg-release in-vitro and affect its structural stability, supporting their detrimental role on HBsAg-secretion. In this light, genotypic-testing can be a valuable tool to optimize the clinical interpretation of HBsAg in genotype-D and to provide information on HBV-pathogenicity and disease-progression.

Ongoing with current combinations of antiretroviral drugs for the treatment of Human Immunodeficiency Virus (HIV) infection can successfully maintain long-term suppression of HIV-1 replication in plasma. Still, none of these therapies is capable of extinguishing the virus from the long-lived cellular reservoir, including monocyte-derived macrophages (MDM), that means the principal obstacle to HIV cure. MDM are widely distributed in all tissues and organs, including central system nervous (CNS) where they represent the most frequent HIV-infected cells that means the principal obstacle to HIV cure. Current FDA-approved antiretroviral drugs target viral reverse transcriptase, protease, integrase, and entry processes (coreceptor or fusion blockade). It is desirable to continue to develop new antiretrovirals directed against alternative targets in the virus lifecycle in order to further optimize therapeutic options, overcome resistance to existing medications, and potentially contribute to the elimination of viral reservoirs.This review provides a comprehensive overview of the activity of antiretroviral drugs (classical and upcoming) in monocytes-derived macrophages (MDM). Defining the antiviral activity of these drugs in this important cellular HIV-1 reservoir provides crucial hints about their efficacy in HIV-1 infected patients.

Objectives: We evaluated natural resistance to the new antiretroviral fostemsavir and its potential association with other HIV-1 gp120 polymorphisms., Methods: A total of 1997 HIV-1 B subtype gp120 sequences from the Los Alamos HIV Database were analysed for mutation prevalence at fostemsavir resistance-associated positions and potential association with other gp120 polymorphisms. The role of each fostemsavir resistance-related position and the correlated gp120 mutations, both in protein stability and in reducing the binding affinity between antibody and/or T cell lymphocyte epitopes and the MHC molecules, was estimated., Results: The prevalence of fostemsavir resistance mutations was as follows: L116Q (0.05%), S375H/M/T (0.55%/1.35%/17.73%, the latter being far less relevant in determining resistance), M426L (7.56%), M434I (4.21%) and M475I (1.65%). Additionally, the M426R polymorphism had a prevalence of 16.32%. A significantly higher prevalence in X4 viruses versus R5 viruses was found only for S375M (0.69% versus 3.93%, P = 0.009) and S375T (16.60% versus 22.11%, P = 0.030). Some fostemsavirv resistance positions positively and significantly correlated with specific gp120 polymorphisms: S375T with I371V; S375M with L134W, I154V and I323T; M475I with K322A; and M426R with G167N, K192T and S195N. The topology of the dendrogram suggested the existence of three distinct clusters (bootstrap ≥0.98) involving these fostemsavir resistance mutations and gp120 polymorphisms. Interestingly, all clustered mutations are localized in class I/II-restricted T cell/antibody epitopes, suggesting a potential role in immune HIV escape., Conclusions: A low prevalence of known fostemsavir resistance mutations was found in the HIV-1 B subtype. The detection of novel HIV-1 gp120 polymorphisms potentially relevant for fostemsavir resistance deserves new in-depth in vitro investigations., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Immune-suppression driven Hepatitis B Virus (HBV)-reactivation poses serious concerns since it occurs in several clinical settings and can result in severe forms of hepatitis. Previous studies showed that HBV strains, circulating in patients with HBV-reactivation, are characterized by an enrichment of immune-escape mutations in HBV surface antigen (HBsAg). Here, we focused on specific immune-escape mutations associated with the acquisition of N-linked glycosylation sites in HBsAg (NLGSs). In particular, we investigated profiles of NLGSs in 47 patients with immunosuppression-driven HBV-reactivation and we evaluated their impact on HBsAg-antigenicity and HBV-replication in vitro. At HBV-reactivation, despite a median serum HBV-DNA of 6.7 [5.3-8.0] logIU/mL, 23.4% of patients remained HBsAg-negative. HBsAg-negativity at HBV-reactivation correlated with the presence of >1 additional NLGSs ( p < 0.001). These NLGSs are located in the major hydrophilic region of HBsAg (known to be the target of antibodies) and resulted from the single mutation T115N, T117N, T123N, N114ins, and from the triple mutant S113N+T131N+M133T. In vitro, NLGSs strongly alter HBsAg antigenic properties and recognition by antibodies used in assays for HBsAg-quantification without affecting HBsAg-secretion and other parameters of HBV-replication. In conclusion, additional NLGSs correlate with HBsAg-negativity despite HBV-reactivation, and hamper HBsAg-antigenicity in vitro, supporting the role of NGSs in immune-escape and the importance of HBV-DNA for a proper diagnosis of HBV-reactivation.

Background and objectives: To enter the target cell, HIV-1 binds not only CD4 but also a co-receptor β-chemokine receptor 5 (CCR5) or α chemokine receptor 4 (CXCR4). Limited information is available on the impact of co-receptor usage on HIV-1 replication in monocyte-derived macrophages (MDM) and on the homeostasis of this important cellular reservoir. Materials and Methods: Replication (measured by p24 production) of the CCR5-tropic 81A strain increased up to 10 days post-infection and then reached a plateau. Conversely, the replication of the CXCR4-tropic NL4.3 strain (after an initial increase up to day 7) underwent a drastic decrease becoming almost undetectable after 10 days post-infection. The ability of CCR5-tropic and CXCR4-tropic strains to induce cell death in MDM was then evaluated. While for CCR5-tropic 81A the rate of apoptosis in MDM was comparable to uninfected MDM, the infection of CXCR4-tropic NL4.3 in MDM was associated with a rate of 14.3% of apoptotic cells at day 6 reaching a peak of 43.5% at day 10 post-infection. Results: This suggests that the decrease in CXCR4-tropic strain replication in MDM can be due to their ability to induce cell death in MDM. The increase in apoptosis was paralleled with a 2-fold increase in the phosphorylated form of p38 compared to WT. Furthermore, microarray analysis showed modulation of proapoptotic and cancer-related genes induced by CXCR4-tropic strains starting from 24 h after infection, whereas CCR5 viruses modulated the expression of genes not correlated with apoptotic-pathways. Conclusions: In conclusion, CXCR4-tropic strains can induce a remarkable depletion of MDM. Conversely, MDM can represent an important cellular reservoir for CCR5-tropic strains supporting the role of CCR5-usage in HIV-1 pathogenesis and as a pharmacological target to contribute to an HIV-1 cure., Competing Interests: The authors declare no conflict of interest.

Keywords: carbazole; tetrahydrocarbazole; antiviral agents., Competing Interests: The authors declare no conflict of interest.