Preliminary Evidence of the Differential Expression of Human Endogenous Retroviruses in Kawasaki Disease and SARS-CoV-2-Associated Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some clinical features overlapping with Kawasaki disease (KD). Our research group and others have highlighted that the spike protein of SARS-CoV-2 can trigger the activation of human endogenous retroviruses (HERVs), which in turn induces inflammatory and immune reactions, suggesting HERVs as contributing factors in COVID-19 immunopathology. With the aim to identify new factors involved in the processes underlying KD and MIS-C, we analysed the transcriptional levels of HERVs, HERV-related genes, and immune mediators in children during the acute and subacute phases compared with COVID-19 paediatric patients and healthy controls. The results showed higher levels of HERV-W, HERV-K, Syn-1, and ASCT-1/2 in KD, MIS-C, and COV patients, while higher levels of Syn-2 and MFSD2A were found only in MIS-C patients. Moreover, KD and MIS-C shared the dysregulation of several inflammatory and regulatory cytokines. Interestingly, in MIS-C patients, negative correlations have been found between HERV-W and IL-10 and between Syn-2 and IL-10, while positive correlations have been found between HERV-K and IL-10. In addition, HERV-W expression positively correlated with the C-reactive protein. This pilot study supports the role of HERVs in inflammatory diseases, suggesting their interplay with the immune system in this setting. The elevated expression of Syn-2 and MFSD2A seems to be a distinctive trait of MIS-C patients, allowing to distinguish them from KD ones. The understanding of pathological mechanisms can lead to the best available treatment for these two diseases, limiting complications and serious outcomes.

Biological Evaluation of Triorganotin Derivatives as Potential Anticancer Agents.

Metal-derived platinum complexes are widely used to treat solid tumors. However, systemic toxicity and tumor resistance to these drugs encourage further research into similarly effective compounds. Among others, organotin compounds have been shown to inhibit cell growth and induce cell death and autophagy. Nevertheless, the impact of the ligand structure and mechanisms involved in the toxicity of organotin compounds have not been clarified. In the present study, the biological activities of commercially available bis(tributyltin) oxide and tributyltin chloride, in comparison to those of specially synthesized tributyltin trifluoroacetate (TBT-OCOCF3) and of cisplatin, were assessed using cells with different levels of tumorigenicity. The results show that tributyltins were more cytotoxic than cisplatin in all the tested cell lines. NMR revealed that this was not related to the interaction with DNA but to the inhibition of glucose uptake into the cells. Moreover, highly tumorigenic cells were less susceptible than nontumorigenic cells to the nonunique pattern of death induced by TBT-OCOCF3. Nevertheless, tumorigenic cells became sensitive when cotreated with wortmannin and TBT-OCOCF3, although no concomitant induction of autophagy by the compound was detected. Thus, TBT-OCOCF3 might be the prototype of a family of potential anticancer agents.

Modulation of human endogenous retroviruses and cytokines expression in peripheral blood mononuclear cells from autistic children and their parents.

BACKGROUND: Putative pathogenic effects mediated by human endogenous retroviruses (HERVs) in neurological and psychiatric disorders in humans have been extensively described. HERVs may alter the development of the brain by means of several mechanisms, including modulation of gene expression, alteration of DNA stability, and activation of immune system. We recently demonstrated that autistic children and their mothers share high expression levels of some HERVs and cytokines in peripheral blood mononuclear cells (PBMCs) ex vivo, suggesting a close mother-child association in Autism Spectrum Disorder (ASD). RESULTS: In the present study, PBMCs from autistic children and their parents were exposed to stimulating factors (Interleukin-2/Phytohaemagglutinin) or drugs, as Valproic acid and Efavirenz. The results show that HERVs and cytokines expression can be modulated in vitro by different stimuli in PBMCs from autistic children and their mothers, while no significant changes were found in PBMCs ASD fathers or in controls individuals. In particular, in vitro exposure to interleukin-2/Phytohaemagglutinin or valproic acid induces the expression of several HERVs and cytokines while Efavirenz inhibits them. CONCLUSION: Herein we show that autistic children and their mothers share an intrinsic responsiveness to in vitro microenvironmental changes in expressing HERVs and pro-inflammatory cytokines. Remarkably, the antiretroviral drug Efavirenz restores the expression of specific HERV families to values similar to those of the controls, also reducing the expression of proinflammatory cytokines but keeping the regulatory ones high. Our findings open new perspectives to study the role of HERVs in the biological mechanisms underlying Autism.

Glutathione transferase P silencing promotes neuronal differentiation of retinal R28 cells.

Glutathione transferases (GSTs) play an important role in retinal pathophysiology. Within this family, the GSTP isoform is known as an endogenous regulator of cell survival and proliferation pathways and of cellular responses to oxidative stress. In the present study we silenced GSTP in R28 cells, a retinal precursor cell line with markers of both glial and neuronal origin, and obtained stable clones which were viable and, unexpectedly, characterized by a more neuronal phenotype. The degree of neuronal differentiation was inversely correlated with GSTP residual expression levels. The clone with the lowest expression of GSTP showed metabolic reprogramming, a more favorable redox status and, despite its neuronal phenotype, a sensitivity to glutamate and 4-hydroxynonenal toxicity comparable to that of control cells. Altogether, our evidence shows that near full depletion of GSTP in retinal precursor cells, triggers neuronal differentiation and prosurvival metabolic changes.

Persistence of circulating CD169+monocytes and HLA-DR downregulation underline the immune response impairment in PASC individuals: the potential contribution of different COVID-19 pandemic waves.

The use of CD169 as a marker of viral infection has been widely discussed in the context of COVID-19, and in particular, its crucial role in the early detection of SARS-CoV-2 infection and its association with the severity and clinical outcome of COVID-19 were demonstrated. COVID-19 patients show relevant systemic alteration and immunological dysfunction that persists in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). It is critical to implement the characterization of the disease, focusing also on the possible impact of the different COVID-19 waves and the consequent effects found after infection. On this basis, we evaluated by flow cytometry the expression of CD169 and HLA-DR on monocytes from COVID-19 patients and PASC individuals to better elucidate their involvement in immunological dysfunction, also evaluating the possible impact of different pandemic waves. The results confirm CD169 RMFI is a good marker of viral infection. Moreover, COVID-19 patients and PASC individuals showed high percentage of CD169+ monocytes, but low percentage of HLA-DR+ monocytes and the alteration of systemic inflammatory indices. We have also observed alterations of CD169 and HLA-DR expression and indices of inflammation upon different COVID-19 waves. The persistence of specific myeloid subpopulations suggests a role of CD169+ monocytes and HLA-DR in COVID-19 disease and chronic post-infection inflammation, opening new opportunities to evaluate the impact of specific pandemic waves on the immune response impairment and systemic alterations with the perspective to provide new tools to monitoring new variants and diseases associated to emerging respiratory viruses.

Antioxidant Phytocomplexes Extracted from Pomegranate (Punica granatum L.) Using Hydrodynamic Cavitation Show Potential Anticancer Activity In Vitro.

Hydrodynamic cavitation (HC), as an effective, efficient, and scalable extraction technique for natural products, could enable the affordable production of valuable antioxidant extracts from plant resources. For the first time, whole pomegranate (Punica granatum L.) fruits, rich in bioactive phytochemicals endowed with anti-cancer properties, were extracted in water using HC. Aqueous fractions sequentially collected during the process (M1-M5) were lyophilized (L), filtered (A), or used as such, i.e., crude (C), and analyzed for their biochemical profile and in vitro antioxidant power. The fractions M3 and M4 from the L and C series showed the highest antiradical activity and phytochemical content. While the lyophilized form is preferable for application purposes, sample L-M3, which was produced faster and with lower energy consumption than M4, was used to assess the potential antiproliferative effect on human breast cancer line (AU565-PAR) and peripheral blood mononuclear (PBMC) cells from healthy donors. In a pilot study, cell growth, death, and redox state were assessed, showing that L-M3 significantly reduced tumor cell proliferation and intracellular oxygen reactive species. No effect on PBMCs was detected. Thus, the antioxidant phytocomplex extracted from pomegranate quickly (15 min), at room temperature (30 °C), and efficiently showed potential anticancer activity without harming healthy cells.

Expression profile of HERVs and inflammatory mediators detected in nasal mucosa as a predictive biomarker of COVID-19 severity.

Introduction: Our research group and others demonstrated the implication of the human endogenous retroviruses (HERVs) in SARS-CoV-2 infection and their association with disease progression, suggesting HERVs as contributing factors in COVID-19 immunopathology. To identify early predictive biomarkers of the COVID-19 severity, we analyzed the expression of HERVs and inflammatory mediators in SARS-CoV-2-positive and -negative nasopharyngeal/oropharyngeal swabs with respect to biochemical parameters and clinical outcome. Methods: Residuals of swab samples (20 SARS-CoV-2-negative and 43 SARS-CoV-2-positive) were collected during the first wave of the pandemic and expression levels of HERVs and inflammatory mediators were analyzed by qRT-Real time PCR. Results: The results obtained show that infection with SARS-CoV-2 resulted in a general increase in the expression of HERVs and mediators of the immune response. In particular, SARS-CoV-2 infection is associated with increased expression of HERV-K and HERV-W, IL-1ß, IL-6, IL-17, TNF-α, MCP-1, INF-γ, TLR-3, and TLR-7, while lower levels of IL-10, IFN-α, IFN-ß, and TLR-4 were found in individuals who underwent hospitalization. Moreover, higher expression of HERV-W, IL-1ß, IL-6, IFN-α, and IFN-ß reflected the respiratory outcome of patients during hospitalization. Interestingly, a machine learning model was able to classify hospitalized vs not hospitalized patients with good accuracy based on the expression levels of HERV-K, HERV-W, IL-6, TNF-a, TLR-3, TLR-7, and the N gene of SARS-CoV-2. These latest biomarkers also correlated with parameters of coagulation and inflammation. Discussion: Overall, the present results suggest HERVs as contributing elements in COVID-19 and early genomic biomarkers to predict COVID-19 severity and disease outcome.

Thymosin alpha 1 restores the immune homeostasis in lymphocytes during Post-Acute sequelae of SARS-CoV-2 infection.

The complex alterations of the immune system and the immune-mediated multiorgan injury plays a key role in host response to SARS-CoV-2 infection and in the pathogenesis of COVID-19, being also associated with adverse outcomes. Thymosin alpha 1 (Tα1) is one of the molecules used in the treatment of COVID-19, as it is known to restore the homeostasis of the immune system during infections and cancer. The use of Tα1 in COVID-19 patients had been widely used in China and in COVID-19 patients, it has been shown to decrease hospitalization rate, especially in those with greater disease severity, and reduce mortality by restoring lymphocytopenia and more specifically, depleted T cells. Persistent dysregulation with depletion of naive B and T cell subpopulations and expansion of memory T cells suggest a chronic stimulation of the immune response in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Our data obtained from an ex vivo study, showed that in PASC individuals with a chronically altered immune response, Tα1 improve the restoration of an appropriate response, most evident in those with more severe illness and who need respiratory support during acute phase, and in those with specific systemic and psychiatric symptoms of PASC, confirming Tα1 treatment being more effective in compromised patients. The results obtained, along with promising reports on recent trials on Tα1 administration in patients with COVID-19, offer new insights into intervention also for those patients with long-lasting inflammation with post-infectious symptoms, some of which have a delayed onset.

Multidistrict Host-Pathogen Interaction during COVID-19 and the Development Post-Infection Chronic Inflammation.

Due to the presence of the ACE2 receptor in different tissues (nasopharynx, lung, nervous tissue, intestine, liver), the COVID-19 disease involves several organs in our bodies. SARS-CoV-2 is able to infect different cell types, spreading to different districts. In the host, an uncontrolled and altered immunological response is triggered, leading to cytokine storm, lymphopenia, and cellular exhaustion. Hence, respiratory distress syndrome (ARDS) and systemic multi-organ dysfunction syndrome (MODS) are established. This scenario is also reflected in the composition of the microbiota, the balance of which is regulated by the interaction with the immune system. A change in microbial diversity has been demonstrated in COVID-19 patients compared with healthy donors, with an increase in potentially pathogenic microbial genera. In addition to other symptoms, particularly neurological, the occurrence of dysbiosis persists after the SARS-CoV-2 infection, characterizing the post-acute COVID syndrome. This review will describe and contextualize the role of the immune system in unbalance and dysbiosis during SARS-CoV-2 infection, from the acute phase to the post-COVID-19 phase. Considering the tight relationship between the immune system and the gut-brain axis, the analysis of new, multidistrict parameters should be aimed at understanding and addressing chronic multisystem dysfunction related to COVID-19.

MEOX2 Regulates the Growth and Survival of Glioblastoma Stem Cells by Modulating Genes of the Glycolytic Pathway and Response to Hypoxia.

The most widely accepted hypothesis for the development of glioblastoma suggests that glioblastoma stem-like cells (GSCs) are crucially involved in tumor initiation and recurrence as well as in the occurrence of chemo- and radio-resistance. Mesenchyme homeobox 2 (MEOX2) is a transcription factor overexpressed in glioblastoma, whose expression is negatively correlated with patient survival. Starting from our observation that MEOX2 expression is strongly enhanced in six GSC lines, we performed shRNA-mediated knock-down experiments in two different GSC lines and found that MEOX2 depletion resulted in the inhibition of cell growth and sphere-forming ability and an increase in apoptotic cell death. By a deep transcriptome analysis, we identified a core group of genes modulated in response to MEOX2 knock-down. Among these genes, the repressed ones are largely enriched in genes involved in the hypoxic response and glycolytic pathway, two strictly related pathways that contribute to the resistance of high-grade gliomas to therapies. An in silico study of the regulatory regions of genes differentially expressed by MEOX2 knock-down revealed that they mainly consisted of GC-rich regions enriched for Sp1 and Klf4 binding motifs, two main regulators of metabolism in glioblastoma. Our results show, for the first time, the involvement of MEOX2 in the regulation of genes of GSC metabolism, which is essential for the survival and growth of these cells.

Exogenous miRNAs from Moringa oleifera Lam. recover a dysregulated lipid metabolism.

A balanced diet is critical for human health, and edible plants play an important role in providing essential micronutrients as well as specific microRNAs (miRNAs) that can regulate human gene expression. Here we present the effects of Moringa oleifera (MO) miRNAs (mol-miRs) on lipid metabolism. Through in silico studies we identified the potential genes involved in lipid metabolism targeted by mol-miRs. To this end, we tested the efficacy of an aqueous extract of MO seeds (MOES), as suggested in traditional African ethnomedicine, or its purified miRNAs. The biological properties of MO preparations were investigated using a human derived hepatoma cell line (HepG2) as a model. MOES treatment decreased intracellular lipid accumulation and induced apoptosis in HepG2. In the same cell line, transfection with mol-miRs showed similar effects to MOES. Moreover, the effect of the mol-miR pool was investigated in a pre-obese mouse model, in which treatment with mol-miRs was able to prevent dysregulation of lipid metabolism.

Infection Rate of Respiratory Viruses in the Pandemic SARS-CoV-2 Period Considering Symptomatic Patients: Two Years of Ongoing Observations.

BACKGROUND: In the last two years, the SARS-CoV-2 pandemic has determined radical changes in human behaviors and lifestyles, with a drastic reduction in socialization due to physical distancing and self-isolation. These changes have also been reflected in the epidemiological patterns of common respiratory viruses. For this reason, early discrimination of respiratory viruses is important as new variants emerge. METHODS: Nasopharyngeal swabs of 2554 patients, with clinically suspected Acute Respiratory Infections (ARIs) from October 2019 to November 2021, were collected to detect 1 or more of the 23 common respiratory pathogens, especially viruses, via BioFilmArray RP2.1plus, including SARS-CoV-2. Demographical characteristics and epidemiological analyses were performed as well as a laboratory features profile of positive patients. RESULTS: An observational study on 2300 patients (254 patients were excluded because of missing data) including 1560 men and 760 women, median age of 64.5 years, was carried out. Considering the respiratory virus research request, most of the patients were admitted to the Emergency Medicine Department (41.2%, of patients), whereas 29.5% were admitted to the Infectious Diseases Department. The most frequently detected pathogens included SARS-CoV-2 (31.06%, 707/2300, from March 2020 to November 2021), InfA-B (1.86%, 43/2300), HCoV (2.17% 50/2300), and HSRV (1.65%, 38/2300). Interestingly, coinfection rates decreased dramatically in the SARS-CoV-2 pandemic period. The significative decrease in positive rate of SARS-CoV-2 was associated with the massive vaccination. CONCLUSION: This study represents a dynamic picture of the epidemiological curve of common respiratory viruses during the two years of pandemic, with a disregarded trend for additional viruses. Our results showed that SARS-CoV-2 had a preferential tropism for the respiratory tract without co-existing with other viruses. The possible causes were attributable either to the use of masks, social isolation, or to specific respiratory receptors mostly available for this virus, external and internal lifestyle factors, vaccination campaigns, and emergence of new SARS-CoV-2 variants.

Platinum-(IV)-derivative satraplatin induced G2/M cell cycle perturbation via p53-p21(waf1/cip1)-independent pathway in human colorectal cancer cells.

AIM: Platinum-(IV)-derivative satraplatin represents a new generation of orally available anti-cancer drugs that are under development for the treatment of several cancers. Understanding the mechanisms of cell cycle modulation and apoptosis is necessary to define the mode of action of satraplatin. In this study, we investigate the ability of satraplatin to induce cell cycle perturbation, clonogenicity loss and apoptosis in colorectal cancer (CRC) cells. METHODS: CRC cells were treated with satraplatin, and the effects of satraplatin on apoptosis and the cell cycle were evaluated by flow cytometry. Western blot analysis was used to investigate the effects of satraplatin on cell cycle and apoptosis-related proteins. RT-qPCR was used to evaluate p53-related mRNA modulation. RESULTS: Satraplatin induced an accumulation of CRC cells predominantly in the G(2)/M phase. Increased p53 protein expression was observed in the p53 wild-type HCT116 and LoVo cells together with p21(waf1/cip1) protein up-regulation. However, p21(waf1/cip1) protein accumulation was not observed in the p53 mutant HCT15, HT29, and WiDr cells, even when p53 protein expression was compromised, suggesting that the cell cycle perturbation is p53-p21(waf1/cip1) independent. Following a candidate approach, we found an elevated expression of 14-3-3σ protein levels in CRC cells, which was independent of the status of p53, further supporting the role of satraplatin in the perturbation of the G(2)/M cell cycle phase. Moreover, satraplatin treatment induced apoptosis along with Bcl-2 protein down-regulation and abrogated the clonogenic formation of CRC cells in vitro. CONCLUSION: Collectively, our data suggest that satraplatin induces apoptosis in CRC cells, which is preceded by cell cycle arrest at G(2)/M due to the effect of 14-3-3σ and in a p53-p21(waf1/cip1)-independent manner. Taken together, these findings highlight the potential use of satraplatin for CRC treatment.

The 2018-2020 Ebola Outbreak in the Democratic Republic of Congo: A Better Response Had Been Achieved Through Inter-State Coordination in Africa.

The Ebola virus disease, formerly known as Ebola hemorrhagic fever, is a severe and often fatal zoonosis in humans. The 2013-2016 West African Ebola outbreak had distinctive characteristics, and it was the largest and most complex epidemic since the virus discovery in 1976. Although the 2018-2020 Ebola outbreak in the Democratic Republic of the Congo had many similarities, there were additional challenges due to the presence of armed rebel groups at the epicenters of the epidemic. Despite these challenges, the extraordinary commitment of the World Health Organization (WHO) regional office for Africa, in collaboration with Africa Union (AU) member states through the Africa Centres for Disease Control and Prevention (Africa CDC), and WHO's prompt declaration of a Public Health Emergency of International Concern (PHEIC) shepherded an effective coordinated response to contain the epidemic. Learning from previous Ebola virus epidemics and the current Coronavirus disease 2019 (COVID-19) pandemic, the AU member states should strengthen inter-state coordination towards the development and implementation of a preparedness and readiness plan which will enable the continent to build and sustain resilient capacities to prevent, detect, and respond to future outbreaks following the International Health Regulations (IHR).

Micro-Vesicles of Moringa oleifera Seeds in Heterozygous Rats for DAT Gene: Effects of Oral Intake on Behavioral Profile and Hematological Parameters.

Previous studies have shown multiple biological properties of Moringa oleifera, a plant native to Africa and Asia. In the present study, potential physiological properties of microvesicles extracted from Moringa oleifera seeds were assessed. For this purpose, we investigated behavioral profile and hematological parameters in a recent rat model characterized by dysregulation in dopamine transporter, a key regulator of dopaminergic system. Experimental design consisted of male Wistar-DAT rats aged between two and four months: wild-type (WT) (n = 5) and heterozygous (DATHET) (n = 4) control groups, which drank tap water; WT (n = 5) and DATHET (n = 6) groups which drank a solution of Moringa microvesicles and water (2: 68 mL per day), which was orally administered for two months. Rats were monitored for spontaneous locomotor activity on a 24/7 basis. In the early lit hours, treated DATHET subjects showed higher locomotor activity, proposing a sleep-delay effect of Moringa. In forced swimming test, WT subjects who took Moringa exhibited more depressive behavior. In DATHET rats, Moringa seemed to potentiate the struggle to find a way out, counteracting an initial panic. Hemoglobin and hematocrit underwent opposite changes in either genotype, supporting the opposite effects on behavioral phenotype observed. Future work is clearly needed to further explore these preliminary profiles.

High CD169 Monocyte/Lymphocyte Ratio Reflects Immunophenotype Disruption and Oxygen Need in COVID-19 Patients.

BACKGROUND: Sialoadhesin (CD169) has been found to be overexpressed in the blood of COVID-19 patients and identified as a biomarker in early disease. We analyzed CD169 in the blood cells of COVID-19 patients to assess its role as a predictive marker of disease progression and clinical outcomes. METHODS: The ratio of the median fluorescence intensity of CD169 between monocytes and lymphocytes (CD169 RMFI) was analyzed by flow cytometry in blood samples of COVID-19 patients (COV) and healthy donors (HDs) and correlated with immunophenotyping, inflammatory markers, cytokine mRNA expression, pulmonary involvement, and disease progression. RESULTS: CD169 RMFI was high in COV but not in HDs, and it correlated with CD8 T-cell senescence and exhaustion markers, as well as with B-cell maturation and differentiation in COV. CD169 RMFI correlated with blood cytokine mRNA levels, inflammatory markers, and pneumonia severity in patients who were untreated at sampling, and was associated with the respiratory outcome throughout hospitalization. Finally, we also report the first evidence of the specific ability of the spike protein of SARS-CoV-2 to trigger CD169 RMFI in a dose-dependent manner in parallel with IL-6 and IL-10 gene transcription in HD PBMCs stimulated in vitro. CONCLUSION: CD169 is induced by the spike protein and should be considered as an early biomarker for evaluating immune dysfunction and respiratory outcomes in COVID-19 patients.

NH-sulfoximine: A novel pharmacological inhibitor of the mitochondrial F1 Fo -ATPase, which suppresses viability of cancerous cells.

BACKGROUND AND PURPOSE: The mitochondrial F1 Fo -ATPsynthase is pivotal for cellular homeostasis. When respiration is perturbed, its mode of action everts becoming an F1 Fo -ATPase and therefore consuming rather producing ATP. Such a reversion is an obvious target for pharmacological intervention to counteract pathologies. Despite this, tools to selectively inhibit the phases of ATP hydrolysis without affecting the production of ATP remain scarce. Here, we report on a newly synthesised chemical, the NH-sulfoximine (NHS), which achieves such a selectivity. EXPERIMENTAL APPROACH: The chemical structure of the F1 Fo -ATPase inhibitor BTB-06584 was used as a template to synthesise NHS. We assessed its pharmacology in human neuroblastoma SH-SY5Y cells in which we profiled ATP levels, redox signalling, autophagy pathways and cellular viability. NHS was given alone or in combination with either the glucose analogue 2-deoxyglucose (2-DG) or the chemotherapeutic agent etoposide. KEY RESULTS: NHS selectively blocks the consumption of ATP by mitochondria leading a subtle cytotoxicity associated via the concomitant engagement of autophagy which impairs cell viability. NHS achieves such a function independently of the F1 Fo -ATPase inhibitory factor 1 (IF1). CONCLUSION AND IMPLICATIONS: The novel sulfoximine analogue of BTB-06584, NHS, acts as a selective pharmacological inhibitor of the mitochondrial F1 Fo -ATPase. NHS, by blocking the hydrolysis of ATP perturbs the bioenergetic homoeostasis of cancer cells, leading to a non-apoptotic type of cell death.

Evidence of the pathogenic HERV-W envelope expression in T lymphocytes in association with the respiratory outcome of COVID-19 patients.

BACKGROUND: Despite an impressive effort in clinical research, no standard therapeutic approach for coronavirus disease 2019 (COVID-19) patients has been established, highlighting the need to identify early biomarkers for predicting disease progression and new therapeutic interventions for patient management. The present study aimed to evaluate the involvement of the human endogenous retrovirus -W envelope (HERV-W ENV) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection considering recent findings that HERVs are activated in response to infectious agents and lead to various immunopathological effects. We analysed HERV-W ENV expression in blood cells of COVID-19 patients in correlation with clinical characteristics and have discussed its potential role in the outcome of the disease. METHODS: We analysed HERV-W ENV expression in blood samples of COVID-19 patients and healthy donors by flow cytometry and quantitative reverse transcriptase PCR analysis, and evaluated its correlation with clinical signs, inflammatory markers, cytokine expression, and disease progression. FINDINGS: HERV-W ENV was highly expressed in the leukocytes of COVID-19 patients but not in those of healthy donors. Its expression correlated with the markers of T-cell differentiation and exhaustion and blood cytokine levels. The percentage of HERV-W ENV-positive lymphocytes correlated with inflammatory markers and pneumonia severity in COVID-19 patients. Notably, HERV-W ENV expression reflects the respiratory outcome of patients during hospitalization. INTERPRETATION: Given the known immuno- and neuro-pathogenicity of HERV-W ENV protein, it could promote certain pathogenic features of COVID-19 and therefore serve as a biomarker to predict clinical progression of disease and open to further studies for therapeutic intervention. FUNDING: Information available at the end of the manuscript.

Thymosin Alpha 1 Mitigates Cytokine Storm in Blood Cells From Coronavirus Disease 2019 Patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is characterized by immune-mediated lung injury and complex alterations of the immune system, such as lymphopenia and cytokine storm, that have been associated with adverse outcomes underlining a fundamental role of host response in severe acute respiratory syndrome coronavirus 2 infection and the pathogenesis of the disease. Thymosin alpha 1 (Tα1) is one of the molecules used in the management of COVID-19, because it is known to restore the homeostasis of the immune system during infections and cancer. METHODS: In this study, we captured the interconnected biological processes regulated by Tα1 in CD8+ T cells under inflammatory conditions. RESULTS: Genes associated with cytokine signaling and production were upregulated in blood cells from patients with COVID-19, and the ex vivo treatment with Tα1-mitigated cytokine expression, and inhibited lymphocyte activation in a CD8+ T-cell subset specifically. CONCLUSION: These data suggest the potential role of Tα1 in modulating the immune response homeostasis and the cytokine storm in vivo.

The novel proapoptotic activity of nonnatural enantiomer of Lentiginosine.

D-(-)-Lentiginosine [(-)-4], the nonnatural enantiomer of the iminosugar indolizidine alkaloid L-(+)-lentiginosine, acts as apoptosis inducer on tumor cells of different origin, in contrast to its natural enantiomer. Although D-(-)-4 exhibited a proapoptotic activity towards tumor cells at level lower than the chemotherapeutic agent, SN38, it was less proapoptotic towards normal cells and less cytotoxic. Apoptosis induced by D-(-)-4 was caspase-dependent, as shown by the increased expression and activity of caspase-3 and -8 in treated cells, and by inhibition following treatment with the pan caspase inhibitor, ZVAD-FMK. This study highlighted how a natural iminosugar alkaloid and its synthetic enantiomer, which were simply known for their inhibition against a fungal glucoamylase, could behave in a complete different way when tested towards cell growth and death of cells of different origin.