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In 2021, avian influenza A (H5N1) clade 2.3.4.4b virus spread to North America and then to Central and South America in October 2022, extending from Colombia to Chile in three months. During 2023, several countries, mostly in the Americas, reported outbreaks in poultry, wild birds and mammals, as well as the emergence of two cases in humans (one in Ecuador in January and one in Chile in March). As of September 20th, 2023, 17 countries in the Americas Region have recorded cases of A (H5N1) in birds and mammals. On February 14th, 2023, Argentina confirmed the first case of avian influenza in wild birds, which was later detected in backyard and commercial poultry, and in the South-American sea lion (Otaria flavescens) in Tierra del Fuego, in the south of the country. So far, 21 suspected cases have been recorded in humans; however, all of them tested negative for Influenza A virus. Hemagglutinin sequence data of animal viruses analyzed in this report showed that Argentinian viruses clustered together with those isolated in other countries of the region. Epidemiological data suggested the possibility of multiple simultaneous entries of the avian virus, highlighting the role of migratory avian populations in the introduction and dissemination of the disease in Argentina. Continued comprehensive surveillance of these viruses in animals and people worldwide, along with ongoing preparedness efforts, are critical to determine the public health risk., (Copyright © 2024 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Series of novel amides of isoferulic acid, where the phenolic hydroxyl was replaced by a difluoromethyl group, were synthesized and their in vitro antibacterial activities assayed against fourteen bacterial strains (six Gram-positive and eight Gram-negative). A one-pot methodology was developed to obtain the 3'-(difluoromethyl)-4'-methoxycinnamoyl amides using Deoxofluor ® as a fluorinating agent. The N -isopropyl, N -isopentyl, and N -(2-phenylethyl) amides 11b , 11d and 11g were the most active and selective against Mycobacterium smegmatis (MIC = 8 µg/mL) with 11b and 11g displaying negligible or no cytotoxicity against HepG2 and A549 cells. Thirteen analogs of N -isopropylamide 11b were also synthesized and their antibacterial activity assayed. Results show that the difluoromethyl moiety enhanced antibacterial activity and selectivity towards M. smegmatis , changing the microorganism inhibition profile of the parent compound. The selectivity exhibited by some of the compounds towards M. smegmatis makes them potential leads in the search for new narrow spectrum antibiotics against M. tuberculosis ., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The antibacterial assays were performed by Laboratorios Richmond (see acknowledgments).

Since antiretroviral therapy suppresses but does not eradicate HIV-1 infection, methods to purge viral reservoirs are required. Many strategies involve the reactivation of chronically HIV infected cells to induce the expression of integrated viral genome. In this study, five bioactive compounds, the plant derivatives 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), nordihydroguaiaretic acid (NDGA), and curcumin (Cur) and the synthetic stigmasterol analogs (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) and (22S,23S)-3 β -bromo-5 α ,22,23-trihydroxystigmastan-6-one (compound 2), were evaluated for their ability to elicit HIV replication in promonocytic (U1) and lymphocytic (H9+) HIV-1 chronically infected cells. The results revealed that natural compounds CDM, NDGA, and Cur were able to increase HIV-1 p24 antigen, determined by ELISA, only in latently infected promonocytic cells. CDM would reactivate HIV from latency by modulating the release of IL-6 and TNF- α , since the amount of both cytokines measured through ELISA significantly increased in U1 treated cells. Besides, NDGA increased ROS production, which might be related to the increase on p24 level observed in NDGA treated U1. These findings suggest that CDM, NDGA, and Cur might be candidates for further studies on latency-reversing therapeutics to eliminate latently HIV-1 reservoirs.

Human embryonic stem cells (hESCs) are self-renewing pluripotent cells that can differentiate into specialized cells and hold great promise as models for human development and disease studies, cell-replacement therapies, drug discovery and in vitro cytotoxicity tests. The culture and differentiation of these cells are both complex and expensive, so it is essential to extreme aseptic conditions. hESCs are susceptible to Mycoplasma sp. infection, which is hard to detect and alters stem cell-associated properties. The purpose of this work was to evaluate the efficacy and cytotoxic effect of Plasmocin(TM) and ciprofloxacin (specific antibiotics used for Mycoplasma sp. eradication) on hESCs. Mycoplasma sp. infected HUES-5 884 (H5 884, stable hESCs H5-brachyury promoter-GFP line) cells were effectively cured with a 14 days Plasmocin(TM) 25 µg/ml treatment (curative treatment) while maintaining stemness characteristic features. Furthermore, cured H5 884 cells exhibit the same karyotype as the parental H5 line and expressed GFP, through up-regulation of brachyury promoter, at day 4 of differentiation onset. Moreover, H5 cells treated with ciprofloxacin 10 µg/ml for 14 days (mimic of curative treatment) and H5 and WA09 (H9) hESCs treated with Plasmocin(TM) 5 µg/ml (prophylactic treatment) for 5 passages retained hESCs features, as judged by the expression of stemness-related genes (TRA1-60, TRA1-81, SSEA-4, Oct-4, Nanog) at mRNA and protein levels. In addition, the presence of specific markers of the three germ layers (brachyury, Nkx2.5 and cTnT: mesoderm; AFP: endoderm; nestin and Pax-6: ectoderm) was verified in in vitro differentiated antibiotic-treated hESCs. In conclusion, we found that Plasmocin(TM) and ciprofloxacin do not affect hESCs stemness and pluripotency nor cell viability. However, curative treatments slightly diminished cell growth rate. This cytotoxic effect was reversible as cells regained normal growth rate upon antibiotic withdrawal.

Synovial sarcoma (SS) is the most frequent nonrhabdomyosarcomatous soft tissue sarcoma encountered in adolescents and young adults, and despite advances in the treatment of local disease, metastases remain the main cause of death. The aim of this study was to characterize a single-center series of pediatric SS molecularly to seek any biomarkers or pathways that might make suitable targets for new agents. Seventeen cases of pediatric SS showing the SYT-SSX fusion transcript were screened immunohistochemically, biochemically, molecularly, and cytogenetically (depending on the available material) to investigate any expression/activation of epidermal growth factor receptor, platelet-derived growth factor receptor alpha (PDGFRalpha), PDGFRbeta, Akt, and deregulated Wnt pathway. The most relevant outcome was the finding of activated epidermal growth factor receptor, PDGFRalpha, and PDGFRbeta, which activated Akt in both the monophasic and biphasic histologic subtypes. Consistently, Akt activation was completely abolished in an SS cell line assay when stimulated by PDGF-AA and treated with the phosphatidylinositol 3-kinase inhibitor LY294002. Our results also showed the nuclear localization of beta-catenin and cyclin D1 gene products in monophasic SS and the movement of beta-catenin into the cytoplasm in the glandular component of the biphasic subtype. Although they need to be confirmed in larger series, these preliminary data suggest that therapeutic strategies including specific inhibitors of the phosphatidylinositol 3-kinase/Akt pathway might be exploited in SS.

Background: HIV triggers the decline of CD4+ T cells and leads to progressive dysfunction of cell-mediated immunity. Although an increased susceptibility to cell death occurs during the acute phase of HIV infection, persistently-infected macrophages and quiescent T-cells seem to be resistant to cell death, representing a potential reservoir for virus production., Results: Lymphoid (H9/HTLVIIIB and J1.1) and pro-monocytic (U1) HIV-1 persistently-infected cell lines were treated with hydrogen peroxide (H2O2) and staurosporine (STS) for 24 h, and susceptibility to apoptosis was evaluated and compared with uninfected counterparts (H9, Jurkat and U937 respectively). When exposed to different pro-apoptotic stimuli, all persistently-infected cell lines showed a dramatic reduction in the frequency of apoptotic cells in comparison with uninfected cells. This effect was independent of the magnitude of viral replication, since the induction of viral production in lymphoid or pro-monocytic cells by exposure to TNF-alpha or PMA did not significantly change their susceptibility to H2O2- or STS-induced cell death. A mechanistic analysis revealed significant diferences in mitochondrial membrane potential (MMP) and caspase-3 activation between uninfected and persistently-infected cells. In addition, Western blot assays showed a dramatic reduction of the levels of pro-apototic Bax in mitochondria of persistently-infected cells treated with H2O2 or STS, but not in uninfected cells., Conclusion: This study represents the first evidence showing that resistance to apoptosis in persistently-infected lymphoid and monocytic cells is independent of active viral production and involves modulation of the mitochondrial pathway. Understanding this effect is critical to specifically target the persistence of viral reservoirs, and provide insights for future therapeutic strategies in order to promote complete viral eradication.

Since the appearance of resistance to antiretroviral treatment is unavoidable, the host cell's transcription factor NF-kappaB is a novel HIV target. The goal of this study was to characterize the effect of two immunomodulators, curcumin (Cur) and sulfasalazine (Sul), with a protease inhibitor, indinavir (IDV), on HIV-1 persistently infected CD4+ T-cells. Viral p24 antigen production, viral infectivity (tested on MAGI cells) and viral relative infectivity (viral infectivity/p24) were analysed. When used alone, both immunomodulators were able to reduce viral infectivity. When in combination, both 10 microM IDV plus 10 microM Cur and 10 microM IDV plus 250 microM Sul showed a significant reduction in viral infectivity and viral relative infectivity when compared to the reduction produced by IDV alone. Thus, the use of immunomodulators with IDV could help to reduce HIV-1 production in persistently infected cells.

Viral-induced apoptosis might be mediated by oxidative stress. It has already been described that cell death in vesicular stomatitis virus (VSV)-infected cells occurs by apoptosis. In this study, oxidative stress parameters present in VSV-infected Vero cells were analyzed. Lipid peroxides (LP) were evaluated in cellular extracts and expressed as thiobarbituric acid-reactive substances. LP levels exhibited a rise at different times post infection, according to the multiplicity of infection (MOI), while the presence of cycloheximide determined a reduction on LP. Also, an increase in protein degradation products and a decrease in polyunsaturated fatty acids content was observed, indicating that cellular proteins and lipids began to be susceptible to degradation during VSV infection. In addition, we analyzed cell viability of VSV-infected Vero cells, which were incubated in the presence of butylated hydroxyanisole. This antioxidant was able to protect Vero cells, at least at MOIs assayed in this study, and to reduce viral yield only when VSV infection was done at MOI 0.05. Further, superoxide dismutases, which occupy the first step within the antioxidant enzyme cascade, also exhibit a rise in VSV-infected Vero cells, at different MOI. These results suggest that both an oxidative stress and an antioxidative cell response precede the induction of apoptosis by VSV.

Different immunomodulatory activities present in Trichilia glabra (TG) leaf extracts have already been described. Particularly, chloroform-methanol extracts were responsible for an in-vivo anti-inflammatory effect. The effect of such extracts on the infectivity of enveloped and naked viruses were investigated. Methanolic fraction extracts were active against herpes simplex virus type 1 (HSV-1) and vesicular stomatitis virus (VSV), while no activity against poliovirus type 3 was observed. VSV was slightly more affected than HSV-1: 2.8 log10 reduction in VSV titer against 2.4 log10 reduction in HSV-1 titer when 0.25 mg/ml F2 fraction was tested and a reduction of 2.7 log10 in VSV virus titer and of 1.5 log10 in HSV-1 virus titer was observed when 0.25 mg/ml F3 fraction was tested. Results obtained in this work suggest a potential pharmaceutical use of TG extract components.