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Background/Objectives: In recent years, silver nanoparticles (AgNPs) have garnered significant attention due to their potent antimicrobial properties, which hold promise for various applications. However, concerns about their potential toxicity have also emerged, particularly regarding their impact on human and animal health. This study investigates the acute toxicological effects of AgNPs synthesized using a green route with an aqueous extract of a native Cerrado plant (AgNPs-Cb) in mice. Methods: The AgNPs-Cb were intravenously administered at a concentration of 64 µM, and the mice were euthanized after 24 h for the collection of blood and organ samples (liver, spleen, kidneys, and lungs) for hematological, biochemical, and histological analyses. Results: Hematological analysis, including complete blood count (CBC) and differential leukocyte count, showed no statistically significant alterations in the groups treated with AgNPs-Cb, Cb extract, and Ag+, compared with the control group (p < 0.05). Notably, only the Ag+ group exhibited a significant increase in red blood cell count and hematocrit levels, suggesting that the nanoformulation of silver might mitigate the hematological impact seen with free silver ions. Biochemical analyses of liver and kidney function markers also revealed no significant differences across the treatment groups. Conclusions: These findings indicate that AgNPs-Cb may offer a safer alternative for antimicrobial applications, reducing the risk of acute toxicity in mammals while maintaining efficacy against pathogens. Further studies are needed to explore the underlying mechanisms and long-term effects of AgNPs-Cb exposure.

Zika virus (ZIKV) has a strong tropism for the nervous system and has been related to post-infection neurological syndromes. Once neuronal cells are infected, the virus is capable of modulating cell metabolism, leading to neurotoxicity and cellular death. The negative effect of ZIKV in neuron cells has been characterized. However, the description of molecules capable of reversing these cytotoxic effects is still under investigation. In this context, it has been largely demonstrated that docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, is highly neuroprotective. Here, we hypothesized that DHA’s neuroprotective proprieties could have an influence on ZIKV-induced neurotoxicity in SH-SY5Y cells. Our data showed that pre-treatment of SH-SY5Y cells with DHA increased the cell viability and proliferation in ZIKV-infected cells. Moreover, DHA triggered an anti-inflammatory response in those infected cells. Besides, DHA was capable of restoring mitochondria function and number in ZIKV-infected SH-SY5Y cells. In addition, cells pre-treated with DHA prior to ZIKV infection presented a lower viral load at different times of infection. Taking together, these results demonstrated that DHA has a potential anti-inflammatory and neuroprotective effect against ZIKV infection in these neuron-like cells and could be a useful tool in the treatment against this virus.

Gut microbiota composition can modulate neuroendocrine function, inflammation, and cellular and immunological responses against different pathogens, including viruses. Zika virus (ZIKV) can infect adult immunocompetent individuals and trigger brain damage and antiviral responses. However, it is not known whether ZIKV infection could impact the gut microbiome from adult immunocompetent mice. Here, we investigated modifications induced by ZIKV infection in the gut microbiome of immunocompetent C57BL/6J mice. Adult C57BL/6J mice were infected with ZIKV and the gut microbiota composition was analyzed by next-generation sequencing of the V4 hypervariable region present in the bacterial 16S rDNA gene. Our data showed that ZIKV infection triggered a significant decrease in the bacteria belonging to Actinobacteria and Firmicutes phyla, and increased Deferribacteres and Spirochaetes phyla components compared to uninfected mice. Interestingly, ZIKV infection triggered a significant increase in the abundance of bacteria from the Spirochaetaceae family in the gut microbiota. Lastly, we demonstrated that modulation of microbiota induced by ZIKV infection may lead to intestinal epithelium damage and intense leukocyte recruitment to the intestinal mucosa. Taken together, our data demonstrate that ZIKV infection can impact the gut microbiota composition and colon tissue homeostasis in adult immunocompetent mice.

Abstract Background Zika virus (ZIKV) infection has been associated with prolonged viral excretion in human semen and causes testicular atrophy and infertility in 10-week-old immunodeficient mice. Methods Male IFNAR−/− mice, knockout for type I interferon receptor, were immunized with GLS-5700, a deoxyribonucleic acid-based vaccine, before a subcutaneous ZIKV challenge with 6 × 105 plaque-forming units at 13 weeks of age. On day 28 postinfection, testes and epididymides were collected in some mice for histological and functional analyses, whereas others were mated with naive female wild-type C57BL/6J. Results Although all mice challenged with ZIKV developed viremia, most of them were asymptomatic, showed no weight loss, and survived infection. On day 28 postinfection, none of the unvaccinated, infected mice (9 of 9) exhibited abnormal spermatozoa counts or motility. However, 33% (3 of 9) and 36% (4 of 11) of mated males from this group were infertile, from 2 independent studies. Contrarily, males from the noninfected and the vaccinated, infected groups were all fertile. On days 75 and 207 postinfection, partial recovery of fertility was observed in 66% (2 of 3) of the previously infertile males. Conclusions This study reports the effects of ZIKV infection on male fertility in a sublethal, immunodeficient mouse model and the efficacy of GLS-5700 vaccination in preventing male infertility. Male IFNAR−/− mice infected with ZIKV at an older age were shown to be infertile without overt signs of disease. This outcome was prevented by immunization with a DNA vaccine. A partial recovery of fertility was observed later after infection.

Zika virus is an arbovirus that has rapidly spread within the Americas since 2014, presenting a variety of clinical manifestations and neurological complications resulting in congenital malformation, microcephaly, and possibly, in male infertility. These significant clinical manifestations have led investigators to develop several candidate vaccines specific to Zika virus. In this review we describe relevant targets for the development of vaccines specific for Zika virus, the development status of various vaccine candidates and their different platforms, as well as their clinical progression.

Foam cells are specialized lipid-loaded macrophages derived from monocytes and are a key pathological feature of atherosclerotic lesions. Lysophosphatidylcholine (LPC) is a major lipid component of the plasma membrane with a broad spectrum of proinflammatory activities and plays a key role in atherosclerosis. However, the role of LPC in lipid droplet (LD) biogenesis and the modulation of inflammasome activation is still poorly understood. In the present study, we investigated whether LPC can induce foam cell formation through an analysis of LD biogenesis and determined whether the cell signaling involved in this process is mediated by the inflammasome activation pathway in human endothelial cells and monocytes. Our results showed that LPC induced foam cell formation in both types of cells by increasing LD biogenesis via a NLRP3 inflammasome-dependent pathway. Furthermore, LPC induced pyroptosis in both cells and the activation of the inflammasome with IL-1β secretion, which was dependent on potassium efflux and lysosomal damage in human monocytes. The present study described the IL-1β secretion and foam cell formation triggered by LPC via an inflammasome-mediated pathway in human monocytes and endothelial cells. Our results will help improve our understanding of the relationships among LPC, LD biogenesis, and NLRP3 inflammasome activation in the pathogenesis of atherosclerosis.

Obesity is a chronic disease with rising worldwide prevalence and largely associated with several other comorbidities, such as cancer, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome. Hepatic steatosis, a hallmark of NAFLD, is strongly correlated with obesity and has been correlated with changes in the gut microbiota, which can promote its development through the production of short-chain fatty acids (SCFAs) that regulate insulin resistance, bile acid, choline metabolism, and inflammation. Recent studies have suggested a controversial role for the inflammasome/caspase-1 in the development of obesity and non-alcoholic steatohepatitis (NASH). Here, we evaluated the role of inflammasome NLRP3 and caspases 1/11 in the establishment of obesity and hepatic steatosis in diet-induced obese mice, correlating them with the global lipid profile of the liver and gut microbiota diversity. After feeding wild-type, caspases 1/11, and NLRP3 knockout mice with a standard fat diet (SFD) or a high-fat diet (HFD), we found that the caspases 1/11 knockout mice, but not NLRP3 knockout mice, were more susceptible to HFD-induced obesity, and developed enhanced hepatic steatosis even under SFD conditions. Lipidomics analysis of the liver, assessed by MALDI-MS analysis, revealed that the HFD triggered a significant change in global lipid profile in the liver of WT mice compared to those fed an SFD, and this profile was modified by the lack of caspases 1/11 and NLRP3. The absence of caspases 1/11 was also correlated with an increased presence of triacylglycerol in the liver. Gut microbial diversity analysis, using 16S rRNA gene sequencing, showed that there was also an increase of Proteobacteria and a higher Firmicutes/Bacteroidetes ratio in the gut of caspases 1/11 knockout mice fed an HFD. Overall, mice without caspases 1/11 harbored gut bacterial phyla involved with weight gain, obesity, and hepatic steatosis. Taken together, our data suggest an important role for caspases 1/11 in the lipid composition of the liver and in the modulation of the gut microbial community composition. Our results further suggest that HFD-induced obesity and the absence of caspases 1/11 may regulate both lipid metabolism and gut microbial diversity, and therefore may be associated with NAFLD and obesity.

Paracoccidioides brasiliensis is the etiologic agent of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis that is geographically confined to Latin America. The pro-inflammatory cytokine IL-1β that is mainly derived from the activation of the cytoplasmic multiprotein complex inflammasome is an essential host factor against opportunistic fungal infections; however, its role in infection with a primary fungal pathogen, such as P. brasiliensis, is not well understood. In this study, we found that murine bone marrow-derived dendritic cells responded to P. brasiliensis yeast cells infection by releasing IL-1β in a spleen tyrosine kinase (Syk), caspase-1 and NOD-like receptor (NLR) family member NLRP3 dependent manner. In addition, P. brasiliensis-induced NLRP3 inflammasome activation was dependent on potassium (K+) efflux, reactive oxygen species production, phagolysosomal acidification and cathepsin B release. Finally, using mice lacking the IL-1 receptor, we demonstrated that IL-1β signaling has an important role in killing P. brasiliensis by murine macrophages. Altogether, our results demonstrate that the NLRP3 inflammasome senses and responds to P. brasiliensis yeast cells infection and plays an important role in host defense against this fungus.

Zika virus (ZIKV) has been reported by several groups as an important virus causing pathological damage in the male reproductive tract. ZIKV can infect and persist in testicular somatic and germ cells, as well as spermatozoa, leading to cell death and testicular atrophy. ZIKV has also been detected in semen samples from ZIKV-infected patients. This has huge implications for human reproduction. Global scientific efforts are being applied to understand the mechanisms related to arboviruses persistency, pathogenesis, and host cellular response to suggest a potential target to develop robust antiviral therapeutics and vaccines. Here, we discuss the cellular modulation of the immunologic and physiologic properties of the male reproductive tract environment caused by arboviruses infection, focusing on ZIKV. We also present an overview of the current vaccine effects and therapeutic targets against ZIKV infection that may impact the testis and male fertility.

Background Adipose tissue metabolic plasticity and inflammation critically influence tumor progression through endocrine signaling. While white adipose tissue (WAT) has been linked to pro-tumorigenic effects in obesity-related cancers, the influence of brown adipose tissue (BAT) and its secretome on breast cancer remains incompletely understood. Furthermore, how caspase-1/11–mediated inflammasome signaling regulates adipose tissue endocrine function in this context is largely unexplored. This study investigated the differential effects of WAT and BAT secretomes on breast cancer aggressiveness and elucidate the impact of caspase-1/11 deficiency on adipose tissue-tumor crosstalk. Methods Conditioned media (CM) were generated from WAT and BAT of wild-type (WT) and caspase-1/11 knockout (KO) C57BL/6 mice, including animals subjected to cold-induced BAT activation. 4T1 breast cancer cells were exposed to these secretomes, and carcinogenic parameters were assessed, including viability (MTT), cell death (Annexin-V/PI), proliferation (CFSE), migration (wound healing assay), lipid droplet biogenesis (BODIPY and Oil Red staining and microscopy), oxidative stress (ROS and nitrite quantification), and cytokine production (ELISA). Additionally, splenocytes were also stimulated with the secretomes to assess their effect on T and NKT cell activation (Flow cytometry). Global proteomic profiling (LC-MS/MS) was performed to identify key molecular pathways affected of exposed breast cancer cells compared to controls. Statistical analyses included ANOVA with Tukey’s or Student’s t-test, as appropriate. Results WAT-CM promoted lipid droplet accumulation in 4T1 cells. In contrast, BAT-CM reduced tumor cell viability, cell proliferation, and migration further triggering oxidative stress and cell death. Immunophenotypic analysis revealed that BAT-CM modulated immune activation. These antitumor effects were amplified by caspase-1/11 deficiency and cold-induced BAT activation. Proteomic analyses revealed distinct modulation of metabolic, inflammatory, and immune-related pathways in WAT- and BAT-CM-treated tumor cells. Histological and cytokine analyses demonstrated that caspase-1/11 deficiency led to reduced adipocyte size, increased BAT macrophage infiltration, and a softened inflammatory profile. Conclusions Our findings uncover a novel anti-tumor role for the BAT secretome in breast cancer, modulated by caspase-1/11-dependent inflammasome signaling and cold-induced activation. Targeting adipose tissue plasticity and inflammasome pathways may offer new strategies to reprogram the tumor microenvironment. These results open novel perspectives for exploring BAT-derived factors as metabolic-based therapeutics for breast cancer.