The innate immune system represents the host’s first-line defense against pathogens, dead cells or environmental factors. One of the most important inflammatory pathways is represented by the activation of the NOD-like receptor (NLR) protein family. Some NLRs induce the assembly of large caspase-1-activating complexes called inflammasomes. Different types of inflammasomes have been identified that can respond to distinct bacterial, viral or fungal infections; sterile cell damage or other stressors, such as metabolic imbalances. Epigenetic regulation has been recently suggested to provide a complementary mechanism to control inflammasome activity. This regulation can be exerted through at least three main mechanisms, including CpG DNA methylation, histones post-translational modifications and noncoding RNA expression. The repression or promotion of expression of different inflammasomes (NLRP1, NLRP2, NLRP3, NLRP4, NLRP6, NLRP7, NLRP12 and AIM2) through epigenetic mechanisms determines the development of pathologies with variable severity. For example, our team recently explored the role of microRNAs (miRNAs) targeting and modulating the components of the inflammasome as potential biomarkers in bladder cancer and during therapy. This suggests that the epigenetic control of inflammasome-related genes could represent a potential target for further investigations of molecular mechanisms regulating inflammatory pathways.

Varicocele (VC) is the most common abnormality identified in men evaluated for hypofertility. Increased levels of reactive oxygen species (ROS) and reduced antioxidants concentrations are key contributors in varicocele-mediated hypofertility. Moreover, inflammation and alterations in testicular immunity negatively impact male fertility. In particular, NLRP3 inflammasome activation was hypothesized to lead to seminal inflammation, in which the levels of specific cytokines, such as IL-1β and IL-18, are overexpressed. In this review, we described the role played by oxidative stress (OS), inflammation, and NLRP3 inflammasome activation in VC disease. The consequences of ROS overproduction in testis, including inflammation, lipid peroxidation, mitochondrial dysfunction, chromatin damage, and sperm DNA fragmentation, leading to abnormal testicular function and failed spermatogenesis, were highlighted. Finally, we described some therapeutic antioxidant strategies, with recognized beneficial effects in counteracting OS and inflammation in testes, as possible therapeutic drugs against varicocele-mediated hypofertility.

We investigated the association between circulating microRNAs (miRNAs) potentially involved in the lung inflammatory process and fibrosis development among COVID-19-related acute respiratory distress syndrome (ARDS) survivors. At 4 ± 2 months from clinical recovery, COVID-19-related ARDS survivors matched for age, sex, and clinical characteristics underwent chest high-resolution computerized tomography (HRCT) and were selected based on imaging pattern evolution into fully recovered (N = normal), pulmonary opacities (PO) and fibrosis-like lesions (FL). Based on the previous literature, we performed plasma miRNA profiling of exosomal miRNAs belonging to the NLRP3-inflammasome platform with validated (miR-17-5p, miR-223-3p) and putative targets (miR-146a-5p), miRNAs involved in the post-transcriptional regulation of acute phase cytokines (miR128-3p, miR3168, miR125b-2-3p, miR106a-5p), miRNAs belonging to the NLRP4-inflammasome platform (miR-141-3p) and miRNAs related to post-transcriptional regulation of the fibrosis process (miR-21-5p). miR-17-5p, miR-223-3p, and miR-146a-5p were significantly down-regulated in patients with FL when compared to patients with PO. miR-146a-5p was also down-regulated in patients with FL than in N. The expression of the remaining miRNAs did not differ by group. In patients with long-term pulmonary radiological sequelae following COVID-19-related ARDS, a down-regulation of miR-17-5p, miR-146a-3p, and miR-223-3p correlated to fibrosis development in patients showing persistent hyper-reactivity to inflammatory stimulation. Our results support the hypothesis that NLRP3-Inflammasome could be implicated in the process of fibrotic evolution of COVID-19-associated ARDS.

Indole-3-carboxaldehyde (I3A), a microbial tryptophan metabolite, exhibits significant immunomodulatory activity at the host-microbial interface. However, its rapid transformation into metabolites like indole-3-carboxylic acid (I3CA) raises questions about their therapeutic potential. This study aimed to evaluate the pharmacological contributions of I3CA through the development of a proper delivery strategy. I3CA was formulated into enteric microparticles to enhance stability and targeted release. The formulations were characterized for size, morphology, drug content, encapsulation efficiency, and in vitro release profiles. Pharmacokinetic studies in mice assessed absorption, distribution, and half-lives of I3CA. In vitro assays evaluated AhR-dependent immunomodulatory activity, while murine models of intestinal and pulmonary inflammation tested therapeutic efficacy. Although not gastro-resistant, the obtained I3CA-MP formulation showed acceptable enteric behavior, releasing I3CA completely within 6-8 h in vitro. I3CA exhibited additive AhR-dependent immunomodulatory effects and showed rapid absorption and distribution in mice, with half-lives comparable to I3A. In murine models, I3CA mirrored the therapeutic benefits of I3A, reducing inflammation in colitis and aspergillosis, and enhancing epithelial barrier function. This study highlights I3CA as a key contributor to the pharmacological effects of I3A, emphasizing the importance of metabolite cascades in postbiotic therapeutics. The developed enteric delivery system effectively harnesses the therapeutic potential of I3CA, offering new insights into host-microbe metabolic interactions and paving the way for innovative postbiotic-based treatments.

Aspergillus fumigatus is an environmental fungus recently included in the fungal high-priority pathogens by the World Health Organization. While immunodeficiency and/or pre-existing lung damage represent a well-recognized fertile ground for fungal growth, it is increasingly being recognized that severe viral infections may similarly favor A. fumigatus colonization and infection, as recently experienced in the Coronavirus disease 2019 (COVID-19) pandemic. Herein, in a murine model of COVID-19-associated pulmonary aspergillosis (CAPA), obtained by the concomitant exposure to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein and A. fumigatus conidia, we found that the microbial compound indole-3-aldehyde (3-IAld) was able to ameliorate CAPA by working at multiple levels during viral infection and fungal superinfection, including epithelial barrier protection, promotion of antiviral responses, and limiting viral replication. As a consequence, 3-IAld limited the pathogenic sequelae of fungal superinfection as revealed by the controlled fungal burden and restrained inflammatory pathology. These results point to indole compounds as potential agents to prevent CAPA.

This article explores an integrative framework for medical rehabilitation that combines regenerative medicine, systemic homeostasis, and microbiome modulation to optimize recovery and long-term health. Moving beyond conventional rehabilitation approaches focused on symptomatic recovery, this multidimensional paradigm emphasizes cellular repair, physiological balance, and microbial health as interdependent pillars of effective recovery. The framework leverages advancements in stem cell therapy, immune system modulation, and microbiota-targeted interventions to address both immediate functional restoration and long-term systemic resilience. By highlighting the synergistic interplay between these components, this article provides actionable insights into transforming medical rehabilitation into a proactive and holistic endeavor, paving the way for enhanced therapeutic outcomes and sustained patient well-being.