Background NOD-like receptors (NLRs) and inflammasome complexes play critical roles in the neuroinflammatory responses triggered by chronic ethanol exposure. We previously demonstrated that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) attenuated binge-like alcohol consumption-induced NLRP3 inflammasome activation in the adolescent hippocampus; however, their broader effects on additional NLR pathways and brain regions remained unclear. Methods and Results This study investigates the therapeutic potential of intravenously administered adipose-derived MSC-EVs (20 µg/dose every 10 days) in a murine model of chronic alcoholism, established by providing 10
Hydrogen sulfide is a gasotransmitter with biological functions, including roles in antioxidant defenses, mitochondrial bioenergetics, and cellular signaling via cysteine persulfidation. Several longevity-promoting interventions enhance endogenous hydrogen sulfide generation. However, whether enhanced hydrogen sulfide generation extends healthspan and lifespan in mammals remains unknown. Here, we investigated the in vivo effects of the non-enzymatic hydrogen sulfide generation promoted by natural diallyl sulforated compounds. Diallyl sulforated compounds extended lifespan and improved the main aspects of healthspan, including glucoregulation, locomotor function, and neurocognition in wild-type male mice across their lifespan. At the histological and molecular levels, we observed reductions in hepatic lipid-droplet size, attenuation of transcriptional and proteomic signatures associated with mTOR and immune-related pathways, and increased cysteine persulfidation in proteins. In humans, greater protein persulfidation in individuals with polypathological conditions was associated with increased muscle strength and lower triglyceride levels, supporting its physiological relevance. Our findings uncover the potential of enhanced hydrogen sulfide generation to promote healthy aging.
Background . Over the last decade, the field of microbiology has been revolutionised by genome-wide genetic data and advanced genomic tools. This progress has been particularly instrumental in discerning hidden ecological traits across various taxonomic groups and in reclassifying species through genome-to-genome comparisons, offering a more accurate representation of microbial phylogenetic relationships. Here, we conducted a comprehensive analysis of the Bifidobacterium genus (N = 785 genomes) to investigate the phylogenetic relationships within this diverse bacterial group, focusing on species primarily inhabiting the human intestinal tract, representing a large-scale repertoire of genomic information, a wide diversity in terms of well-known species, and well-annotated genome entries for unambiguous analysis. Results . By exhaustively evaluating more than 600K comparisons based on genome-wide alignments, using Average Nucleotide Identity (ANI) metrics at both intra- and inter-species levels, we identified different boundaries for species demarcation compared with those typically accepted for bacteria. Applying robust ANI thresholds helped to resolve conflicts and ambiguities in the sub-speciation of certain Bifidobacterium biotypes. As a result, we propose reclassifying several subspecies of Bifidobacterium longum , Bifidobacterium animalis , and Bifidobacterium catenulatum as new species. Conclusions . This reclassification directly impacts our understanding of the ecology of this diverse bacterial group, the signals of genome divergence across certain biotypes, and on how their speciation traits influence their interactions with humans. Furthermore, by comprehensively analysing the core proteome, evidence of molecular evolution and selection pressure in several sets of functional genes is intuited in this bacterial group of broad interest. This has direct implications for how these bacteria adapt to their specific niches and compete with other microbes.
This work investigates the photophysical and photochemical behavior of pristine (p-CNOs) and individualizedoxidized (ox-CNOs) carbon nano-onions (CNOs), demonstrating their great photothermal conversion and photodynamic properties for reactive oxygen species (ROS) production. Using electron paramagnetic resonance (EPR) and biological flow cytometry assays under near-infrared irradiation (NIR) and heating, we demonstrated that surface oxide groups are fundamental for ROS generation. ox-CNOs mediate the efficient generation of superoxide (O2 center dot-) and singlet oxygen (1O2) species, while p-CNOs do not produce ROS. Investigating principles of ROS generation, we observed that these species can be generated by different external stimuli, suggesting that superoxide formation is promoted by increased surface heating, whereas singlet oxygen generation is photoinduced by NIR irradiation. The biocompatibility of CNOs was investigated across multiple cell lines, exhibiting high biocompatibility, and showing ox-CNOs' effective endocytic internalization and lysosomal localization without cellular damage. In vitro photothermal (PTT) and photodynamic (PDT) therapies studies under NIR irradiation revealed that the cytotoxicity differences observed between p-CNOs and ox-CNOs are predominantly dependent on the photodynamic contribution, and that ROS-induced generation can play a fundamental role in controlled cancer therapies. These insights advance our understanding of the diverse functionalities of CNOs, highlighting their potential for phototherapy applications.
Background:Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) triggered by a shift in peripheral inflammation. A main mechanism by which peripheral alterations are transmitted to the brain is the infiltration of extracellular vesicles (EV). Hyperammonemic rats are a model of MHE that reproduces cognitive impairment. Injection of EV from plasma or peripheral blood mononuclear cells (PBMC) of hyperammonemic rats to normal rats induces neuroinflammation, alterations in neurotransmission, and cognitive impairment. PBMC contain different cell types. The aims were 1) to identify which cell type produces the pathological EV in hyperammonemic rats; 2) to identify the mechanisms by which hyperammonemia increases EV release from monocytes and induces the formation of pathological EV; and 3) to analyze the role of TNFα and PKA in these mechanisms. Methods:EV were isolated from primary cultures of CD4+ lymphocytes or monocytes from control or hyperammonemic rats and added to hippocampal slices from control rats to assess induction of neuroinflammation and changes in neurotransmission. To assess the role of TNFα and protein kinase A (PKA) in the production of pathological EV by monocytes from hyperammonemic rats, we blocked TNFα with anti-TNFα or inhibited PKA. Lysosomal-autophagy dysfunction was assessed with LysoTracker and by analyzing cathepsin L, LAMP2, and LC3. Results:In hyperammonemic rats, monocytes but not CD4+ lymphocytes release pathological EV. Hyperammonemia increases the EV release by monocytes and their content of TNFR1 and TNFα. These EV induce activation of glia and of the TNFα-TNFR1-S1PR2-IL-1β-CCL2-BDNF-TrkB pathway and alterations in membrane expression of NMDA and AMPA receptors in hippocampal slices from control rats. Hyperammonemia increases TNFα levels in monocytes, which increases cAMP and PKA activity and reduces LC3 content. This leads to autophagy-lysosome dysfunction, with altered LC3, cathepsin L, and LAMP2 content and pH that increases the release of EV and their TNFR1 and TNFα content. All these changes are reversed by blocking TNFα with anti-TNFα or inhibiting PKA with an inhibitor. Conclusions:These data unveil that monocytes produce the pathological EV in hyperammonemia and the underlying mechanisms and provide the bases for new treatments to improve cognitive and motor function in hyperammonemia and MHE.
