Diabetic nephropathy (DN) continues being the primary cause of chronic hemodialysis and terminal renal disease worldwide. At tissue levels the DN occurs with glomerulopathy affecting the integrity of the filtration barrier and with an extensive glomerular and tubule-interstitial fibrosis. Current available therapeutic approaches have only demonstrated a modest effect on progression of kidney injury. Therefore, more research concerning the pathomechanisms and possible interventions are needed. Interestingly, in the last years it has been documented that DN progresses with growing levels of the nucleoside adenosine. This finding increased the interest in the events controlling the extracellular levels of the nucleoside. While the metabolism of extracellular ATP and cyclic AMP are well recognized sources, evidences regarding the role of the equilibrative nucleoside transporters in controlling adenosine availability and promoting diabetic glomerulopathy have recently acquired a pivotal role. The physiological effects of nucleoside are mediated by the P1 family of adenosine receptors. It has been shown in vivo that the use of an antagonist of the A2B receptor subtype can block the most remarkable early alterations seen in diabetic glomerulopathy. Furthermore, using models of chronic kidney injury it was demonstrated that fibrosis can also be blocked using treatment with the antagonist of A2B receptor subtype. This review highlights these findings that correlate the activity of a low affinity adenosine receptor with an increase in the ligand availability in the pathological state. In addition, we discuss the possible therapeutic interventions of adenosine signaling with regards to DN treatment.

Altered nucleoside levels may be linked to pathogenic signaling through adenosine receptors. We hypothesized that adenosine dysregulation contributes to fibrosis in diabetic kidney disease. Our findings indicate that high glucose levels and experimental diabetes decreased uptake activity through the equilibrative nucleoside transporter 1 (ENT1) in proximal tubule cells. In addition, a correlation between increased plasma content of adenosine and a marker of renal fibrosis in diabetic rats was evidenced. At the cellular level, exposure of HK2 cells to high glucose, TGF-β and the general adenosine receptor agonist NECA, induced the expression of profibrotic cell activation markers α-SMA and fibronectin. These effects can be avoided by using a selective antagonist of the adenosine A₃ receptor subtype in vitro. Furthermore, induction of fibrosis marker α-SMA was prevented by the A₃ receptor antagonist in diabetic rat kidneys. In conclusion, we evidenced the contribution of purinergic signaling to renal fibrosis in experimental diabetic nephropathy.

The widespread production and poor management of plastic waste have led to the pervasive presence of microplastics (MPs) in environmental and biological systems. Among various polymers, polyethylene (PE) is the most widely produced plastic globally, primarily due to its use in single-use packaging. Its persistence in ecosystems and resistance to degradation processes result in the continuous formation of PE-derived MPs. These particles have been detected in human biological matrices, including blood, lungs, placenta, and even the brain, raising increasing concerns about their bioavailability and potential health effects. Once internalized, PE MPs can interact with cellular membranes, induce oxidative stress, inflammation, and apoptosis, and interfere with epigenetic regulatory pathways. In vitro studies on epithelial, immune, and neuronal cells reveal concentration-dependent cytotoxicity, mitochondrial dysfunction, membrane disruption, and activation of pro-inflammatory cytokines. Moreover, recent findings suggest that PE MPs can induce epithelial-to-mesenchymal transition (EMT), senescence, and epigenetic dysregulation, including altered expression of miRNAs and DNA methyltransferases. These cellular changes highlight the potential role of MPs in disease development, especially in cardiovascular, metabolic, and possibly cancer-related conditions. Despite growing evidence, no standardized method currently exists for quantifying MPs in human samples, complicating comparisons across studies. Further, MPs can carry harmful additives and environmental contaminants such as bisphenols, phthalates, dioxins, and heavy metals, which enhance their toxicity. Global estimates indicate that humans ingest and inhale tens of thousands of MPs particles each year, yet long-term human research remains limited. Given these findings, it is crucial to expand research on PE MP toxicodynamics and to establish regulatory policies to reduce their release. Promoting alternative biodegradable materials and improved waste management practices will be vital in decreasing human exposure to MPs and minimizing potential health risks.

Glioblastoma multiforme is one of the most malignant types of cancer. This is mainly due to a cell subpopulation with an extremely aggressive potential, called glioblastoma stem-like cells (GSCs). These cells produce high levels of extracellular adenosine which has been associated with increased chemoresistance, migration, and invasion in glioblastoma. In this study, we attempted to elucidate the mechanisms that control extracellular adenosine levels in GSC subtypes. By using primary and U87MG-derived GSCs, we associated increased extracellular adenosine with the mesenchymal phenotype. [³H]-adenosine uptake occurred mainly through the equilibrative nucleoside transporters (ENTs) in GSCs, but mesenchymal GSCs have lower expression and ENT1-mediated uptake activity than proneural GSCs. By analyzing expression and enzymatic activity, we determined that ecto-5′-nucleotidase (CD73) is predominantly expressed in proneural GSCs, driving AMPase activity. While in mesenchymal GSCs, both CD73 and Prostatic Acid Phosphatase (PAP) contribute to the AMP (adenosine monophosphate) hydrolysis. We did not observe significant differences between the expression of proteins involved in the metabolization of adenosine among the GCSs subtypes. In conclusion, the lower expression and activity of the ENT1 transporter in mesenchymal GSCs contributes to the high level of extracellular adenosine that these GSCs present.