Biology subjects

Bucci, C.

Publications and source records attributed to Bucci, C..

4 recordsLinked to original sources

bioRxiv2026

An N, S-acetylated L-cysteine-cysteamine conjugate hinders pyocyanin redox cycling to weaken Pseudomonas aeruginosa biofilm and dampens LPS-driven acute pulmonary inflammation

The persistence of P. aeruginosa infections is largely driven by the secretion of several factors during invasion, including the redox-active phenazine pyocyanin (PYO), which promotes biofilm formation and oxidative stress. Biofilms contribute to chronic infections and antibiotic resistance, limiting the efficacy of conventional therapies. We found that a synthetic compound, I-152, a conjugate of N-acetyl-L-cysteine (NAC) and S-acetylcysteamine (also known as S-acetyl-{beta}-mercaptoethylamine; SMEA), effectively restored colistin susceptibility against P. aeruginosa by altering biofilm nanomechanical properties. These perturbations in matrix integrity were associated with I-152s ability to hinder the phenazine redox cycle, shifting PYO to a reduced state as well as enabling S-conjugate formation. The compound decreased PYO accumulation in bacterial cultures and PYO-generated reactive oxygen species (ROS) in macrophage cells. Together with PYO, LPS is another driver of ROS-dependent inflammatory signaling in the host, which leads to an uncontrolled cytokine response and organ damage, especially in patients with cystic fibrosis. I-152 treatment downregulated the expression of LPS-induced inflammatory cytokines, i.e., IL-6 and TNF-, in bone marrow-derived macrophages (BMDM) isolated from transgenic CFTR-/- and CFTR+/+ mice. Consistently, I-152 partially counteracted the inflammatory response in the P. aeruginosa LPS-induced acute lung injury murine model. Taken together, these results support I-152 as an adjunctive treatment for P. aeruginosa respiratory infections through a dual mechanism: combating antimicrobial resistance in biofilms and dampening host inflammation in the respiratory system. HighlightsO_LII-152 potentiates colistin activity against P. aeruginosa by compromising the biofilm surface C_LIO_LII-152 rewires the pyocyanin (PYO) redox state and forms covalent adducts with it C_LIO_LIPYO accumulation and PYO-induced ROS generation in macrophages is impaired by I-152 C_LIO_LIEx vivo, I-152 dampens excessive pro-inflammatory response to P. aeruginosa LPS in CFTR-/- and CFTR+/+ BM-derived macrophages C_LIO_LII-152 (140 mg/Kg) attenuates LPS-driven inflammation and lung damage in CFTR+/+ mice C_LI

pharmacology and toxicology↗

bioRxiv2026

Motor Neuron Dysfunction in SORD Deficiency: Implications for Therapeutic Development in Peripheral Neuropathies

Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have been identified as one of the most common causes of autosomal-recessive Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary neuropathy, collectively referred to as SORD deficiency. These mutations result in loss of sorbitol dehydrogenase activity, a key enzyme in the polyol pathway that metabolizes glucose, leading to marked accumulation of sorbitol in patient-derived fibroblasts. However, the mechanisms by which SORD dysfunction drives axonal degeneration remain poorly understood, and robust in vitro models of human SORD-deficient motor neurons (MNs) are still lacking. To address this gap, we established a human in vitro model of SORD deficiency by generating induced pluripotent stem cells (iPSCs) from fibroblasts affected individual carrying biallelic SORD mutations (SORDc.757delG/c.316_425+165del), and unaffected heterozygous carriers (SORDc.757delG/wt and SORDwt/c.316_425+165del). These iPSCs were subsequently differentiated into motor neuron progenitors (MNPs) and MNs. Comprehensive analysis of SORD-deficient human cells--including fibroblasts, MNPs, and MNs--revealed pronounced structural and functional abnormalities in the mitochondrial compartment, characterized by mitochondrial fragmentation and increased proton leak. Importantly, fibroblasts derived from two additional unrelated patients carrying the SORD mutation (SORDc.757delG/ c.757delG) further confirmed that SORD deficiency is associated with a mitochondrial phenotype. At the molecular level, SORD deficiency led to upregulation of aldose reductase (AR), another key enzyme of the polyol pathway, resulting in disruption of cellular redox homeostasis and increased oxidative stress. Consistent with these alterations, MNs derived from CMT2/SORD patients exhibited clear neurodegenerative features, including severe defects in neurite branching and synaptic architecture, ultimately impairing neuronal connectivity. Notably, pharmacological inhibition of AR effectively rescued both mitochondrial dysfunction and neuronal structural defects, supporting the targeting of AR as a promising therapeutic strategy for polyol pathway-associated neuropathies as CMT2/SORD and diabetic neuropathy.

cell biology↗

bioRxiv2021

Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

Recent evidence has uncovered an important role of Rab7 in regulating mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigated how mitochondrial morphology and function were impacted by the CMT2B associated Rab7V162M mutation in fibroblasts from human CMT2B patients as well as in a knockin mouse model. In contrast to recently published results from studies of using heterologous overexpression systems, our results have demonstrated significant mitochondrial fragmentation in fibroblasts of both human CMT2B patients and CMT2B mouse embryonic fibroblasts (MEFs). Furthermore, we have shown that mitochondria were fragmented and axonal mitochondrial movement was dysregulated in primary cultured E18 dorsal root ganglion (DRG) sensory neurons, but not in E18 hippocampal and cortical primary neurons. We also show that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalized the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study has revealed, for the first time, that expression of CMT2B Rab7 mutation at physiological level enhances Drp1 activity to promote mitochondrial fission, that may potentially underlie selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

neuroscience↗

bioRxiv2020

ACE2 polymorphisms and individual susceptibility to SARS-CoV-2 infection: insights from an in silico study

The current SARS covid-19 epidemic spread appears to be influenced by ethnical, geographical and sex-related factors that may involve genetic susceptibility to diseases. Similar to SARS-CoV, SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells, notably type II alveolar epithelial cells. Importantly, ACE2 gene is highly polymorphic. Here we have used in silico tools to analyze the possible impact of ACE2 single-nucleotide polymorphisms (SNPs) on the interaction with SARS-CoV-2 spike glycoprotein. We found that S19P (common in African people) and K26R (common in European people) were, among the most diffused SNPs worldwide, the only two SNPs that were able to potentially affect the interaction of ACE2 with SARS-CoV-2 spike. FireDock simulations demonstrated that while S19P may decrease, K26R might increase the ACE2 affinity for SARS-CoV-2 Spike. This finding suggests that the S19P may genetically protect, and K26R may predispose to more severe SARS-CoV-2 disease.

microbiology↗