Biology subjects

Rojas, M. A.

Publications and source records attributed to Rojas, M. A..

3 recordsLinked to original sources

bioRxiv2025

Novel Role of AcylCoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) in Diabetic Retinopathy

Hypercholesterolemia and excessive cholesterol ester (CE) production have been linked to chronic inflammation and vascular dysfunction during cardiovascular disease. Upregulation of AcylCoA:cholesterol acyltransferase 1 (ACAT1/SOAT1), the enzyme responsible for retinal CE formation, has been implicated in pathological retinal neovascularization. Here we determine the role of this process in diabetic retinopathy (DR). Ins2Akita diabetic mice were treated with the specific ACAT1/SOAT1 inhibitor K604 (10 mg/Kg, i.p.) beginning at 10 weeks for 2 weeks or 8 months for 2 months. ACAT1/SOAT1 expression and CE formation were assayed along with oxidative stress, inflammation, vascular pathology, and neuronal function. ACAT1/SOAT1 expression was also assayed in human retinas and vitrectomy specimens. Retinas from early-stage Ins2Akita mice exhibited increases in CE deposition, superoxide production, and expression of ACAT1/SOAT1, LDLR, TREM1, MCSF, and VEGF along with leukostasis, vascular leakage, acellular capillary formation, retinal ganglion cell loss, and impaired visual function. Late-stage increases in CE, ACAT1/SOAT, oxidative stress, inflammation, and impaired visual function were also observed. These changes were significantly inhibited by K604 treatment. The protective effects were independent of changes in systemic glucose or body weight. Human retina and vitrectomy samples also showed increases in ACAT1/SOAT1 and CE, respectively. Specific inhibition of ACAT1/SOAT1 with K604 normalizes ACAT1/SOAT1 expression and CE formation and prevents increases in oxidative stress and inflammation and preserves retinal structure and function in both early and late stages of DR. These findings identify ACAT1/SOAT1 as a promising therapeutic target for both early intervention and later stage treatment of DR. One sentence summaryInhibiting cholesterol esterification limits retinal neurovascular injury in diabetes.

cell biology↗

bioRxiv2025

Novel Role of Copper Transporter CTR1 and Therapeutic Potential of Copper Chelators in Retinal Ischemia-Reperfusion Injury

BackgroundRetinal ischemia contributes to vision loss in ischemic and diabetic retinopathies through oxidative stress, neurovascular injury, and inflammation. Copper (Cu), while essential, can be toxic in excess and is regulated by Cu transporters such as CTR1. However, the role of CTR1 in ischemic retinopathy remains unclear. Methods and ResultsRetinal ischemia-reperfusion (IR) injury was induced by elevating intraocular pressure to 110 mmHg for 40 minutes in the right eye of Ctr1 heterozygous (Ctr1/-) and wild-type (WT) mice. In WT mice, IR triggered rapid CTR1 upregulation and increased retinal Cu levels (measured by ICP-MS). IR injury caused retinal ganglion cell loss, inner retinal thinning, vascular degeneration, and apoptosis, all of which were significantly attenuated in Ctr1/- mice. Ctr1/- mice also exhibited reduced microglial (Iba1) and glial cells (GFAP) activation and preserved visual function, as assessed by electroretinography. Mechanistically, IR-induced reactive oxygen species (O2-) production (DHE staining), upregulation of NADPH oxidase components (NOX2, p47phox), and NF-{kappa}B activation were markedly suppressed in Ctr1/- mice. Treatment with the Cu chelator tetrathiomolybdate (TTM) similarly reduced retinal thinning, neurovascular damage, apoptosis, gliosis, and oxidative stress after IR injury. ConclusionsCTR1 plays a central role in mediating Cu-dependent oxidative stress, neurovascular degeneration, and inflammation following retinal IR injury. Targeting the CTR1- Cu axis may represent a novel therapeutic strategy for ischemic retinopathy.

cell biology↗

bioRxiv2024

Profiling extremophile bacterial communities recovered from a mining tailing against soil ecosystems through comparative genome-resolved metagenomics and evolutionary analysis

Microbial communities inhabiting mining environments harbor a diverse array of bacteria with specialized metabolic capacities adapted to extreme conditions. Here, we utilized comparative genome-resolved metagenomics of a high-quality Illumina-sequenced sample from the Cauquenes copper tailing in central Chile. We investigate the metabolic roles and evolutionary behaviors of the resident microorganisms, focusing on capacities related to copper, iron, and sulfur metabolism. We recovered 44 medium and high-quality metagenome-assembled genomes (MAGs), primarily classified belonging to phylum Actinobacteriota (21), Proteobacteria (10), and Acidobacteriota (6). These MAGs were compared to the Global Soil MAGs project (SMAG catalog), which includes bacteria from conventional or natural ecosystems, to uncover specialized properties of mining bacteria. Notably, we discovered a new phylum, Nitrospirota_A, and provided insights into the unexplored taxonomic classifications at the lowest ranks such as genus and species. Functional potential analysis revealed that the mining community has enhanced molecular capabilities associated with sulfur and copper metabolism. Evolutionary analysis revealed that mining genes involved in targeted metabolism are under strong negative selection, indicating conservative evolutionary pressure within the mining environment. In particular, it was possible to identify a MAG from the genus Acidithrix with a global dN/dS ratio greater than 1, suggesting positive selection. Additionally, core proteins essential for bacterial survival, such as flagellar motors, cell cycle regulators, and biogenesis proteins, were also under positive selection. The latter points to the need for enhanced mobility in these microorganisms to locate resources efficiently. We demonstrate that copper mining communities are diverse and possess a significant metabolic repertoire under extreme conditions in sulfur and copper proteins. Those specialized genes appear to be in a conservative state rather than undergoing adaptive evolution. This study enhances our understanding of extremophile mining microbiomes, highlighting their high variability in classification, metabolic functions, evolution, and adaptation, which can be leveraged for further biotechnological applications.

genomics↗