Biology subjects

Chini, E. N.

Publications and source records attributed to Chini, E. N..

3 recordsLinked to original sources

bioRxiv2025

Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment

Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg)-mediated immunosuppression. In aged EOC-bearing mice, we observed reduced survival, accompanied by impaired CD4 and CD8T cell responses and a marked expansion of FOXP3 Tregs exhibiting elevated IL-10 and TGF{beta} expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged mice, along with a fivefold increase in intracellular succinate levels. This accumulation of succinate within the aged tumor microenvironment was found to potentiate Treg suppressive function. Notably, pharmacologic inhibition of -ketoglutarate dehydrogenase reversed this effect, restoring effector T cell activity. These findings highlight succinate driven metabolic reprogramming as a central mechanism of age related Treg dysfunction in EOC and suggest that targeting succinate metabolism may offer a promising strategy to rejuvenate antitumor immunity in elderly patients.

immunology↗

bioRxiv2025

Estrogens protect bone mass by inhibiting NAD+ metabolism in osteoclasts

Estrogens protect against bone loss by reducing osteoclast number and bone resorption, primarily via direct actions on osteoclast precursors. In these cells, estrogens attenuate RANKL-induced stimulation of mitochondrial complex I, which is crucial for ATP generation through NADH oxidation. NAD+ promotes redox reactions and activates NAD+-dependent enzymes, including the mitochondrial deacetylase SIRT3. However, the contribution of NAD+ to the skeletal effects of estrogens remains unknown. We show that NAD+ levels and SIRT3 activity are upregulated by RANKL and inhibited by 17{beta}-estradiol (E2) in mouse and human osteoclast precursors. Increasing NAD+ or the mitochondrial NAD+/NADH ratio reverses the inhibitory effects of E2 on SIRT3 activity and osteoclastogenesis in vitro. Deletion of Nampt, a key NAD salvage enzyme, reduces NAD+ and prevents bone loss in ovariectomized mice. Similarly, deletion of Sirt3 in osteoclast precursors mitigates estrogen deficiency-induced bone resorption. These findings indicate that suppression of NAD+ levels and mitochondrial redox metabolism by estrogens contributes to their anti-resorptive effects via inhibition of SIRT3.

molecular biology↗

bioRxiv2020

CD38 dependent NAD+ depletion contributes to oligodendrocyte loss and inhibition of myelin regeneration

Western-style diets cause disruptions in myelinating cells and astrocytes within the mouse CNS. CD38 has increased expression in the cuprizone and EAE demyelination models and is the main NAD+ depleting enzyme in CNS tissue. Altered NAD+ metabolism has been linked to both high fat consumption and Multiple Sclerosis (MS). We identified increased CD38 expression in the male mouse spinal cord following chronic high fat consumption or focal lysolecithin-induced demyelinating injury as well as in reactive astrocytes within an active MS lesion. CD38-catalytically inactive mice are significantly protected from high fat-induced NAD+ depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. 78c, a CD38 inhibitor, increased NAD+ and attenuated neuroinflammatory changes in astrocytes induced by saturated fat. Conditioned media from saturated fat-treated astrocytes impaired oligodendrocyte differentiation pointing to indirect mechanisms of oligodendrogliopathy. Combined saturated fat and lysolecithin demyelination in cerebellar slices resulted in additional deficits in myelin proteins that were mitigated by concomitant 78c treatment. Importantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal demyelination. Our findings suggest high fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NAD+ase CD38, and highlight the use of CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration.

neuroscience↗