Biology subjects

Keshari, K. R.

Publications and source records attributed to Keshari, K. R..

3 recordsLinked to original sources

bioRxiv2024

Task Activation Results in Regional 13C-Lactate Signal Increase in the Human Brain

Hyperpolarized-13C magnetic resonance imaging (HP-13C MRI) was used to image changes in 13C-lactate signal during a visual stimulus condition in comparison to an eyes-closed control condition. Whole-brain 13C-pyruvate, 13C-lactate and 13C-bicarbonate production was imaged in healthy volunteers (N=6, ages 24-33) for the two conditions using two separate hyperpolarized 13C-pyruvate injections. BOLD-fMRI scans were used to delineate regions of functional activation. 13C-metabolite signal was normalized by 13C-metabolite signal from the brainstem and the percentage change in 13C-metabolite signal conditions was calculated. A one-way Wilcoxon signed-rank test showed a significant increase in 13C-lactate in regions of activation when compared to the remainder of the brain (p = 0.02, V = 21). No significant increase was observed in 13C-pyruvate (p = 0.11, V = 17) or 13C-bicarbonate (p = 0.95, V = 3) signal. The results show an increase in 13C-lactate production in the activated region that is measurable with HP-13C MRI.

neuroscience↗

bioRxiv2022

Novel adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments

Apoptotic cell clearance (efferocytosis), a process essential for organismal homeostasis, is performed by phagocytes that inhabit a wide range of environments, including physiologic hypoxia. Here, we find macrophages, the predominant tissue-resident phagocyte, display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degradation of apoptotic cells. Analysis of mRNA and protein programs revealed that chronic physiological hypoxia induces two distinct but complimentary states in macrophages. The first, primed state consists of concomitant induction of transcriptional and translational programs broadly associated with metabolism in apoptotic cell-naive macrophages that persist during efferocytosis. The second, poised state consists of transcription, but not translation, of phagocyte function programs in apoptotic cell-naive macrophages that are subsequently translated during efferocytosis. Importantly, we discovered that both states are necessary for enhanced continual efferocytosis. Mechanistically, we find that one such primed state consists of the efficient flux of glucose into a noncanonical pentose phosphate pathway (PPP) loop, whereby PPP-derived intermediates cycle back through the PPP to enhance production of NADPH. Furthermore, we found that PPP-derived NADPH directly supports enhanced continual efferocytosis under chronic physiological hypoxia via its role in phagolysosomal maturation and maintenance of cellular redox homeostasis. Thus, macrophages residing under chronic physiological hypoxia adopt states that both support cell fitness and ensure ability to perform essential homeostatic functions rapidly and safely. Highlights- Macrophages residing in chronic physiological hypoxia have enhanced apoptotic cell uptake and degradation - Chronic physiological hypoxia induces both primed and poised states in macrophages - Both primed and poised state programs directly support enhanced continual efferocytosis - A noncanonical PPP loop, a unique primed state, directly supports enhanced efferocytosis and maintains redox homeostasis

immunology↗

bioRxiv2020

Hyaluronic Acid Fuels Pancreatic Cancer Growth

Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not impair tumor growth, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. Here, we show that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Furthermore, HA facilitates proliferation in nutrient-starved wild-type PDA. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

cancer biology↗