Biology subjects

Kelly, M. E.

Publications and source records attributed to Kelly, M. E..

8 recordsLinked to original sources

bioRxiv2026

Persistent microbial material contributes to Alzheimer disease and is targetable by vaccination

Chronic neuroinflammation is increasingly recognized as a contributor to Alzheimer disease, yet the upstream stimuli that sustain it remain poorly defined. We investigated whether persistent microbial material contributes to Alzheimer disease using the conserved microbial polysaccharide poly-N-acetylglucosamine (PNAG). PNAG-containing microbial material colocalized with amyloid plaques in human Alzheimer disease brain tissue. In fully human neuronal and three-dimensional brain models, purified PNAG and PNAG-containing microbial vesicles activated Toll-like receptor 2-dependent inflammasome signaling and promoted amyloid-{beta} and phosphorylated tau accumulation. Vaccination targeting PNAG improved cognition, reduced glial activation and amyloid pathology, remodeled amyloid processing, and preserved gut microbial community structure in APP/PS1 mice. These findings identify persistent microbial material as an upstream contributor to Alzheimer disease-associated neuroinflammation and a potential therapeutic target.

neuroscience↗

bioRxiv2026

Preclinical efficacy and safety of Tegavivint in Wnt-activated hepatocellular carcinoma

Background & AimsHepatocellular carcinoma (HCC), a predominant form of liver cancer, remains a significant clinical unmet need. Given that 30-50% of HCC cases harbour mutations in the Wnt/{beta}-catenin signalling pathway, targeting this cascade represents a promising therapeutic strategy. However, the clinical translation of Wnt inhibitors has been hindered by severe adverse events observed in preclinical models and early-phase clinical trials, primarily due to the essential role of Wnt signalling in maintaining normal tissues such as the intestine and bone. MethodsWe examined the efficacy of Tegavivint, a first-in-class Wnt pathway inhibitor that targets TBL1, against HCC to elucidate its underlying mechanism of action. We evaluated the dose-response of Tegavivint and its effects on the cell cycle, apoptosis, and Wnt target gene expression using HepG2, HUH6, and HUH7 cell lines in vitro. Furthermore, we employed an orthotopic xenograft transplant model using HepG2 cells in immunodeficient mice to assess the safety profile and on-target anti-cancer efficacy of Tegavivint in vivo. ResultsTegavivint exhibited potent Wnt pathway-suppressing effects in cancer cells with constitutive Wnt pathway activation. Notably, Tegavivint displayed robust anti-tumour activity across a broad range of HCC cell lines, regardless of their Wnt pathway activation status. While Tegavivint inhibited the Wnt pathway and triggered the activation of apoptotic pathways in most cell lines, our findings suggest that it also can induce cell death by activating alternative non-apoptotic pathways in apoptosis-resistant cancer cells. In an orthotopic transplant mouse model, Tegavivint significantly downregulated Wnt pathway target genes, inhibited cell proliferation, induced apoptosis and suppressed growth in tumours. ConclusionsTaken together, our data establish a robust foundation for evaluating Tegavivint as a novel therapeutic option, specifically tailored for HCC patients harbouring Wnt-driven hepatic malignancies.

cancer biology↗

bioRxiv2026

L-pentahomoserine correlates with therapy outcome in esophageal cancer and promotes metabolic adaptations that support cell survival under nutrient-deprived conditions

Esophageal adenocarcinoma (EAC) is the sixth-leading cause of cancer-related death. Although pyrimidine analogue-based neoadjuvant and adjuvant therapies are widely used, patient responses remain variable. Emerging evidence indicates that bacteria-derived metabolites influence tumor biology and therapy outcomes. To identify non-canonical plasma metabolites linked to cancer biology, we performed correlation analyses between untargeted metabolomics profiles and overall survival. This approach revealed a bacterial metabolite called L-pentahomoserine, or L-2-amino-5-hydroxypentanoic acid (L-2A5HPA), to be positively associated with overall survival. Notably, L-2A5HPA promoted cell survival under nutrient limitation by redirecting glucose metabolism towards aspartate and pyrimidine biosynthesis. In vitro, L-2A5HPA uptake varied among cell lines and was controlled by stereospecific transporters. Furthermore, metabolic profiling in mouse models of liver cancer showed different levels of L-2A5HPA and a strong correlation with pyrimidine intermediates, dihydroorotate and orotate. The link between L-2A5HPA, pyrimidine nucleotide metabolism, and cell survival provides mechanistic insight into its association with patient outcome. Our findings position L-2A5HPA as a metabolite with potential to become a prognostic biomarker for EAC and underscores its role in metabolic adaptation under nutrient-deprived conditions.

cancer biology↗

bioRxiv2025

Intestinal catabolism of dietary fructose promotes obesity and insulin resistance via ileal lacteal remodeling

High-fructose corn syrup (HFCS) consumption is a risk factor for obesity and metabolic syndrome, yet the underlying mechanisms are incompletely understood. Catabolism of dietary fructose primarily occurs in the small intestine and liver, with fructose breakdown in the liver being pathological, while small intestinal fructose clearance protects the liver. Here, we unexpectedly found that inhibition of fructose catabolism specifically in the small intestine mitigates fructose-induced obesity and insulin resistance. Mechanistically, blocking intestinal fructose catabolism reduces dietary fat absorption, which is associated with a decrease in the surface area of the ileal lacteals and alterations in gut microbiome. Fecal transplantation experiments revealed that such a microbiome stimulates the intestine-resident macrophages, promoting lacteal growth and boosting dietary fat absorption. Given the preclinical and clinical studies reporting the effect of fructose catabolism suppression on mitigating diet-induced obesity, our data suggest that such effects are partly mediated by intestinal lacteal remodeling. Significance StatementHere, we uncover a previously unappreciated link between intestinal fructose catabolism and ileal lacteal remodeling, suggesting the mechanisms by which fructose intake promotes obesity. Using mice lacking the fructose-processing enzyme specifically in the intestine, we show that blocking intestinal fructose metabolism protects against diet-induced obesity by reducing fat absorption. Changes in gut microbiome and immune cell interactions drive this effect.

physiology↗

bioRxiv2024

Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids

Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FA) and glucose under cold stress but favors FA as the primary fuel for heat production. It remains unclear how BAT steer fuel preference toward FA over glucose. Here we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the {beta}-adrenergic receptor-PKA-PGC-1 axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FA under cold conditions. HighlightsO_LIGot1 is markedly induced by cold in BAT via a {beta}-adrenergic receptor-PKA-PGC-1 axis C_LIO_LIThe increase in cytosolic GOT1 activates the malate-aspartate shuttle (MAS) C_LIO_LIMAS activation promotes fatty acid oxidation while reducing glucose oxidation C_LIO_LILoss of MAS activity in BAT by Got1 deletion shifts the fuel preference to glucose C_LI

cell biology↗

bioRxiv2024

Sex-dependent metabolic remodeling of kidneys revealed by arteriovenous metabolomics

Sex is a fundamental biological variable important in biomedical research, drug development, clinical trials, and prevention approaches. Among many organs, kidneys are known to exhibit remarkable structural, histological, and pathological differences between sexes. However, whether and how kidneys display distinct metabolic activities between sexes is poorly understood. By developing kidney-specific arteriovenous (AV) metabolomics combined with transcriptomics, we report striking sex differences in both basal metabolic activities and adaptive metabolic remodeling of kidneys after a fat-enriched ketogenic diet (KD), a regimen known to mitigate kidney diseases and improve immunotherapy for renal cancer. At the basal state, female kidneys show highly accumulated aldosterone and various acylcarnitines. In response to the KD, aldosterone levels remain high selectively in females but the sex difference in acylcarnitines disappears. AV data revealed that, under KD, female kidneys avidly take up circulating fatty acids and release 3-hydroxybutyrate (3-HB) whereas male kidneys barely absorb fatty acids but consistently take up 3-HB. Although both male and female kidneys take up gluconeogenic substrates such as glycerol, glutamine and lactate, only female kidneys exhibit net glucose release. Kidney transcriptomics data incompletely predict these sex differences, suggesting post-transcriptional/translational regulation mechanisms. This study provides foundational insights into the sex-dependent and diet-elicited metabolic flexibility of the kidneys in vivo, serving as a unique resource for understanding variable disease prevalence and drug responses between male and female kidneys.

biochemistry↗

bioRxiv2023

Long-Term Oral Tamoxifen Administration Decreases Brain Derived Neurotrophic Factor in the Hippocampus of Female Long-Evans Rats

Tamoxifen is a selective estrogen receptor modulator (SERM) that is commonly used as an adjuvant drug therapy for estrogen receptor-positive breast cancers. While this drug is effective at reducing the rate of cancer recurrence, many patients report unwanted cognitive and affective side effects such as brain fog, confusion, memory impairment, anxiety, and depression. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We therefore used long-term ad lib consumption of medicated food pellets in adult female rats to model chronic tamoxifen exposure in a clinically-relevant way. Gonadally-intact adult female Long-Evans Hooded rats consumed tamoxifen medicated food pellets for approximately 12 weeks while control animals received standard chow. At the conclusion of the experiment, animals were euthanized, and blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography-tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry and quantified using background-subtracted optical densitometry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. Together, these findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure, and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients.

neuroscience↗

bioRxiv2021

Ipsilesional motor cortex activation with high-force unimanual handgrip contractions of the less-affected limb in participants with stroke

Stroke is a leading cause of severe disability that often presents with unilateral motor impairment. Conventional rehabilitation approaches focus on motor practice of the affected limb and aim to suppress brain activity in the contralesional hemisphere to facilitate ipsilesional hemispheric neuroplasticity subserving motor recovery. Previous research has also demonstrated that exercise of the less-affected limb can promote motor recovery of the affected limb through the interlimb transfer of the trained motor task, termed cross-education. One of the leading theories for cross-education proposes that the interlimb transfer manifests from ipsilateral cortical activity during unimanual motor tasks, and that this ipsilateral cortical activity results in motor related neuroplasticity giving rise to contralateral improvements in motor performance. Conversely, exercise of the less-affected limb promotes contralesional brain activity which is typically viewed as contraindicated in stroke recovery due to the interhemispheric inhibitory influence onto the ipsilesional hemisphere. High-force unimanual handgrip contractions are known to increase ipsilateral brain activation in control participants, but it remains to be determined if this would be observed in participants with stroke. Therefore, this study aimed to determine how parametric increases in handgrip force during repeated contractions with the less-affected limb impacts brain activity bilaterally in participants with stroke and in a cohort of neurologically intact controls. In this study, higher force contractions were found to increase brain activation in the ipsilesional/ipsilateral hemisphere in both groups (p = .002), but no between group differences were observed. These data suggest that high-force exercise with the less-affected limb may promote ipsilesional cortical plasticity to promote motor recovery of the affected-limb in participants with stroke.

neuroscience↗