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1. Investigation of the pharmacokinetic properties of synthetic heparan sulfate oligosaccharides

   https://doi.org/10.1093/glycob/cwac068  

   Arnold, Katelyn; Wang, Zhangjie; Lucas, Andrew; Zamboni, William; Xu, Yongmei; Liu, Jian (October 2022, Glycobiology)

   Abstract Heparan sulfate (HS) is a sulfated polysaccharide with a wide range of biological activities. There is an increasing interest in the development of structurally homogeneous HS oligosaccharides as therapeutics. However, the factors influencing the pharmacokinetic properties of HS-based therapeutics remain unknown. Here, we report the pharmacokinetic properties of a panel of dodecasaccharides (12-mers) with varying sulfation patterns in healthy mice and uncover the pharmacokinetic properties of an octadecasaccharide (18-mer) in acutely injured mice. In the 12-mer panel, 1 12-mer, known as dekaparin, is anticoagulant, and 3 12-mers are nonanticoagulant. The concentrations of 12-mers in plasma and urine were determined by the disaccharide analysis using liquid chromatography coupled with tandem mass spectrometry. We observed a striking difference between anticoagulant and nonanticoagulant oligosaccharides in the 12-mer panel, showing that anticoagulant dekaparin had a 4.6-fold to 8.6-fold slower clearance and 4.4-fold to 8-fold higher plasma exposure compared to nonanticoagulant 12-mers. We also observed that the clearance of HS oligosaccharides is impacted by disease. Using an antiinflammatory 18-mer, we discovered that the clearance of 18-mer is reduced 2.8-fold in a liver failure mouse model compared to healthy mice. Our results suggest that oligosaccharides are rapidly cleared renally if they have low interaction with circulating proteins. We observed that the clearance rate of oligosaccharides is inversely associated with the degree of binding to target proteins, which can vary in response to pathophysiological conditions. Our findings uncover a contributing factor for the plasma and renal clearance of oligosaccharides which will aid the development of HS-based therapeutics. 

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2. G-Quadruplex and i-Motif Structures in the SHMT1 5’UTR Modulate Gene Expression

   https://doi.org/10.1101/2025.11.24.690261  

   Palumbo, Rosalia M; Kasaju, Manju; Hershey, Sophia C; McCann, Morgan E; Woon, Zoe H; Heisler, David B; Mihailescu, Mihaela-Rita (March 2026, American Chemical Society)

   Abstract Multiple sclerosis (MS) is a fatal neurodegenerative disease that progresses by eroding the myelin sheath and exposing the neuron, leading to neuronal degradation and death. While MS remains without an effective treatment or cure, studies have identified genes that are dysregulated in MS patients and predicted to be involved with disease progression. These genes are primarily involved in controlling DNA methylation: a process required for regulating gene expression, which is critical for cellular health. Having identified potential genetic risk factors, research is focused on how to manipulate the expression of these genes by offsetting DNA methylation errors in patients through the targeting of DNA and RNA secondary structure formation. Serine hydroxy methyltransferase 1 (SHMT1), a key player in DNA methylation, was determined to be upregulated in MS patients. Here, we identified and characterized a hybrid 3+1 G-quadruplex (GQ) and i-motif (iM) structures in theSHMT1DNA 5’ untranslated region and a parallel GQ in the corresponding mRNA. Additionally, we found that the GQ/iM structures suppress the mRNA levels and protein expression of a reporter gene. Together, these data suggest that GQ/iM structures are necessary forSHMT1regulation, which could serve as a target for therapeutic intervention for MS patients. 

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3. Basement Membrane Mimetic Hydrogel Cooperates with Rho‐Associated Protein Kinase Inhibitor to Promote the Development of Acini‐Like Salivary Gland Spheroids

   https://doi.org/10.1002/anbr.202300088  

   Fowler, Eric W.; Witt, Robert L.; Jia, Xinqiao (November 2023, Advanced NanoBiomed Research)

   Successful engineering of functional salivary glands necessitates the creation of cell‐instructive environments for ex vivo expansion and lineage specification of primary human salivary gland stem cells (hS/PCs). Herein, basement membrane mimetic hydrogels are prepared using hyaluronic acid, cell adhesive peptides, and hyperbranched polyglycerol (HPG), with or without sulfate groups, to produce “hyperGel+” or “hyperGel”, respectively. Differential scanning fluorescence experiments confirm the ability of the sulfated HPG precursor to stabilize fibroblast growth factor 10. The hydrogels are nanoporous, cytocompatible, and cell‐permissive, enabling the development of multicellular hS/PC spheroids in 14 days. The incorporation of sulfated HPG species in the hydrogel enhances cell proliferation. Culture of hS/PCs in hyperGel+ in the presence of a Rho kinase inhibitor Y‐27632 (Y‐27) leads to the development of spheroids with a central lumen, increases the expression of acinar marker aquaporin‐3 at the transcript level (AQP3), and decreases the expression of ductal marker keratin 7 at both the transcript (KRT7) and the protein levels (K7). Reduced expression of transforming growth factor beta (TGF‐β) targets SMAD2/3 is also observed in Y27‐treated cultures, suggesting attenuation of TGF‐β signaling. Thus, hyperGel+ cooperates with the Rho‐associated protein kinase inhibitor to promote the development of lumened spheroids with enhanced expression of acinar markers. 

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4. Tau regulates Arc stability in neuronal dendrites via a proteasome-sensitive but ubiquitin-independent pathway

   https://doi.org/10.1016/j.jbc.2024.107237  

   Yakout, Dina W; Shroff, Ankit; Wei, Wei; Thaker, Vishrut; Allen, Zachary D; Sajish, Mathew; Nazarko, Taras Y; Mabb, Angela M (May 2024, Journal of Biological Chemistry)

   DeMartino, George (Ed.)

   Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule-associated protein tau, a main component of neurofibrillary tangles. Alzheimer’s disease (AD) is the most common type of tauopathy and dementia, with amyloid-beta pathology as an additional hallmark feature of the disease. Besides its role in stabilizing microtubules, tau is localized at postsynaptic sites and can regulate synaptic plasticity. The activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that plays a key role in synaptic plasticity, learning, and memory. Arc has been implicated in AD pathogenesis and regulates the release of amyloid-beta. We found that decreased Arc levels correlate with AD status and disease severity. Importantly, Arc protein was upregulated in the hippocampus of Tau KO mice and dendrites of Tau KO primary hippocampal neurons. Overexpression of tau decreased Arc stability in an activity-dependent manner, exclusively in neuronal dendrites, which was coupled to an increase in the expression of dendritic and somatic surface GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. The tau-dependent decrease in Arc was found to be proteasome-sensitive, yet independent of Arc ubiquitination and required the endophilin-binding domain of Arc. Importantly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. These observations provide a potential molecular basis for synaptic dysfunction mediated through the accumulation of tau in dendrites. Our findings confirm that Arc is misregulated in AD and further show a physiological role for tau in regulating Arc stability and AMPA receptor targeting. 

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5. Tyrosine and Phenylalanine Activate Neuronal DNA Repair but Exhibit Opposing Effects on Global Transcription and Adult Female Mice Are Resilient to TyrRS / YARS1 Depletion

   https://doi.org/10.1002/iub.70030  

   Jhanji, Megha; Bhan, Ashita; Arrowood, Colin; Yakout, Dina W; Shroff, Ankit; McManus, Danielle; Gifford, Henrietta; Vacharasin, Janay; Lizarraga, Sofia B; Nazarko, Taras Y; et al (June 2025, IUBMB Life)

   ABSTRACT Serum tyrosine and phenylalanine levels increase during aging and age‐associated disorders. We previously showed that tyrosyl‐tRNA synthetase (TyrRS/YARS1) is reduced in Alzheimer's Disease (AD) brains, and tyrosine and phenylalanine decrease TyrRS in neurons. Here, we found that tau is a negative regulator, whereas estrogen and leucine act as positive regulators of TyrRS. Young female mice exhibit increased TyrRS in the cortex compared to male mice. Notably, youngTauknockout male, but not female mice showed increased cortical TyrRS. Tau accumulation in middle‐aged female mice did not decrease cortical TyrRS compared to males, suggesting that middle‐aged females are resilient to tau‐mediated TyrRS depletion. Tyrosine and phenylalanine treatment decreased tubulin tyrosination, activated DNA repair pathways, and protected against etoposide (ETO) and camptothecin (CPT)‐induced toxicity, respectively, in neurons. While tyrosine facilitated topoisomerase 1 (TOP1) recruitment to chromatin and inhibited global transcription, in contrast, phenylalanine recruited topoisomerase 2 beta (TOP2β) to chromatin and stimulated global transcription. Furthermore, tyrosine decreased the presence of DNA fragments in a comet assay whereas phenylalanine increased them. Addition ofcis‐resveratrol (cis‐RSV) protected against tyrosine‐induced transcription inhibition by facilitating the recruitment of both TOP1 and TOP2β to chromatin and increasing tubulin tyrosination. Moreover,cis‐RSV decreased both total and phosphorylated tau and protected neurons against amyloid beta (Aβ)‐induced neurite degeneration and DNA damage. Gene expression profiling using human embryonic stem cell (hESC)‐derived neurons demonstrated thatcis‐RSV is a broad‐spectrum neuroprotective and anti‐viral agent. In contrast,trans‐RSV mimics phenylalanine‐induced gene expression, including downregulation of long genes and induction of an AD‐like gene expression signature. This work suggests that age and disease‐associated increases in serum tyrosine and phenylalanine levels would activate neuronal DNA repair while inhibiting transcription and tubulin tyrosination.cis‐RSV protects against their toxicity by restoring tubulin tyrosination, TOP1 and TOP2β‐mediated transcription, and decreasing tau in primary neurons. 

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