Biology subjects

Chen, M. X.

Publications and source records attributed to Chen, M. X..

5 recordsLinked to original sources

bioRxiv2024

A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogels potential for PTOA treatment in active patients.

bioengineering↗

bioRxiv2024

A Lipidomics-Based Method to Eliminate Negative Urine Culture in General Population

Urinary tract infections (UTIs) pose a significant challenge to human health. Accurate and timely detection remains pivotal for effective intervention. Current urine culture techniques, while essential, often encounter challenges where urinalysis yields positive results, but subsequent culture testing produces a negative result. This highlights potential discrepancies between the two methods and emphasizes the need for improved correlation in urinary tract infection (UTI) detection. Employing advanced lipidomics techniques, we deployed the fast lipid analysis technique (FLAT) on a clinical cohort suspected of having UTIs. Lipid fingerprinting by MALDI-TOF MS, directly from urine samples without ex vivo growth, correctly identified the common uropathogens within a 1-hour timeframe when compared to urine culture. FLAT analysis also identified urine samples without culturable pathogens (negative UTIs) with 99% agreement, whereas urinalysis showed 37% agreement with the gold standard urine culture. In 402 urine samples suspected for UTI from out-patients, FLAT assay rapidly ruled out negative urines without the need for culture in 77% of all cases. The potential impact of this innovative lipidomic-based approach extends beyond conventional diagnostic limitations, offering new avenues for early detection and targeted management of urinary tract infections. This research marks a paradigm shift in urine culture methodology, paving the way for improved clinical outcomes and public health interventions.

microbiology↗

bioRxiv2023

Metabolic Reprogramming of the Neovascular Niche Promotes Regenerative Angiogenesis in Proliferative Retinopathy

Healthy blood vessels supply neurons to preserve metabolic function. In blinding ischemic proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological neuroretina revascularization. We show that metabolic shifts in the neurovascular niche define this angiogenic dichotomy between healthy and diseased blood vessel growth. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neurovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological EC to a physiological phenotype, hastening vascular regeneration of the ischemic retina. Our findings identify SIRT3 as a metabolic switch in the neurovascular niche, offering a new therapeutic target for optimizing ischemic tissue revascularization. HighlightsO_LIPathological EC favor FAO over glycolysis. C_LIO_LIUnique signature for pathological EC found in proliferative retinopathy model. C_LIO_LISirt3 deletion shifts astrocytes and EC metabolism from FAO to glycolysis. C_LIO_LIMetabolic reprogramming of the vascular niche enhances physiological revascularization. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/566898v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@70020eorg.highwire.dtl.DTLVardef@19719acorg.highwire.dtl.DTLVardef@1168ddeorg.highwire.dtl.DTLVardef@1bc25e0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Endothelial FABP4 constitutes the majority of basal circulating hormone levels and regulates lipolysis-driven insulin secretion

Fatty acid binding protein 4 (FABP4) is a lipid chaperone secreted from adipocytes upon stimulation of lipolysis. Circulating FABP4 levels strongly correlate with body mass index and obesity-related pathologies in experimental models and humans. While adipocytes have been presumed to be the major source of hormonal FABP4, this question has not been addressed definitively in vivo. We generated mice with FABP4 deletion in cells known to express the gene; adipocytes (Adipo-KO), endothelial cells (Endo-KO), myeloid cells (Myeloid-KO), and the whole body (Total-KO) to examine the contribution of these cell types to basal and stimulated plasma FABP4 levels. Unexpectedly, baseline plasma FABP4 was only reduced by [~]25% in Adipo-KO mice, whereas Endo-KO mice showed [~]75% decreases compared to wildtype controls. In contrast, Adipo-KO mice exhibited [~]62% reduction in FABP4 responses to lipolysis, while there was minimal reduction in Endo-KO mice, indicating that adipocytes are the main FABP4 source in lipolysis. We did not detect any myeloid cell contribution to circulating FABP4. Surprisingly, despite the nearly intact FABP4 responses, Endo-KO mice showed blunted lipolysis-induced insulin secretion, identical to Total-KO mice. We conclude that the endothelium is the major source of baseline hormonal FABP4 and is required for the insulin response to lipolysis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/511807v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1b2d566org.highwire.dtl.DTLVardef@1d82083org.highwire.dtl.DTLVardef@3e9726org.highwire.dtl.DTLVardef@1357648_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

Molecular and cellular adaptations in hippocampal parvalbumin neurons mediate behavioral responses to chronic social stress

Parvalbumin-expressing interneurons (PV neurons) maintain inhibitory control of local circuits implicated in behavioral responses to environmental stressors. However, the roles of molecular and cellular adaptations in PV neurons in stress susceptibility or resilience have not been clearly established. Here, we show behavioral outcomes of chronic social defeat stress (CSDS) are mediated by differential neuronal activity and gene expression in hippocampal PV neurons in mice. Using in vivo electrophysiology and chemogenetics, we find increased PV neuronal activity in the ventral dentate gyrus is required and sufficient for behavioral susceptibility to CSDS. PV neuron-selective translational profiling indicates mitochondrial oxidative phosphorylation is the most significantly altered pathway in stress-susceptible versus resilient mice. Among differentially expressed genes associated with stress-susceptibility and resilience, we find Ahnak, an endogenous regulator of L-type calcium channels which are implicated in the regulation of mitochondrial function and gene expression. Notably, Ahnak deletion in PV neurons impedes behavioral susceptibility to CSDS. Altogether, these findings indicate behavioral effects of chronic stress can be controlled by selective modulation of PV neuronal activity or a regulator of L-type calcium signaling in PV neurons.

neuroscience↗