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Biomolecule sensors based on organic electrochemical transistors
Biosensors based on organic electrochemical transistors (OECTs) have been a research highlight in recent years owing to their remarkable biocompatibility, low operating voltage, and substantial signal amplification capability. Especially, as an emerging fundamental device for biosensing, OECTs show great potential for pH, ions, molecules, and biomarker sensing. This review highlights the research progress of biomolecule sensors based on OECTs, focusing on recent publications in the past 5 years. Specifically, OECT-based biomolecule sensors for small molecules (glucose, dopamine, lactate, etc. that act as signals or effectors), and macromolecules (DNA, RNA, proteins, etc. that are often used as markers in physiology and medicine), are summarized. Additionally, emerging technologies and materials used to enhance sensitivity, detection limits, and detection ranges are described comprehensively. Last, aspects of OECT-based biomolecule sensors that need further improvement are discussed along with future opportunities and challenges.
Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity
Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity. Outside the conventional housekeeping role, autophagy is also involved in the ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and alterations in glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that the deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and rescues their ataxic gait. Taken together, this work reveals a mechanism for regulating GLUT2 levels in neurons and provides insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain.
Variable bioenergetic sensitivity of neurons and astrocytes to insulin and extracellular glucose
Energy flow within cellular elements of the brain is a well-orchestrated, tightly regulated process, however, details underlying these functions at the single-cell level are still poorly understood. Studying hypometabolism in aging and neurodegenerative diseases may benefit from experimentation on unicellular bioenergetics. Here, we examined energy status in neurons and astrocytes using mixed hippocampal cultures and PercevalHR, an ATP:ADP nanosensor. We assessed exposures of several compounds including KCl, glutamate, FCCP, insulin, and glucose. A mitochondrial stress test was performed, and PercevalHR’s fluorescence was corrected for pH using pHrodo. Results demonstrate that PercevalHR can reliably report on the energetic status of two cell types that communicate in a mixed-culture setting. While KCl, glutamate, and FCCP showed clear changes in PercevalHR fluorescence, insulin and glucose responses were found to be more subtle and sensitive to extracellular glucose. These results may highlight mechanisms that mediate insulin sensitivity in the brain.
A blood glucose fluctuation-responsive delivery system promotes bone regeneration and the repair function of Smpd3-reprogrammed BMSC-derived exosomes
Blood glucose fluctuation leads to poor bone defect repair in patients with type 2 diabetes (T2DM). Strategies to safely and efficiently improve the bone regeneration disorder caused by blood glucose fluctuation are still a challenge. Neutral sphingophospholipase 2 (Smpd3) is downregulated in jawbone-derived bone marrow mesenchymal stem cells (BMSCs) from T2DM patients. Here, we investigated the effect of Smpd3 on the osteogenic differentiation of BMSCs and utilized exosomes from stem cells overexpressing Smpd3 as the main treatment based on the glucose responsiveness of phenylboronic acid-based polyvinyl alcohol crosslinkers and the protease degradability of gelatin nanoparticles. The combined loading of Smpd3-overexpressing stem cell-derived exosomes (Exos-Smpd3) and nanosilver ions (Ns) to construct a hydrogel delivery system (Exos-Smpd3@Ns) promoted osteogenesis and differentiation of BMSCs in a glucose-fluctuating environment, ectopic osteogenesis of BMSCs in a glucose-fluctuating environment and jawbone regeneration of diabetic dogs in vitro. Mechanistically, Smpd3 promoted the osteogenesis and differentiation of jawbone-derived BMSCs by activating autophagy in the jawbone and inhibiting macrophage polarization and oxidative stress caused by blood glucose fluctuations. These results reveal the role and mechanism of Smpd3 and the Smpd3 overexpression exosome delivery system in promoting BMSC function and bone regeneration under blood glucose fluctuations, providing a theoretical basis and candidate methods for the treatment of bone defects in T2DM patients.
Consensus on the key characteristics of metabolism disruptors
Metabolism-disrupting agents (MDAs) are chemical, infectious or physical agents that increase the risk of metabolic disorders. Examples include pharmaceuticals, such as antidepressants, and environmental agents, such as bisphenol A. Various types of studies can provide evidence to identify MDAs, yet a systematic method is needed to integrate these data to help to identify such hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we developed 12 KCs of MDAs based on our knowledge of processes underlying metabolic diseases and the effects of their causal agents: (1) alters function of the endocrine pancreas; (2) impairs function of adipose tissue; (3) alters nervous system control of metabolic function; (4) promotes insulin resistance; (5) disrupts metabolic signalling pathways; (6) alters development and fate of metabolic cell types; (7) alters energy homeostasis; (8) causes inappropriate nutrient handling and partitioning; (9) promotes chronic inflammation and immune dysregulation in metabolic tissues; (10) disrupts gastrointestinal tract function; (11) induces cellular stress pathways; and (12) disrupts circadian rhythms. In this Consensus Statement, we present the logic that revealed the KCs of MDAs and highlight evidence that supports the identification of KCs. We use chemical, infectious and physical agents as examples to illustrate how the KCs can be used to organize and use mechanistic data to help to identify MDAs.
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