Biology subjects

Shen, I.

Publications and source records attributed to Shen, I..

3 recordsLinked to original sources

bioRxiv2025

Quantification of SARM1 activity in human peripheral blood mononuclear cells

SARM1 (sterile and TIR motif-containing protein-1) is an NADase enzyme that has been identified as the central executioner of Wallerian axon degeneration. Given this, SARM1 is of high interest as a candidate therapeutic target and SARM1 inhibitors are currently in clinical trials for prevention and treatment of neurodegeneration. Beyond neuroscience, emerging studies reveal that SARM1 activation may also drive aspects of bone fragility, liver pathology, adipose tissue expansion, and insulin resistance in settings of metabolic disease. However, we lack methods to quantify SARM1 activation in humans using clinical isolates to better define patients at high risk of SARM1-mediated tissue damage, informing the future clinical application of SARM1 inhibitors. Unlike neurons, peripheral blood mononuclear cells (PBMCs) represent an easily accessible population of cells for clinical screening. We hypothesized that by pairing activators and inhibitors of SARM1 with analysis of downstream changes in cellular metabolites, we could quantify both the basal SARM1 activity and the SARM1 activation potential of human PBMCs. Our results reveal that SARM1 agonist pyrinuron, also known as Vacor, activates a dose-dependent increase in cAPDR and the cADPR:ADPR ratio that is arrested when paired with SARM1 inhibitor DSRM-3716. Various changes in secondary metabolites were also characterized and reported herein. Overall, these findings demonstrate that human PBMCs have detectable SARM1 activation potential and could be leveraged as a clinical readout of SARM1 expression and activity across diverse disease contexts.

cell biology↗

bioRxiv2020

Neuroskeletal effects of chronic bioelectric nerve stimulation in health and diabetes

Background/AimsBioelectric nerve stimulation (eStim) is a novel clinical paradigm that can promote nerve regeneration after trauma, including within the context of diabetes. However, its ability to prevent the onset of diabetic peripheral neuropathy (DPN) has not yet been evaluated. Beyond the nerve itself, DPN has emerged as a potential contributor to sarcopenia and bone disease; thus, we hypothesized that eStim could serve as a strategy to simultaneously promote neural and musculoskeletal health in diabetes. MethodsTo address this question, an eStim paradigm pre-optimized to promote nerve regeneration was applied to the sciatic nerve, which directly innervates the tibia and lower limb, for 8-weeks in control and streptozotocin-induced type 1 diabetic (T1D) rats. Metabolic, gait, nerve and bone assessments were used to evaluate the progression of diabetes and the effect of sciatic nerve eStim on neuropathy and musculoskeletal disease, while also considering the effects of cuff placement and chronic eStim in otherwise healthy animals. ResultsRats with T1D exhibited increased mechanical allodynia in the hindpaw, reduced muscle mass, decreased cortical and cancellous bone volume fraction (BVF), reduced cortical bone tissue mineral density (TMD), and decreased bone marrow adiposity. T1D also had an independent effect on gait. Placement of the cuff electrode alone was sufficient to alter gait patterns and to promote unilateral reductions in tibia length, cortical BVF, and bone marrow adiposity. Alterations in gait patterns and left-right balance to tibia length were restored with eStim, but it did not prevent T1D-induced changes in muscle, bone, marrow adiposity or mechanical sensitivity. Beyond this, chronic eStim resulted in an independent, bilateral reduction in cortical TMD. ConclusionOverall, these results provide new insight into the pathogenesis of diabetic neuroskeletal disease and its regulation by eStim. Though eStim did not prevent neural or musculoskeletal complications in T1D, our results demonstrate that clinical applications of peripheral neuromodulation ought to consider the impact of device placement and eStim on long-term skeletal health in both healthy individuals and those with metabolic disease. This includes monitoring for compounded bone loss to prevent unintended consequences including decreased bone mineral density and increased fracture risk.

bioengineering↗

bioRxiv2020

A neuroskeletal atlas of the mouse limb

Nerves in bone play well-established roles in pain and vasoregulation and have been associated with progression of skeletal disorders including osteoporosis, fracture, arthritis and tumor metastasis. However, isolation of the region-specific mechanisms underlying these relationships is limited by our lack of comprehensive maps of skeletal innervation. To overcome this, we mapped sympathetic adrenergic and sensory peptidergic axons within the limb in two strains of mice (B6 and C3H). In the periosteum, these maps were related to the surrounding musculature, including entheses and myotendinous attachments to bone. Locally, three distinct patterns of innervation (Type I, II, III) were defined within established sites that are important for bone pain, bone repair, and skeletal homeostasis. In addition, we mapped the major nerve branches and areas of specialized mechanoreceptors. This work is intended to serve as a guide during the design, implementation, and interpretation of future neuroskeletal studies and was compiled as a resource for the field as part of the NIH SPARC consortium.

systems biology↗