Biology subjects

Yang, J. Z.

Publications and source records attributed to Yang, J. Z..

4 recordsLinked to original sources

bioRxiv2026

Mechanical Stretch Counteracts Hypomagnetic Field-Induced Changes in YAP Nuclear Localization in C2C12 Myoblasts

The geomagnetic field (GMF) is a persistent environmental factor that influences biological processes. Reduced geomagnetic field exposure can alter cellular processes, but its effects on cellular mechanotransduction and responsiveness to mechanical stimulation remain poorly understood. Here, we developed an in vitro platform combining a programmable uniaxial stretching device with a mu-metal shielding chamber to independently manipulate mechanical stretch and magnetic field exposure. Using C2C12 myoblasts, we evaluated culture conditions and cyclic stretching parameters to identify a regimen that promoted nuclear localization of the mechanosensitive transcriptional coactivator yes-associated protein (YAP). We then compared cell and nuclear morphology and YAP nucleocytoplasmic localization under geomagnetic field (GMF) and hypomagnetic field (HMF; approximately 5 nT) conditions, with or without cyclic stretch. Under static conditions, HMF exposure increased cell and nuclear areas, promoted nuclear elongation, reduced nuclear circularity, and decreased the nuclear YAP level. Cyclic stretch induced nuclear alignment perpendicular to the stretching direction under both magnetic field conditions, without significantly altering cell or nuclear area or nuclear elongation. Importantly, cyclic stretch increased nuclear YAP localization under both GMF and HMF conditions, restoring it in HMF-exposed cells to levels comparable to those in stretched cells under GMF. These findings indicate that C2C12 myoblasts remain responsive to mechanical stimulation under HMF conditions and that cyclic stretch can counteract the HMF-associated reduction in nuclear YAP localization. Our platform provides a foundation for investigating how magnetic and mechanical cues jointly regulate myoblast behavior.

biophysics↗

bioRxiv2022

Small molecule-mediated insulin hypersecretion induces transient unfolded protein response and loss of function in pancreatic islet beta cells

Pancreatic islet beta cells require a fine-tuned ER stress response for normal function; abnormal ER stress contributes to diabetes pathogenesis. Here, we identified a small molecule, SW016789, with time-dependent effects on beta cell ER stress and function. Acute treatment with SW016789 potentiated nutrient-induced calcium influx and insulin secretion, while chronic exposure to SW016789 transiently induced ER stress and shut down secretory function in a reversible manner. Distinct from the effects of thapsigargin, SW016789 did not affect beta cell viability or apoptosis, potentially due to a rapid induction of adaptive genes, weak signaling through the eIF2 kinase PERK, and lack of oxidative stress gene Txnip induction. We determined that SW016789 acted upstream of voltage-dependent calcium channels (VDCCs) and potentiated nutrient- but not KCl-stimulated calcium influx. Measurements of metabolomics, oxygen consumption rate, and G protein-coupled receptor signaling did not explain the potentiating effects of SW016789. In chemical co-treatment experiments we discovered synergy between SW016789 and activators of protein kinase C (PKC) and VDCCs, suggesting involvement of these pathways in the mechanism of action. Finally, chronically elevated calcium influx was required for the inhibitory impact of SW016789, as blockade of VDCCs protected human islets and MIN6 beta cells from hypersecretion-induced dysfunction. We conclude that beta cells undergoing this type of pharmacological hypersecretion have the capacity to suppress their function to mitigate ER stress and avoid apoptosis. These results have the potential to uncover beta cell ER stress mitigation factors and add support to beta cell rest strategies to preserve function.

cell biology↗

bioRxiv2020

Targeted over-expression of PPARγ in pig skeletal muscle improves oxidative fiber formation and intramuscular fat deposition

PPAR{gamma} is a master regulator of adipogenesis and lipogenesis. To understand its roles in fat deposition and fiber formation in skeletal muscle, we successfully generated muscle-specific overexpression of PPAR{gamma} by pig cloning procedures. The content of intramuscular fat was significantly increased in PPAR{gamma} transgenic pigs while the muscle mass as lean percentage of body weight was not changed. The proteomics analysis demonstrated oxidative metabolism of fatty acids and respiratory chain were increased in PPAR{gamma} pigs. Furthermore, expressions of oxidative muscle fiber-related genes such as MyHC1 and TNNT1 were enhanced. CAMK2, MEF2 and PGC1 were also significantly increased in skeletal muscle of PPAR{gamma} pigs, indicating that Ca2+-sensitive phosphatases and kinases may play an important role in the switch of muscle fiber types when PPAR{gamma} activity is elevated in skeletal muscle. The results support skeletal muscle-specific overexpression of PPAR{gamma} can promote oxidative fiber formation and intramuscular fat deposition in pigs.

genetics↗

bioRxiv2018

Chromomycin A2 potently inhibits glucose-stimulated insulin secretion from pancreatic beta cells.

Enhancers or inhibitors of insulin secretion could become therapeutics as well as lead to the identification of requisite {beta}-cell regulatory pathways and increase our understanding of pancreatic islet function. Toward this goal, we previously used an insulin-linked luciferase that is co-secreted with insulin in MIN6 {beta}-cells to perform a high-throughput natural product screen for chronic effects on glucose-stimulated insulin secretion. Using multiple phenotypic analyses, we identified that one of the top natural product hits, chromomycin A2 (CMA2), potently inhibited insulin secretion through at least three mechanisms: disruption of Wnt signaling, interfering with {beta}-cell gene expression, and suppression of triggering calcium (Ca2+) influx. Chronic treatment with CMA2 largely ablated glucose-stimulated insulin secretion even post-washout, but did not inhibit glucose-stimulated generation of ATP or Ca2+ influx. However, by using the KATP channel-opener diazoxide, we uncovered defects in depolarization-induced Ca2+ influx which may contribute to the suppressed secretory response. Glucose-responsive ERK1/2 and S6 phosphorylation were also disrupted by chronic CMA2 treatment. The FUSION bioinformatic database indicated that the phenotypic effects of CMA2 clustered with a number of Wnt/GSK3 pathway-related genes. Consistently, CMA2 decreased GSK3 phosphorylation and suppressed activation of a {beta}-catenin activity reporter. CMA2 and a related compound mithramycin are described to have DNA-interaction properties, possibly abrogating transcription factor binding to critical {beta}-cell gene promoters. We observed that CMA2, but not mithramycin, suppressed expression of PDX1 and UCN3. However, neither expression of INSI/II nor insulin content was affected by chronic CMA2. The mechanisms of CMA2-induced insulin secretion defects may involve components both proximal and distal to Ca2+ influx. Therefore, CMA2 is an example of a chemical that can simultaneously disrupt {beta}-cell function through both non-cytotoxic and cytotoxic mechanisms. Future applications of CMA2 and similar aureolic acid analogs for disease therapies should consider the potential impacts on pancreatic islet function.

cell biology↗