作者: Cheng, Anya ; Singh, Bhagat ; Snavely, Andrew R ; Woolf, Clifford J ; Splaine, Jennifer ; Barrett, Lee B ; Petrova, Veselina ; Hermawan, Crystal ; Chen, Kuchuan ; Zhen, Shannon ; Pandey, Roshan ; Smith, Jennifer A

Abstract:

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient’s quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles – AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

2024-10-09·NANO LETTERS

ChiSCAT: Unsupervised Learning of Recurrent Cellular Micromotion Patterns from a Chaotic Speckle Pattern

Article

作者: Rimmbach, Christian ; Trelin, Andrii ; Kussauer, Sophie ; Reinhard, Friedemann ; Weinbrenner, Paul ; David, Robert ; Clasen, Anja

There is considerable evidence that action potentials are accompanied by "intrinsic optical signals", such as a nanometer-scale motion of the cell membrane. Here we present ChiSCAT, a technically simple imaging scheme that detects such signals with interferometric sensitivity. ChiSCAT combines illumination by a chaotic speckle pattern and interferometric scattering microscopy (iSCAT) to sensitively detect motion in any direction. The technique features reflective high-NA illumination, common-path suppression of vibrations, and a large field of view. This approach maximizes sensitivity to motion, but does not produce a visually interpretable image. We show that unsupervised learning based on matched filtering and motif discovery can recover underlying motion patterns and detect action potentials. We demonstrate these claims in an experiment on blebbistatin-paralyzed cardiomyocytes. ChiSCAT opens the door to action potential measurement in scattering tissue, including a living brain.

2024-10-01·FREE RADICAL BIOLOGY AND MEDICINE

Harmonization of experimental procedures to assess mitochondrial respiration in human permeabilized skeletal muscle fibers

Article

作者: Larsen, Steen ; Goodpaster, Bret H ; Pesta, Dominik ; Guimera, Roger ; Gama-Perez, Pau ; Gnaiger, Erich ; Prats, Clara ; Gonzalez-Franquesa, Alba ; Sales-Pardo, Marta ; Garcia-Roves, Pablo M ; Doerrier, Carolina ; Soendergaard, Stine D ; Chroeis, Karoline Maise ; Coen, Paul M ; Distefano, Giovanna

AIM:

High-resolution respirometry in human permeabilized muscle fibers is extensively used for analysis of mitochondrial adaptions to nutrition and exercise interventions, and is linked to athletic performance. However, the lack of standardization of experimental conditions limits quantitative inter- and intra-laboratory comparisons.

METHODS:

In our study, an international team of investigators measured mitochondrial respiration of permeabilized muscle fibers obtained from three biopsies (vastus lateralis) from the same healthy volunteer to avoid inter-individual variability. High-resolution respirometry assays were performed together at the same laboratory to assess whether the heterogenity in published results are due to the effects of respiration media (MiR05 versus Z) with or without the myosin inhibitor blebbistatin at low- and high-oxygen regimes.

RESULTS:

Our findings reveal significant differences between respiration media for OXPHOS and ET capacities supported by NADH&succinate-linked substrates at different oxygen concentrations. Respiratory capacities were approximately 1.5-fold higher in MiR05 at high-oxygen regimes compared to medium Z near air saturation. The presence or absence of blebbistatin in human permeabilized muscle fiber preparations was without effect on oxygen flux.

CONCLUSION:

Our study constitutes a basis to harmonize and establish optimum experimental conditions for respirometric studies of permeabilized human skeletal muscle fibers to improve reproducibility.

100 项与 Blebbistatin 相关的药物交易

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