Protein nanoparticles induce the activation of voltage-dependent non-selective ion channels to modulate biological osmotic pressure in cytotoxic cerebral edema.

Introduction: Cytotoxic cerebral edema is a serious complication associated with cerebral ischemic stroke and is widely treated using the hypertonic dehydrant. Here, we propose, for the first time, the decrease of intracellular osmosis as a treatment strategy for alleviating cytotoxic cerebral edema. Methods: We established a fluorescence resonance energy transfer-based intermediate filament tension probe for the study and in situ evaluation of osmotic gradients, which were examined in real-time in living cells from primary cultures as well as cell lines. The MCAO rat model was used to confirm our therapy of cerebral edema. Results: Depolymerization of microfilaments/microtubules and the production of NLRP3 inflammasome resulted in an abundance of protein nanoparticles (PNs) in the glutamate-induced swelling of astrocytes. PNs induced changes in membrane potential and intracellular second messengers, thereby contributing to hyper-osmosis and the resultant astrocyte swelling via the activation of voltage-dependent nonselective ion channels. Therefore, multiple inhibitors of PNs, sodium and chloride ion channels were screened as compound combinations, based on a decrease in cell osmosis and astrocyte swelling, which was followed by further confirmation of the effectiveness of the compound combination against alleviated cerebral edema after ischemia. Discussion: The present study proposes new pathological mechanisms underlying "electrophysiology-biochemical signal-osmotic tension," which are responsible for cascade regulation in cerebral edema. It also explores various compound combinations as a potential treatment strategy for cerebral edema, which act by multi-targeting intracellular PNs and voltage-dependent nonselective ion flux to reduce astrocyte osmosis.

Sintilimab-induced inflammatory myopathy in a patient with esophageal cancer: a case report.

The use of immune checkpoint inhibitors (ICIs) has shown remarkable efficacy in the treatment of various malignancies, significantly reshaping cancer treatment. However, as a result of the widespread use of ICIs, several immune-related adverse events (iRAEs) have emerged, some of which can be rare and potentially fatal. In this paper, we reported the earliest case of Sintilimab used in the treatment of esophageal cancer with severe inflammatory myopathy (involving the cardiac, respiratory, and skeletal muscles)in China. This patient was an elderly female who presented to our institution with progressive limb weakness and ptosis. Prior to the onset of symptoms, the patient had undergone a radical esophagectomy for esophageal cancer, experienced several cycles of of radiotherapy and chemotherapy, as well as two doses of Sintilimab treatment. Shortly after initiating immunotherapy, the patient developed symptoms including bilateral ptosis, limb weakness, and difficulty swallowing and breathing. The levels of creatine kinase and troponin I in the patient's blood were significantly elevated, and positive results were observed for anti-skeletal and anti-cardiac muscle antibodies, indicating that the patient might be developing ICIs-related inflammatory myopathy. Fortunately, the patient responded well to treatment including corticosteroids, plasmapheresis, intravenous immunoglobulin, and other supportive therapies. Here, we discuss the incidence, mechanisms, and management strategies of fatal iRAEs. Early detection and timely intervention may be critical in reducing the incidence and mortality rates of iRAEs and improving patient outcomes.