Cell permeabilization using shock-induced bubble collapse provides an attractive choice of drug delivery system. In this work, based on a realistically human brain plasma membrane (PM) model, we investigated the...

Although the interaction mechanism between shock waves and cells is critical for advancing the medical applications of shock waves, we still have little understanding about it. This work aims to study the response of diseased cells subjected to lipid peroxidation to the nanojet from shock wave-induced bubble collapse by using the coarse-grained molecular dynamics simulation. Factors considered in the simulations include the shock velocity (u p), movement time of piston (τp), bubble size (R), and peroxidation level of membranes. Here, we mainly focus on the role of peroxidation levels, that is, the degree (%) and the distribution of oxidized lipids in membranes. The results indicate that the shock damage threshold (u p at which the pore in membranes is formed) of peroxidation membranes is less than that of normal membranes and decreases with the peroxidation degree. Importantly, the distribution of oxidized lipids has more effect on the damage threshold than the peroxidation degree. The threshold of membrane with 33% localized oxidized lipids is lower than that of membrane with 50% average oxidized lipids. The results can be explained by the stretching modulus (κs) and bending modulus (κb) of cell membranes. For example, the κb value (4.3 × 10–20 J) of 100% peroxidation membrane is about half of that (8.4 × 10–20 J) of a membrane without peroxidation. A lower modulus means high deformation under the same impact. Further analysis shows that peroxidation introduces a polar hydrophobic group to the tail of phospholipids that increases the hydrophilicity of tails and warps the tail of phospholipids toward the membrane–water interface, resulting in looser accumulation. This can be confirmed by the increased average phospholipid area with peroxidation levels. Indeed, most of the pores formed during the shock can heal. However, the permeation of water molecules across the healing membrane still increased. All these membrane-level information obtained from this study will be useful for improving the biomedical applications of shock waves.

Revealing how blast shockwaves open the tight junction of the blood–brain barrier (BBB) is very important for understanding blast-induced traumatic brain injury (bTBI) and shockwave-assisted drug delivery; however, the underlying mechanism remains unresolved. Here, we used multiscale molecular dynamics simulations to reveal the disruption mechanism of claudin-5 protein in a relatively complex BBB model by comparing three typical effects from blast loads. The results showed that the opening of claudin-5 did not result from the direct compressive loading of the single shockwave but from indirect cavitation and stretching effects induced by shockwaves. Importantly, stretch-mediated mechanical opening from the asymmetric distribution of overpressure in temporal and spatial dimensions is a novel damage mode. In detail, the nanojet from the cavitation pushed away two adjacent endothelial cell membranes and the embedded claudin-5 was rapidly stretched. Even α-helix showed a drastic conformational breakdown and its content was only 15.9%. Structural changes of this magnitude are difficult to repair in a short time, which may be related to chronic BBB dysfunction and persistent neurological deficits. This is a more common injury, since the tensile response of membranes to blast loads is relatively common. Taken together, we provided a biomechanical underpinning for acute disruption of tight junction proteins in BBB from exposure to blast shockwaves, and this may be helpful as a therapeutic strategy for bTBI.

As the principal water channel in the brain, aquaporin-4 (AQP4) plays a vital role in brain edema, but its role in blast brain edema is unclear. On the basis of molecular simulations, we reveal the atomically detailed picture of AQP4 in response to blast shockwaves. The results show that the shockwave alone closes the AQP4 channel; however, shock-induced bubble collapse opens it. The jet from bubble collapse forcefully increases the distance between helices and the tilt angles of six helices relative to the membrane vertical direction in a very short time. The average channel size increases about 2.6 times, and the water flux rate is nearly 20 times higher than for normal states. It is responsible for abnormal water transport and a potential cause of acute blast brain edema. Additionally, the open AQP4 channel quickly returns to its normal state, which is in turn helpful for edema absorption. Thus, a novel gating mechanism for AQP4 related to the secondary structure change has been provided, which is different from the previous residue-mediated gating mechanism.

Background: The incidence of glycolipid metabolic diseases is extremely high worldwide, which greatly hinders people’s life expectancy and patients’ quality of life. Oxidative stress (OS) aggravates the development of diseases in glycolipid metabolism. Radical oxygen species (ROS) is a key factor in the signal transduction of OS, which can regulate cell apoptosis and contribute to inflammation. Currently, chemotherapies are the main method to treat disorders of glycolipid metabolism, but this can lead to drug resistance and damage to normal organs. Botanical drugs are an important source of new drugs. They are widely found in nature with availability, high practicality, and low cost. There is increasing evidence that herbal medicine has definite therapeutic effects on glycolipid metabolic diseases.Objective: This study aims to provide a valuable method for the treatment of glycolipid metabolic diseases with botanical drugs from the perspective of ROS regulation by botanical drugs and to further promote the development of effective drugs for the clinical treatment of glycolipid metabolic diseases.Methods: Using herb*, plant medicine, Chinese herbal medicine, phytochemicals, natural medicine, phytomedicine, plant extract, botanical drug, ROS, oxygen free radicals, oxygen radical, oxidizing agent, glucose and lipid metabolism, saccharometabolism, glycometabolism, lipid metabolism, blood glucose, lipoprotein, triglyceride, fatty liver, atherosclerosis, obesity, diabetes, dysglycemia, NAFLD, and DM as keywords or subject terms, relevant literature was retrieved from Web of Science and PubMed databases from 2013 to 2022 and was summarized.Results: Botanical drugs can regulate ROS by regulating mitochondrial function, endoplasmic reticulum, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT), erythroid 2-related factor 2 (Nrf-2), nuclear factor κB (NF-κB), and other signaling pathways to improve OS and treat glucolipid metabolic diseases.Conclusion: The regulation of ROS by botanical drugs is multi-mechanism and multifaceted. Both cell studies and animal experiments have demonstrated the effectiveness of botanical drugs in the treatment of glycolipid metabolic diseases by regulating ROS. However, studies on safety need to be further improved, and more studies are needed to support the clinical application of botanical drugs.