Journal of Membrane Biology最新文献

Electroporation method is a useful tool for delivering drugs into various diseased tissues in the human body. As a result of an applied electric field, drug particles enter the intracellular compartment through the temporarily permeabilized cell membrane. Consequently, electroporation method allows better penetration of the drug into the diseased tissue and improves treatment clinically. In this study, a more generalized model of drug transport in a single cell is proposed. The model is able to capture non-homogeneous drug transport in the cell due to non-uniform cell membrane permeabilization. Several numerical experiments are conducted to understand the effects of electric field and drug permeability on drug uptake into the cell. Through investigation, the appropriate electric field and drug permeability are identified, which lead to sufficient drug uptake into the cell. This model can be used by experimentalists to get information prior to conduct any experiment, and it may help reduce the number of actual experiments that might be conducted otherwise.

Osteoarthritis (OA) is the most common type of arthritis. Its high prevalence, especially in the elderly, and its negative impact on physical function make it a leading cause of disability in the elderly. Joint pain as well joint stiffness are the common classic signs of OA. Chondrocyte death together with loss of articular cartilage integrity are the main pathologic changes in OA. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are commonly used for the management of OA; still, their effectiveness is limited, and no therapeutic strategy is able to fully stop OA progression. Ferroptosis is a kind of cell death, distinct from apoptosis and necroptosis, caused by iron-dependent peroxidation of membrane phospholipids that terminates cell life by disintegrating all plasma membranes. It has been suggested that ferroptosis has a critical role in decreased viability of chondrocytes in OA, and here, we review recent findings regarding the pathologic pathways that lead to chondrocyte ferroptosis, and discuss the possible therapeutic utility of ferroptosis inhibition in OA.

Lymphatic drug targeting is an effective approach for targeting immunomodulators, and chemotherapeutic drugs at a specific organ or cellular location. The cellular, paracellular, and dendritic cell trafficking machinery are involved in the lymphatic transport of therapeutic agents. The engineering of triggered and hybrid lymphatic drug delivery systems (LDDS) is a promising strategy to fight cancer metastasis and microbial pandemics. Hybrid lymphatic drug delivery systems can be tailored and developed by grafting the conventional LDDS with biological agents. Thus, hybrid LDDS could collect the benefits of conventional and biological delivery systems. Moreover, the fabrication of triggered LDDS increases drug accumulation in the lymphatic system in the response to an internal stimulus such as pH, and redox status or external such as magnetic field, temperature, and light. Stimuli-responsive LDD systems prevent premature release of payload and mediate selective drug biodistribution. This improves therapeutic impact and reduces the systemic side effect of anticancer, immunomodulatory, and antimicrobial therapeutics. This review highlights the challenges and future horizons of nanoscaled-triggered LDDS and their influence on the lymphatic trafficking of therapeutic molecules.

The nature of odoroside A, a cardiac glycoside (CG) extracted from Nerium oleander, as well as its chemical structure is quite similar to a well-known CG, ouabain possessing a steroid skeleton, a five-membered unsaturated lactone ring, and a sugar moiety as a common structure. Like ouabain, odoroside A inhibits the activity of Na⁺/K⁺-ATPase (NKA) and shows significant anticancer activity, however its inhibitory mechanism remains unknown. CGs show various physiological activities, including cardiotonic and anticancer activities, through the inhibition of NKA by direct interaction. Additionally, X-ray crystallographic analysis revealed the inhibitory mechanism of ouabain and digoxin in relation to NKA. By using different molecular modeling techniques, docking simulation of odoroside A and NKA was conducted based on the results of these X-ray crystallographic analyses. Furthermore, a comparison of the results with the binding characteristics of three known CGs (ouabain, digoxin, and digitoxin) was also conducted. Odoroside A fitted into the CG binding pocket on the α-subunit of NKA revealed by X-ray crystallography. It had key interactions with Thr797 and Phe783. Also, three known CGs showed similar interactions with Thr797 and Phe783. Interaction modes of odoroside A were quite similar to those of ouabain, digoxin, and digitoxin. Docking simulations indicated that the sugar moiety enhanced the interaction between NKA and CGs, but did not show enhanced NKA inhibitory activity because the sugar moiety was placed outside the entrance of active site. Thus, these results suggest that the inhibitory mechanism of odoroside A to NKA is the same as the known CGs.

Heart diseases such as arrhythmia are the main causes of sudden death. Arrhythmias are typically caused by mutations in specific genes, damage in the cardiac tissue, or due to some chemical exposure. Arrhythmias caused due to mutation is called inherited arrhythmia. Induced arrhythmias are caused due to tissue damage or chemical exposure. Mutations in genes that encode ion channels of the cardiac cells usually result in (dysfunction) improper functioning of the channel. Improper functioning of the ion channel may lead to major changes in the action potential (AP) of the cardiac cells. This further leads to distorted electrical activity of the heart. Distorted electrical activity will affect the ECG that results in arrhythmia. KCNQ1 P535T mutation is one such gene mutation that encodes the potassium ion channel (KV7.1) of the cardiac ventricular tissue. Its clinical significance is not known. This study aims to perform a simulation study on P535T mutation in the KCNQ1 gene that encodes the potassium ion channel KV7.1 in the ventricular tissue grid. The effect of P535T mutation on transmural tissue grids for three genotypes (wild type, heterozygous, and homozygous) of cells are studied and the generated pseudo-ECGs are compared. Results show the delayed repolarization in the cells of ventricular tissue grid. Slower propagation of action potential in the transmural tissue grid is observed in the mutated (heterozygous and homozygous) genotypes. Longer QT interval is also observed in the pseudo-ECG of heterozygous and homozygous genotype tissue grids. From the pseudo-ECGs, it is observed that KCNQ1 P535T mutation leads to Long QT Syndrome (LQTS) which may result in life-threatening arrhythmias, such as Torsade de Pointes (TdP), Jervell and Lange-Nielsen syndrome (JLNS), and Romano-Ward syndrome (RWS).