Membrane Lipid Replacement for reconstituting mitochondrial function and moderating cancer-related fatigue, pain and other symptoms while counteracting the adverse effects of cancer cytotoxic therapy.

Cancer-related fatigue, pain, gastrointestinal and other symptoms are among the most familiar complaints in practically every type and stage of cancer, especially metastatic cancers. Such symptoms are also related to cancer oxidative stress and the damage instigated by cancer cytotoxic therapies to cellular membranes, especially mitochondrial membranes. Cancer cytotoxic therapies (chemotherapy and radiotherapy) often cause adverse symptoms and induce patients to terminate their anti-neoplastic regimens. Cancer-related fatigue, pain and other symptoms and the adverse effects of cancer cytotoxic therapies can be safely moderated with oral Membrane Lipid Replacement (MLR) glycerolphospholipids and mitochondrial cofactors, such as coenzyme Q10. MLR provides essential membrane lipids and precursors to maintain mitochondrial and other cellular membrane functions and reduces fatigue, pain, gastrointestinal, inflammation and other symptoms. In addition, patients with a variety of chronic symptoms benefit from MLR supplements, and MLR also has the ability to enhance the bioavailability of nutrients and slowly remove toxic, hydrophobic molecules from cells and tissues.

The Fluid-Mosaic model of cell membranes: A brief introduction, historical features, some general principles, and its adaptation to current information.

The Fluid-Mosaic Membrane (FMM) model was originally proposed as a general, nanometer-scale representation of cell membranes (Singer and Nicolson, 1972). The FMM model was based on some general principles, such as thermodynamic considerations, intercalation of globular proteins into a lipid bilayer, independent protein and lipid dynamics, cooperativity and other characteristics. Other models had trimolecular structures or membrane globular lipoprotein units. These latter models were flawed, because they did not allow autonomous lipids, membrane domains or discrete lateral dynamics. The FMM model was also consistent with membrane asymmetry, cis- and trans-membrane linkages and associations of membrane components into multi-molecular complexes and domains. It has remained useful for explaining the basic organizational principles and properties of various biological membranes. New information has been added, such as membrane-associated cytoskeletal assemblies, extracellular matrix interactions, transmembrane controls, specialized lipid-protein domains that differ in compositions, rotational and lateral mobilities, lifetimes, functions, and other characteristics. The presence of dense, structured membrane domains has reduced significantly the extent of fluid-lipid membrane areas, and the FMM model is now considered to be more mosaic and dense than the original proposal.

Fifty Years of the Fluid-Mosaic Model of Biomembrane Structure and Organization and Its Importance in Biomedicine with Particular Emphasis on Membrane Lipid Replacement.

The Fluid-Mosaic Model has been the accepted general or basic model for biomembrane structure and organization for the last 50 years. In order to establish a basic model for biomembranes, some general principles had to be established, such as thermodynamic assumptions, various molecular interactions, component dynamics, macromolecular organization and other features. Previous researchers placed most membrane proteins on the exterior and interior surfaces of lipid bilayers to form trimolecular structures or as lipoprotein units arranged as modular sheets. Such membrane models were structurally and thermodynamically unsound and did not allow independent lipid and protein lateral movements. The Fluid-Mosaic Membrane Model was the only model that accounted for these and other characteristics, such as membrane asymmetry, variable lateral movements of membrane components, cis- and transmembrane linkages and dynamic associations of membrane components into multimolecular complexes. The original version of the Fluid-Mosaic Membrane Model was never proposed as the ultimate molecular description of all biomembranes, but it did provide a basic framework for nanometer-scale biomembrane organization and dynamics. Because this model was based on available 1960s-era data, it could not explain all of the properties of various biomembranes discovered in subsequent years. However, the fundamental organizational and dynamic aspects of this model remain relevant to this day. After the first generation of this model was published, additional data on various structures associated with membranes were included, resulting in the addition of membrane-associated cytoskeletal, extracellular matrix and other structures, specialized lipid-lipid and lipid-protein domains, and other configurations that can affect membrane dynamics. The presence of such specialized membrane domains has significantly reduced the extent of the fluid lipid membrane matrix as first proposed, and biomembranes are now considered to be less fluid and more mosaic with some fluid areas, rather than a fluid matrix with predominantly mobile components. However, the fluid-lipid matrix regions remain very important in biomembranes, especially those involved in the binding and release of membrane lipid vesicles and the uptake of various nutrients. Membrane phospholipids can associate spontaneously to form lipid structures and vesicles that can fuse with various cellular membranes to transport lipids and other nutrients into cells and organelles and expel damaged lipids and toxic hydrophobic molecules from cells and tissues. This process and the clinical use of membrane phospholipid supplements has important implications for chronic illnesses and the support of healthy mitochondria, plasma membranes and other cellular membrane structures.

A Brief Introduction to Some Aspects of the Fluid-Mosaic Model of Cell Membrane Structure and Its Importance in Membrane Lipid Replacement.

Early cell membrane models placed most proteins external to lipid bilayers in trimolecular structures or as modular lipoprotein units. These thermodynamically untenable structures did not allow lipid lateral movements independent of membrane proteins. The Fluid-Mosaic Membrane Model accounted for these and other properties, such as membrane asymmetry, variable lateral mobilities of membrane components and their associations with dynamic complexes. Integral membrane proteins can transform into globular structures that are intercalated to various degrees into a heterogeneous lipid bilayer matrix. This simplified version of cell membrane structure was never proposed as the ultimate biomembrane description, but it provided a basic nanometer scale framework for membrane organization. Subsequently, the structures associated with membranes were considered, including peripheral membrane proteins, and cytoskeletal and extracellular matrix components that restricted lateral mobility. In addition, lipid-lipid and lipid-protein membrane domains, essential for cellular signaling, were proposed and eventually discovered. The presence of specialized membrane domains significantly reduced the extent of the fluid lipid matrix, so membranes have become more mosaic with some fluid areas over time. However, the fluid regions of membranes are very important in lipid transport and exchange. Various lipid globules, droplets, vesicles and other membranes can fuse to incorporate new lipids or expel damaged lipids from membranes, or they can be internalized in endosomes that eventually fuse with other internal vesicles and membranes. They can also be externalized in a reverse process and released as extracellular vesicles and exosomes. In this Special Issue, the use of membrane phospholipids to modify cellular membranes in order to modulate clinically relevant host properties is considered.

Fundamentals of Membrane Lipid Replacement: A Natural Medicine Approach to Repairing Cellular Membranes and Reducing Fatigue, Pain, and Other Symptoms While Restoring Function in Chronic Illnesses and Aging.

Membrane Lipid Replacement (MLR) uses natural membrane lipid supplements to safely replace damaged, oxidized lipids in membranes in order to restore membrane function, decrease symptoms and improve health. Oral MLR supplements contain mixtures of cell membrane glycerolphospholipids, fatty acids, and other lipids, and can be used to replace and remove damaged cellular and intracellular membrane lipids. Membrane injury, caused mainly by oxidative damage, occurs in essentially all chronic and acute medical conditions, including cancer and degenerative diseases, and in normal processes, such as aging and development. After ingestion, the protected MLR glycerolphospholipids and other lipids are dispersed, absorbed, and internalized in the small intestines, where they can be partitioned into circulating lipoproteins, globules, liposomes, micelles, membranes, and other carriers and transported in the lymphatics and blood circulation to tissues and cellular sites where they are taken in by cells and partitioned into various cellular membranes. Once inside cells, the glycerolphospholipids and other lipids are transferred to various intracellular membranes by lipid carriers, globules, liposomes, chylomicrons, or by direct membrane-membrane interactions. The entire process appears to be driven by 'bulk flow' or mass action principles, where surplus concentrations of replacement lipids can stimulate the natural exchange and removal of damaged membrane lipids while the replacement lipids undergo further enzymatic alterations. Clinical studies have demonstrated the advantages of MLR in restoring membrane and organelle function and reducing fatigue, pain, and other symptoms in chronic illness and aging patients.

Lead poisoning: acute exposure of the heart to lead ions promotes changes in cardiac function and Cav1.2 ion channels.

Lead ions (Pb2+) possess characteristics similar to Ca2+. Because of this and its redox capabilities, lead causes different toxic effects. The neurotoxic effects have been well documented; however, the toxic effects on cardiac tissues remain allusive. We utilized isolated guinea pig hearts and measured the effects of Pb2+ on their contractility and excitability. Acute exposure to extracellular Pb2+ had a negative inotropic effect and increased diastolic tension. The speed of contraction and relaxation were affected, though the effects were more dramatic on the speed of contraction. Excitability was also altered. Heart beat frequency increased and later diminished after lead ion exposure. Pro-arrhytmic events, such as early after-depolarization and a reduction of the action potential plateau, were also observed. In isolated cardiomyocytes and tsA 201 cells, extracellular lead blocked currents through Cav1.2 channels, diminished their activation, and enhanced their fast inactivation, negatively affecting their gating currents. Thus, Pb2+ was cardiotoxic and reduced cardiac contractility, making the heart prone to arrhythmias. This was due, in part, to Pb2+ effects on the Cav1.2 channels; however, other channels, transporters or pathways may also be involved. Acute cardiotoxic effects were observed at Pb2+ concentrations achievable during acute lead poisoning. The results suggest how Cav1.2 gating can be affected by divalent cations, such as Pb2, and also suggest a more thorough evaluation of heart function in individuals affected by lead poisoning.