The Crucial Roles of Phospholipids in Aging and Lifespan Regulation

Phospholipids are major membrane lipids that consist of lipid bilayers. This basic cellular structure acts as a barrier to protect the cell against various environmental insults and more importantly, enables multiple cellular processes to occur in subcellular compartments. Numerous studies have linked the complexity of membrane lipids to signal transductions, organelle functions, as well as physiological processes, and human diseases. Recently, crucial roles for membrane lipids in the aging process are beginning to emerge. In this study, we summarized current advances in our understanding of the relationship between membrane lipids and aging with an emphasis on phospholipid species. We surveyed how major phospholipid species change with age in different organisms and tissues, and some common patterns of membrane lipid change during aging were proposed. Further, the functions of different phospholipid molecules in regulating healthspan and lifespan, as well as their potential mechanisms of action, were also discussed.

The Role and Molecular Mechanism of P2Y12 Receptors in the Pathogenesis of Atherosclerotic Cardiovascular Diseases

The P2Y receptor family is a class of G protein-coupled receptors activated primarily by adenosine triphosphate (ATP), adenosine diphosphate (ADP), uridine triphosphate (UTP) and uridine diphosphate (UDP). The P2Y12 receptor is expressed on platelets which mediates platelet aggregation and morphological changes. At the same time, during the process of vascular remodeling and atherosclerosis, ADP can also promote the migration and proliferation of vascular smooth muscle and endothelial cells through P2Y12 receptor activating. Furthermore, P2Y12 is involved in many signal transductions processes, such as intimal hyperplasia, monocyte infiltration and so on, which play an important role in immune inflammation and brain injury. In order to solve the diseases induced by P2Y12 receptor, inhibitors such as ticagrelor, clopidogrel were widely used for cardiovascular diseases. However, there were some problems, such as limited antithrombotic effect, remain unsolved. This article summarizes the role and molecular mechanism of P2Y12 receptors in the pathogenesis of cardiovascular-related diseases, providing in-depth expounding on the molecular mechanism of P2Y12 receptor inhibitors and contributing to the treatment of diseases based on P2Y12 receptors.

Acidic microenvironment enhances MT1-MMP-mediated cancer cell motility through integrinβ1/cofilin/F-actin axis

Tumor acidic microenvironment is the main feature of many solid tumors. As a part of the tumor microenvironment, it has a profound impact on the occurrence and development of tumors. However, the research on how tumor cells sense the changes of the external microenvironment and how the intracellular subcellular structures transmit the signals from extracellular to intracellular is unclear. In this study, we identify that the acidic microenvironment enhances cancer cell motility, and the expression of membrane-anchored membrane type 1-matrix metalloproteinase is also associated with cell motility, which indicates more degradation of the ECM under the acidic microenvironment. Moreover, the expression of cofilin is low in the acidic microenvironment, and the F-actin filaments are distributed more along the cells. The cytoskeletal F-actin changes are consistent with the potential of a high-invasive phenotype. Further study reveals the upstream control of the signal transductions from extracellular to intracellular, that is, the integrin β1 functions to trigger the biological responses under the acidic microenvironment. Our results demonstrate that the acidic microenvironment enhances cancer cell motility through the integrin β1/cofilin/F-actin signal axis. This study clearly shows the scheme of the signal transmissions from extracellular to intracellular and further reveals the cytoskeletal roles for the contributions of cancer cell motility under acidic microenvironment, which provides new targets for cancer intervention from the biochemical and biophysical perspectives.

Comparative anatomical and transcriptomic insights into Vaccinium corymbosum flower bud and fruit throughout development

Background Blueberry (Vaccinium spp.) is characterized by the production of berries that are smaller than most common fruits, and the underlying mechanisms of fruit size in blueberry remain elusive. V. corymbosum ‘O’Neal’ and ‘Bluerain’ are commercial southern highbush blueberry cultivars with large- and small-size fruits, respectively, which mature ‘O’Neal’ fruits are 1 ~ 2-fold heavier than those of ‘Bluerain’. In this study, the ontogenetical patterns of ‘O’Neal’ and ‘Bluerain’ hypanthia and fruits were compared, and comparative transcriptomic analysis was performed during early fruit development. Results V. corymbosum ‘O’Neal’ and ‘Bluerain’ hypanthia and fruits exhibited intricate temporal and spatial cell proliferation and expansion patterns. Cell division before anthesis and cell expansion after fertilization were the major restricting factors, and outer mesocarp was the key tissue affecting fruit size variation among blueberry genotypes. Comparative transcriptomic and annotation analysis of differentially expressed genes revealed that the plant hormone signal transduction pathway was enriched, and that jasmonate-related TIFYs genes might be the key components orchestrating other phytohormones and influencing fruit size during early blueberry fruit development. Conclusions These results provided detailed ontogenetic evidence for determining blueberry fruit size, and revealed the important roles of phytohormone signal transductions involving in early fruit development. The TIFY genes could be useful as markers for large-size fruit selection in the current breeding programs of blueberry.

Cellular Signal Transductions and Their Inhibitors Derived from Deep-Sea Organisms

Not only physiological phenomena but also pathological phenomena can now be explained by the change of signal transduction in the cells of specific tissues. Commonly used cellular signal transductions are limited. They consist of the protein–tyrosine kinase dependent or independent Ras-ERK pathway, and the PI3K-Akt, JAK-STAT, SMAD, and NF-κB-activation pathways. In addition, biodegradation systems, such as the ubiquitin–proteasome pathway and autophagy, are also important for physiological and pathological conditions. If we can control signaling for each by a low-molecular-weight agent, it would be possible to treat diseases in new ways. At present, such cell signaling inhibitors are mainly looked for in plants, soil microorganisms, and the chemical library. The screening of bioactive metabolites from deep-sea organisms should be valuable because of the high incidence of finding novel compounds. Although it is still an emerging field, there are many successful examples, with new cell signaling inhibitors. In this review, we would like to explain the current view of the cell signaling systems important in diseases, and show the inhibitors found from deep-sea organisms, with their structures and biological activities. These inhibitors are possible candidates for anti-inflammatory agents, modulators of metabolic syndromes, antimicrobial agents, and anticancer agents.

GPR171 Activation Modulates Nociceptor Functions, Alleviating Pathologic Pain

Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, regarding the somatosensory nociceptor function. Here we report that GPR171, expressed in a nociceptor subpopulation, attenuated pain signals via Gi/o-coupled modulation of the activities of nociceptive ion channels when activated by its newly found ligands. Administration of its natural peptide ligand and a synthetic chemical ligand alleviated nociceptor-mediated acute pain aggravations and also relieved pathologic pain at nanomolar and micromolar ranges. This study suggests that functional alteration of the nociceptor neurons by GPR171 signaling results in pain alleviation and indicates that GPR171 is a promising molecular target for peripheral pain modulation.

Tug-of-war: molecular dynamometers against living cells for analyzing sub-piconewton interaction of specific protein with cell membrane

Protein-membrane interactions play important roles in signal transductions and functional regulation of membrane proteins. Here, we design a molecular dynamometer (MDM) for analyzing protein-membrane interaction on living cells. The MDM...

Pathological Maintenance and Evolution of Breast Cancer: The Convergence of Irreversible Biological Actions of ER Alpha

Estrogen receptor alpha (ERα) is a modulator of breast cancer maintenance and evolution. Hence, analysis of underlying mechanisms by which ERα operates is of importance for the improvement of the hormonal therapy of the disease. This review focuses on the irreversible character of the mechanism of action of ERα, which also concerns other members of the steroid hormones receptors family. ERα moves in permanence between targets localized especially at the chromatin level to accomplish gene transcriptions imposed by the estrogenic ligands and specific antagonists. Receptor association as at the plasma membrane, where it interacts with other recruitment sites, extends its regulatory potency to growth factors and related peptides through activation of signal transductions pathways. If the latter procedure is suitable for the transcriptions in which the receptor operates as a coregulator of another transcription factor, it is of marginal influence with regard to the direct estrogenic regulation procedure, especially in the context of the present review. Irreversibility of the successive steps of the underlying transcription cycle guarantees maintenance of homeostasis and evolution according to vital necessities. To justify this statement, reported data are essentially described in a holistic view rather than in the context of exhaustive analysis of a molecular event contributing to a specific function as well as in a complementary perspective to elaborate new therapeutic approaches with antagonistic potencies against those tumors promoting ERα properties.