Sphingosylphosphorylcholine alleviates pressure overload-induced myocardial remodeling in mice via inhibiting CaM-JNK/p38 signaling pathway.

Apoptosis plays a critical role in the development of heart failure, and sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid naturally occurring in blood plasma. Some studies have shown that SPC inhibits hypoxia-induced apoptosis in myofibroblasts, the crucial non-muscle cells in the heart. Calmodulin (CaM) is a known SPC receptor. In this study we investigated the role of CaM in cardiomyocyte apoptosis in heart failure and the associated signaling pathways. Pressure overload was induced in mice by trans-aortic constriction (TAC) surgery. TAC mice were administered SPC (10 µM·kg-1·d-1) for 4 weeks post-surgery. We showed that SPC administration significantly improved survival rate and cardiac hypertrophy, and inhibited cardiac fibrosis in TAC mice. In neonatal mouse cardiomyocytes, treatment with SPC (10 µM) significantly inhibited Ang II-induced cardiomyocyte hypertrophy, fibroblast-to-myofibroblast transition and cell apoptosis accompanied by reduced Bax and phosphorylation levels of CaM, JNK and p38, as well as upregulated Bcl-2, a cardiomyocyte-protective protein. Thapsigargin (TG) could enhance CaM functions by increasing Ca2+ levels in cytoplasm. TG (3 µM) annulled the protective effect of SPC against Ang II-induced cardiomyocyte apoptosis. Furthermore, we demonstrated that SPC-mediated inhibition of cardiomyocyte apoptosis involved the regulation of p38 and JNK phosphorylation, which was downstream of CaM. These results offer new evidence for SPC regulation of cardiomyocyte apoptosis, potentially providing a new therapeutic target for cardiac remodeling following stress overload.

The Interaction of Mechanics and the Hippo Pathway in Drosophila melanogaster.

Drosophila melanogaster has emerged as an ideal system for studying the networks that control tissue development and homeostasis and, given the similarity of the pathways involved, controlled and uncontrolled growth in mammalian systems. The signaling pathways used in patterning the Drosophila wing disc are well known and result in the emergence of interaction of these pathways with the Hippo signaling pathway, which plays a central role in controlling cell proliferation and apoptosis. Mechanical effects are another major factor in the control of growth, but far less is known about how they exert their control. Herein, we develop a mathematical model that integrates the mechanical interactions between cells, which occur via adherens and tight junctions, with the intracellular actin network and the Hippo pathway so as to better understand cell-autonomous and non-autonomous control of growth in response to mechanical forces.

Immunomodulatory effects of vinegar-egg juice: Potential pharmacological effects of a traditional Chinese food remedy?

Thousands of years of historical practice have proven that the ancient Chinese food, vinegar-egg juice, has immune-boosting effects with the presence of many nutritional factors. However, its mechanism of action in the body remains unclear. In this research project, vinegar-egg juice was chosen to analyze its immune-enhancing effects on mice. The immune enhancing effects of egg, vinegar and vinegar egg juice on lymphocytes of mouse spleen were compared. The effects on immune function of mice were analyzed by studying the organ index, natural killer(NK) cell activity, lymphocyte transformation function and cytokine changes in immune organs after treatment with vinegar-egg juice. The mechanism of immune enhancement was speculated by analyzing the changes of total IKKα/ß/IκBα/NF-κB and its phosphorylated protein kinase by Western blot. Experiments have shown that vinegar and eggs have less immune regulation than vinegar-egg juice. Vinegar-egg juice can regulate the cellular and humoral immunity of spleen lymphocytes, increase the phosphorylated kinases of IKKα/ß, reduce the total protein expression of IκBα, and activate the signaling pathway of IKK/IκB/NF-κB. In addition, compared with the control group, vinegar-egg juice reduced the Firmicutes/Bacteroidetes ratio and increased the relative abundance of beneficial bacteria. Furthermore, vinegar-egg juice can raise phosphatidylserine (PS) and serotonin (5-HT) levels in the body. The results showed that the vinegar-egg juice had obvious immunomodulatory activity. It was speculated that the intake of vinegar-egg juice can increase the activity of NK cells, T lymphocytes and B lymphocytes by increasing 5-HT levels, ultimately enhancing the body's immune function. PRACTICAL APPLICATIONS: In this work, we evaluated the immune regulation of vinegar, egg and vinegar-egg juice in mice. In addition, we investigated the effects of vinegar-egg juice on gut microbiota. And combined with the composition of the vinegar-egg juice, it was found that the intake of vinegar-egg juice could increase the activity of NK cells, T lymphocytes and B lymphocytes by increasing 5-HT levels, ultimately enhancing the body's immune function. On the basis of the results of this study, we recommend vinegar-egg juice can be a potential health food to resist the epidemic and improve autoimmunity in special times of the novel coronavirus outbreak.

A mechanistic motor-clutch model that explains cell shape dynamics to cyclic stretch.

Many cells in the body experience cyclic mechanical loading, which can impact cellular processes and morphology. In vitro studies often report that cells reorient in response to cyclic stretch of their substrate. To explore cellular mechanisms involved in this reorientation, a computational model was developed by adapting previous computational models of the actin-myosin-integrin motor-clutch system developed by others. The computational model predicts that under most conditions, actin bundles align perpendicular to the direction of applied cyclic stretch, but under specific conditions, such as low substrate stiffness, actin bundles align parallel to the direction of stretch. The model also predicts that stretch frequency impacts the rate of reorientation and that proper myosin function is critical in the reorientation response. These computational predictions are consistent with reports from the literature and new experimental results presented here. The model suggests that the impact of different stretching conditions (stretch type, amplitude, frequency, substrate stiffness, etc.) on the direction of cell alignment can largely be understood by considering their impact on cell-substrate detachment events, specifically whether detachments preferentially occur during stretching or relaxing of the substrate.

A Random Walk Approach to Transport in Tissues and Complex Media: From Microscale Descriptions to Macroscale Models.

The biological processes necessary for the development and continued survival of any organism are often strongly influenced by the transport properties of various biologically active species. The transport phenomena involved vary over multiple temporal and spatial scales, from organism-level behaviors such as the search for food, to systemic processes such as the transport of oxygen from the lungs to distant organs, down to microscopic phenomena such as the stochastic movement of proteins in a cell. Each of these processes is influenced by many interrelated factors. Identifying which factors are the most important, and how they interact to determine the overall result is a problem of great importance and interest. Experimental observations are often fit to relatively simple models, but in reality the observations are the output of complicated functions of the physicochemical, topological, and geometrical properties of a given system. Herein we use multistate continuous-time random walks and generalized master equations to model transport processes involving spatial jumps, immobilization at defined sites, and stochastic internal state changes. The underlying spatial models, which are framed as graphs, may have different classes of nodes, and walkers may have internal states that are governed by a Markov process. A general form of the solutions, using Fourier-Laplace transforms and asymptotic analysis, is developed for several spatially infinite regular lattices in one and two spatial dimensions, and the theory is developed for the analysis of transport and internal state changes on general graphs. The goal in each case is to shed light on how experimentally observable macroscale transport coefficients can be explained in terms of microscale properties of the underlying processes. This work is motivated by problems arising in transport in biological tissues, but the results are applicable to a broad class of problems that arise in other applications.

Growth control in the Drosophila wing disk.

The regulation of size and shape is a fundamental requirement of biological development and has been a subject of scientific study for centuries, but we still lack an understanding of how organisms know when to stop growing. Imaginal wing disks of the fruit fly Drosophila melanogaster, which are precursors of the adult wings, are an archetypal tissue for studying growth control. The growth of the disks is dependent on many inter- and intra-organ factors such as morphogens, mechanical forces, nutrient levels, and hormones that influence gene expression and cell growth. Extracellular signals are transduced into gene-control signals via complex signal transduction networks, and since cells typically receive many different signals, a mechanism for integrating the signals is needed. Our understanding of the effect of morphogens on tissue-level growth regulation via individual pathways has increased significantly in the last half century, but our understanding of how multiple biochemical and mechanical signals are integrated to determine whether or not a cell decides to divide is still rudimentary. Numerous fundamental questions are involved in understanding the decision-making process, and here we review the major biochemical and mechanical pathways involved in disk development with a view toward providing a basis for beginning to understand how multiple signals can be integrated at the cell level, and how this translates into growth control at the level of the imaginal disk. This article is categorized under: Analytical and Computational Methods > Computational Methods Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Cellular Models.

A Model for the Hippo Pathway in the Drosophila Wing Disc.

Although significant progress has been made toward understanding morphogen-mediated patterning in development, control of the size and shape of tissues via local and global signaling is poorly understood. In particular, little is known about how cell-cell interactions are involved in the control of tissue size. The Hippo pathway in the Drosophila wing disc involves cell-cell interactions via cadherins, which lead to modulation of Yorkie, a cotranscriptional factor that affects control of the cell cycle and growth, and studies involving over- and underexpression of components of this pathway reveal conditions that lead to tissue over- or undergrowth. Here, we develop a mathematical model of the Hippo pathway that can qualitatively explain these observations, made in both whole-disc mutants and mutant-clone experiments. We find that a number of nonintuitive experimental results can be explained by subtle changes in the balances between inputs to the Hippo pathway and suggest some predictions that can be tested experimentally. We also show that certain components of the pathway are polarized at the single-cell level, which replicates observations of planar cell polarity. Because the signal transduction and growth control pathways are highly conserved between Drosophila and mammalian systems, the model we formulate can be used as a framework to guide future experimental work on the Hippo pathway in both Drosophila and mammalian systems.

Mathematical model with spatially uniform regulation explains long-range bidirectional transport of early endosomes in fungal hyphae.

In many cellular contexts, cargo is transported bidirectionally along microtubule bundles by dynein and kinesin-family motors. Upstream factors influence how individual cargoes are locally regulated, as well as how long-range transport is regulated at the whole-cell scale. Although the details of local, single-cargo bidirectional switching have been extensively studied, it remains to be elucidated how this results in cell-scale spatial organization. Here we develop a mathematical model of early endosome transport in Ustilago maydis. We demonstrate that spatiotemporally uniform regulation, with constant transition rates, results in cargo dynamics that is consistent with experimental data, including data from motor mutants. We find that microtubule arrays can be symmetric in plus-end distribution but asymmetric in binding-site distribution in a manner that affects cargo dynamics and that cargo can travel past microtubule ends in microtubule bundles. Our model makes several testable predictions, including secondary features of dynein and cargo distributions.

Quantitative diagnosis of salivary gland tumors with contrast-enhanced ultrasound--a preliminary study.

OBJECTIVE: To quantitatively analyze the value of qualitative diagnosis of salivary gland masses with contrast-enhanced ultrasound (CEUS). STUDY DESIGN: The enhanced sonographic features of 68 salivary gland masses were analyzed to differentiate them. The final diagnoses were confirmed by biopsy pathology. RESULTS: We observed from the perfusion kinetics of CEUS that most pleomorphic adenomas manifested lower enhancement and well-defined margins; most Warthin tumors presented with higher enhancement and well-defined margins; and most malignant tumors had higher enhancement and poorly defined margins. Their time-intensity curves showed pleomorphic adenomas were hypovascularized with a poor perfusion, whereas Warthin tumors and malignant tumors were hypervascularized with a rich perfusion. Additionally, malignant tumors showed significantly shortened time to peak and richer maximum signal intensity compared with Warthin tumors. CONCLUSIONS: The features of salivary gland masses identified with CEUS were helpful in the differential diagnosis of salivary gland masses.