Intercellular Action Research Articles

Research progress of exosomes from different sources in myocardial ischemia.

Ischemic heart disease refers to the imbalance between the supply and demand of myocardial blood; it has various causes and results in a class of clinical diseases characterized by myocardial ischemia (MI). In recent years, the incidence of cardiovascular disease has become higher and higher, and the number of patients with ischemic heart disease has also increased year by year. Traditional treatment methods include drug therapy and surgical treatment, both of which have limitations. The former maybe develop risks of drug resistance and has more significant side effects, while the latter may damage blood vessels and risk infection. At this stage, a new cell-free treatment method needs to be explored. Many research results have shown that exosomes from different cell sources can protect the ischemic myocardium via intercellular action methods, such as promoting angiogenesis, inhibiting myocardial fibrosis, apoptosis and pyroptosis, and providing a new basis for the treatment of MI. In this review, we briefly introduce the formation and consequences of myocardial ischemia and the biology of exosomes, and then focus on the role and mechanism of exosomes from different sources in MI. We also discuss the role and mechanism of exosomes pretreated with Chinese and Western medicines on myocardial ischemia. We also discuss the potential of exosomes as diagnostic markers and therapeutic drug for MI.

Two pathways regulate insulin-like growth factor genes in the brain and liver of the tropical damselfish Chrysiptera cyanea: A possible role for melatonin in the actions of growth and thyroid hormones

External and internal factors are involved in controlling the growth of fishes. However, little is known about the mechanisms by which external factors trigger stimulus signals. This study explored the physiological roles of melatonin in the transcription of growth-related genes in the brain and liver of Chrysiptera cyanea, a tropical damselfish with long-day preference. In brain samples of this species collected at 4-h intervals, the transcript levels of arylalkylamine N-acetyltransferase2 (aanat2), the rate-limiting enzyme of melatonin synthesis, and growth hormone (gh) peaked at 20:00 and 00:00, respectively. Concomitantly, the transcript levels of insulin-like growth factors (igf1 and igf2) in the brain and liver were upregulated during the scotophase. Levels of iodothyronine deiodinases (dio2 and dio3), enzymes that convert thyroxine (T4) to triiodothyronine (T3) and reverse T3, respectively, increased in the brain (dio2 and dio3) and liver (dio2) during the photophase, whereas dio3 levels in the liver showed the opposite trend. Fish reared in melatonin-containing water exhibited significant increases in the transcription levels of gh and igf1 in the brain and igf1 in the liver, suggesting that growth in this fish is positively regulated by the GH/IGF pathway on a daily basis. Melatonin treatment also stimulated the transcript levels of dio2 and dio3 in the liver, but not in the brain. Fish consuming pellets containing T3, but not T4, showed significant increases in gh and igf1 in the brain and igf1 and igf2 in the liver, suggesting that the intercellular actions of the TH/IGF pathway have an impact on growth on a daily basis. In summary, IGF synthesis and action in the brain and liver undergo dual regulation by distinct hormone networks, which may also be affected by daily, seasonal, or nutritional factors.

Thyroid hormone- and estrogen receptor interactions with natural ligands and endocrine disruptors in the cerebellum.

Although the effects of phytoestrogens on brain function is widely unknown, they are often regarded as "natural" and thus as harmless. However, the effects of phytoestrogens or environmental pollutants on brain function is underestimated. Estrogen (17beta-estradiol, E2) and thyroid hormones (THs) play pivotal roles in brain development. In the mature brain, these hormones regulate metabolism on cellular and organismal levels. Thus, E2 and THs do not only regulate the energy metabolism of the entire organism, but simultaneously also regulate important homeostatic parameters of neurons and glia in the CNS. It is, therefore, obvious that the mechanisms through which these hormones exert their effects are pleiotropic and include both intra- and intercellular actions. These hormonal mechanisms are versatile, and the experimental investigation of simultaneous hormone-induced mechanisms is technically challenging. In addition, the normal physiological settings of metabolic parameters depend on a plethora of interactions of the steroid hormones. In this review, we discuss conceptual and experimental aspects of the gonadal and thyroid hormones as they relate to in vitro models of the cerebellum.

Communicating a Nobel Signal: Exploration of the Heterotrimeric G protein

Cells must sense a host of external signals to be responsive to features in the environment that are vital for survival. Evolutionary pressures have resulted in pathways that translate and amplify such signals into intercellular actions. Visual phototransduction, a model pathway, includes the transmembrane G‐protein‐coupled receptor (GPCR) rhodopsin, activated by light, and the G (guanine‐nucleotide‐binding) protein transducin that communicates to downstream proteins in the photoreceptor. The Blue Valley CAPS 2012–13 SMART Team (Students Modeling a Research Topic) modeled the heterotrimeric G protein transducin (1GOT.pdb) using JMol and their 3D printer. Transducin is composed of a Gα;, containing the GTPase domain, and Gβ; that contains a β‐propeller structure composed of seven similar β‐sheets and an N‐terminal helix that forms a coiled‐coil with one of Gγ two helices. Upon binding of transducin to an activated rhodopsin, GDP is released from Gα. Subsequent GTP binding to Gα causes conformational changes that result in the dissociation and activation of Gα and Gβγ. These separate subunits act upon targets in the downstream cascade resulting in hyperpolarization of the retinal photoreceptor, a sensation of light, and a greater awareness of the environment by the organism. Subsequent hydrolysis of bound GTP to GDP within Gα returns the protein to its inactive state. Supported by a grant from NIH‐SEPA.

Self-organized sorting of heterotypic agents via a chemotaxis paradigm

Cell sorting is a fundamental phenomenon in morphogenesis, a process that leads to shape formation in living organisms. The sorting of heterotypic cell populations is produced by a variety of inter-cellular actions, e.g. differential chemotactic response, adhesion, rigidity, and motility. Via a process called chemotaxis, living cells respond to chemicals released by other cells into the environment. Inspired by the biological phenomena of chemotaxis and cell sorting in heterotypic cell aggregates, we propose a chemotaxis-based algorithm that sorts self-organizing heterotypic agents. In our algorithm, two types of agents are initially randomly placed in a toroidal environment. Agents emit a chemical signal and interact with nearby agents. Given the appropriate parameters, the two kinds of agents self-organize into a complex aggregate consisting of a single group of one type of agent surrounded by agents of the second type. This paper describes the chemotaxis-based sorting algorithm, the behaviors of our self-organizing heterotypic agents, evaluation of the final aggregates and parametric studies of the algorithm.

A theory for the arrangement of sensory organs inDrosophila

We study the arrangements of recurved bristles on the anterior wing margin of wild-type and mutant Drosophila. The epidermal or neural fate of a proneural cell depends on the concentrations of proteins of the achaete-scute complex. At puparium formation, concentrations of proteins are nearly identical in all cells of the anterior wing and each cell has the potential for neural fate. In wild-type flies, the action of regulatory networks drives the initial state to one where a bristle grows out of every fifth cell. Recent experiments have shown that the frequency of recurved bristles can be made to change by adjusting the mean concentrations of the zinc-finger transcription factor Senseless and the micro-RNA miR-9a. Specifically, mutant flies with reduced levels of miR-9a exhibit ectopic bristles, and those with lower levels of both miR-9a and Senseless show regular organization of recurved bristles, but with a lower periodicity of 4. We argue that these characteristics can be explained assuming an underlying Turing-type bifurcation whereby a periodic pattern spontaneously emerges from a uniform background. However, bristle patterns occur in a discrete array of cells, and are not mediated by diffusion. We argue that intracellular actions of transmembrane proteins such as Delta and Notch can play a role of diffusion in destabilizing the homogeneous state. In contrast to diffusion, intercellular actions can be activating or inhibiting; further, there can be lateral cross-species interactions. We introduce a phenomenological model to study bristle arrangements and make several model-independent predictions that can be tested in experiments. In our theory, miRNA-9a is one of the components of the underlying network and has no special regulatory role. The loss of periodicity in its absence is due to the transfer of the system to a bistable state.

A LOGICAL CHARACTERIZATION OF ROBUSTNESS, MUTANTS AND SPECIES IN COLONIES OF AGENTS

We study a modelling framework and computational paradigm called Colonies of Synchronizing Agents (CSAs), which abstracts intracellular and intercellular mechanisms of biological tissues. The model is based on a multiset of agents (cells) in a common environment (a tissue). Each agent has a local contents, stored in the form of a multiset of atomic objects (e.g., representing molecules), updated by multiset rewriting rules which may act on individual agents (intracellular action) or synchronize the contents of pairs of agents (intercellular action). In this paper we investigate dynamic properties of CSAs, by means of temporal logic, and we give a logical characterization of some notions inspired by biology such as robustness, mutants and species. We reveal the relation that exists between the concept of robustness for CSAs and the bisimulation relation on colonies. We also present some decidability results for particular cases of robustness.

Modeling action potential generation and propagation in NRK fibroblasts.

Normal rat kidney (NRK) fibroblasts change their excitability properties through the various stages of cell proliferation. The present mathematical model has been developed to explain excitability of quiescent (serum deprived) NRK cells. It includes as cell membrane components, on the basis of patch-clamp experiments, an inwardly rectifying potassium conductance (G(Kir)), an L-type calcium conductance (G(CaL)), a leak conductance (G(leak)), an intracellular calcium-activated chloride conductance [G(Cl(Ca))], and a gap junctional conductance (G(gj)), coupling neighboring cells in a hexagonal pattern. This membrane model has been extended with simple intracellular calcium dynamics resulting from calcium entry via G(CaL) channels, intracellular buffering, and calcium extrusion. It reproduces excitability of single NRK cells and cell clusters and intercellular action potential (AP) propagation in NRK cell monolayers. Excitation can be evoked by electrical stimulation, external potassium-induced depolarization, or hormone-induced intracellular calcium release. Analysis shows the roles of the various ion channels in the ultralong ( approximately 30 s) NRK cell AP and reveals the particular role of intracellular calcium dynamics in this AP. We support our earlier conclusion that AP generation and propagation may act as a rapid mechanism for the propagation of intracellular calcium waves, thus contributing to fast intercellular calcium signaling. The present model serves as a starting point to further analyze excitability changes during contact inhibition and cell transformation.

Intercellular action of nitric oxide increases cGMP in cerebellar Purkinje cells.

cGMP is thought to play a role in cerebellar signalling yet its production within Purkinje cells has never been detected. In the present study, the hydrolysis of a fluorescent substrate analogue, 2'-O-anthranyloyl cyclic GMP, by type 5 phosphodiesterase was monitored within Purkinje cells in slices and in culture. Nitric oxide, either endogenously released from adjacent neurons or pharmacologically applied, accelerated the rate of hydrolysis in a manner that was dependent on soluble guanylyl cyclase, demonstrating that nitric oxide triggers cyclic GMP production in Purkinje cells, which in turn activates type 5 phosphodiesterase. We conclude that NO acts as an intercellular messenger in the cerebellar cortex and that parallel fibre terminals are a probable source of nitric oxide.

Structure, Activity, and Immune (T and B Cell) Recognition of Botulinum Neurotoxins

Botulism, which was first reported over a century ago, is caused by botulinum neurotoxins produced by Clostridium botulinum in seven immunological serotypes (A through G). The primary structures of a number of these BoNTs have been determined and are reviewed here, together with their gene structure and synthesis. The biological actions of BoNTs, which result in their ability to block neurotransmitter release have been the subject of intensive study, and in this review we discuss the binding of BoNTs to the cell surface as well as the mechanism of their intercellular action. The ability of BoNTs to block neurotransmitter release has been exploited in therapeutic applications to reduce muscle hyperactivity for the treatment of a variety of clinical conditions associated with involuntary muscle spasm and contractions. The advantages, limitations, and risks of these applications are discussed. Certain compounds provide some limited protection against BoNT. However, more effective protection has been obtained immunologically either by passive immunity (i.e., by administration of anti-BoNT Abs) or by immunization with inactivated toxin. More recently, excellent protection has been obtained by immunization with the receptor-binding region comprising the C-terminal (residues 860 to 1296) fragment (Hc) of the heavy chain of BoNT/A. Here we review the mapping of the epitopes on the Hc region of BoNT/A that are recognized by anti-BoNT/A Abs raised in horse, human, and mouse. The epitopes on the Hc that are recognized by anti-Hc Abs and by Hc-primed T lymphocytes were mapped in two mouse strains [BALB/c (H-2d) and SJL (H-2s)]. The peptides, which contain Ab or T cell epitopes (or both) on the Hc, were used as immunogens in BALB/c and SJL mice and we identified those peptides whose Ab and/or T-cell response cross-react with Hc. Identification of these peptides is an important first step in the intricate requirements for the design of a synthetic vaccine.

Autolysis of Lactococcus lactis caused by induced overproduction of its major autolysin, AcmA.

The optical density of a culture of lactococcus lactis MG1363 was reduced more than 60% during prolonged stationary phase. Reduction in optical density (autolysis) was almost absent in a culture of an isogenic mutant containing a deletion in the major autolysin gene, acmA. An acmA mutant carrying multiple coples of a plasmid encoding AcmA lysed to a greater extent than the wild-type strain did. Intercellular action of AcmA was shown by mixing end-exponential-phase cultures of an acmA deletion mutant and a tripeptidase (pepT) deletion mutant. PepT, produced by the acmA mutant, was detected in the supernatant of the mixed culture, but no PepT was present in the culture supernatant of the acmA mutant. A plasmid was constructed in which acmA, lacking its own promoter, was placed downstream of the inducible promoter/operator region of the temperate lactococcal bacteriophage r1t. After mitomycin induction of an exponential-phase culture of L. lactis LL302 carrying this plasmid, the cells became subject to autolysis, resulting in the release of intracellular proteins.

Phenotypic characterisation of rat striatal neurones in primary culture

The aim of this study was to determine to what extent the neuronal phenotypes present in primary cultures of rat striatal neurones correspond to those present in vivo. A large percentage of cultured striatal neurones contained relatively high levels of proenkephalin mRNA. In addition, a high level of expression was found for the prosomatostatin mRNA. Protachykinin mRNA and proneuropeptide Y mRNA were also expressed, but at a comparatively low level. No prodynorphin mRNA could be detected. Considerable numbers of neurones were also found to express NADPH-diaphorase activity, while a smaller number of neurones were positive for acetylcholinesterase. The NADPH-diaphorase and the acetylcholinesterase could be detected both in cell bodies, and in neuronal processes contacting groups of neighbouring neurones. Since nitric oxide does not require synaptic specialisations to exert its intercellular actions, this provides strong evidence that NADPH-positive neurones communicate with other cells in primary culture. These observations demonstrate that when striatal neurones are grown in primary culture, a range of neurochemical phenotypes are present which correspond closely to those present in the mature striatum in vivo. Together with the evidence for cell-cell interactions, this suggests that primary striatal cultures will provide a suitable model to study the molecular mechanisms controlling striatal function.

Intercellular action of nitric oxide in adult rat cerebellar slices

Nitric oxide (NO) is a novel messenger molecule that is produced following glutamate receptor activation and which stimulates cyclic GMP (cGMP) formation. To determine if the mode of action of NO is predominantly intra- or inter-cellular in intact brain tissue, we tested the ability of haemoglobin (Hb), a NO-binding protein that remains extracellular, to inhibit cGMP accumulation induced by glutamate receptor agonists in adult rat cerebellar slices. Responses to agonists acting selectively on N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors were inhibited by Hb (IC50 approximately 20 microM) suggesting that NO functions predominantly as a mediator of communication between cells. The effects of NO-donating drugs (e.g. nitroprusside) were also inhibited by Hb, implying that they yield NO extracellularly.

Considerations on the time factor in radiobiology.

Although extension of the time period during which a given dose of radiation is administered commonly reduces effectiveness, there are well established instances where the reverse is true. Theoretical considerations are presented which relate reduction or enhancement to the shape of the dose-effect curve. While in many instances these changes of sensitivity may be due to intracellular processes it appears that in the case of carcinogenesis by low doses of neutrons, time dependent intercellular action must be involved.