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At least 1,117 records · Page 62Linked to original sources
PubMed2003

Pharmacological modulation of local feedback mechanisms as a therapeutic approach in breast cancer treatment.

Breast function and development are regulated by a network of local and systemic signals which can exert either stimulatory or inhibitory effects. Many of these signals are mediated by topically produced hormones and cytokines, which are both believed to be part of complex feedback loops. Over the last few years it has become increasingly clear that local feedback mechanisms also play an integral part in the growth and local invasion of malignant breast tumors. The intratumoral development of positive feedback loops can not only enhance the malignant phenotype and growth rate of tumor cells, but is also thought to stimulate the formation of vascular elements to ensure a sufficient supply of nutrients. In addition, the disruption of physiological negative feedback loops in breast tissue might result in the loss of cell cycle control and eventually lead to increased tumor growth and local breakdown of adjacent stroma. It is therefore not surprising that many of these loops involve interactions between tumor cells and their stromal environment, and are located at the site of tumor invasion. Since several of the potentially involved cytokines are already known and a number of specific inhibitors are now available, it is possible to interrupt pathological intercellular communication by selectively inhibiting intratumoral key feedback mechanisms. While the identification of each new intratumoral feedback loop can help us in our quest for for novel specific antineoplastic strategies, we now also know that some of the most commonly used endocrine therapies are probably so effective because they also interfere with local intercellular communication.

Breast Neoplasms↗
PubMed2006

A novel N14Y mutation in Connexin26 in keratitis-ichthyosis-deafness syndrome: analyses of altered gap junctional communication and molecular structure of N terminus of mutated Connexin26.

Connexins (Cxs) are transmembranous proteins that connect adjacent cells via channels known as gap junctions. The N-terminal 21 amino acids of Cx26 are located at the cytoplasmic side of the channel pore and are thought to be essential for the regulation of channel selectivity. We have found a novel mutation, N14Y, in the N-terminal domain of Cx26 in a case of keratitis-ichthyosis-deafness syndrome. Reduced gap junctional intercellular communication was observed in the patient's keratinocytes by the dye transfer assay using scrape-loading methods. The effect of this mutation on molecular structure was investigated using synthetic N-terminal peptides from both wild-type and mutated Cx26. Two-dimensional (1)H nuclear magnetic resonance and circular dichroism measurements demonstrated that the secondary structures of these two model peptides are similar to each other. However, several novel nuclear Overhauser effect signals appeared in the N14Y mutant, and the secondary structure of the mutant peptide was more susceptible to induction of 2,2,2-trifluoroethanol than wild type. Thus, it is likely that the N14Y mutation induces a change in local structural flexibility of the N-terminal domain, which is important for exerting the activity of the channel function, resulting in impaired gap junctional intercellular communication.

3T3 Cells↗
PubMed2005

Systems modeling: a pathway to drug discovery.

Systems modeling is emerging as a valuable tool in therapeutics. This is seen by the increasing use of clinically relevant computational models and a rise in systems biology companies working with the pharmaceutical industry. Systems models have helped understand the effects of pharmacological intervention at receptor, intracellular and intercellular communication stages of cell signaling. For instance, angiogenesis models at the ligand-receptor interaction level have suggested explanations for the failure of therapies for cardiovascular disease. Intracellular models of myeloma signaling have been used to explore alternative drug targets and treatment schedules. Finally, modeling has suggested novel approaches to treating disorders of intercellular communication, such as diabetes. Systems modeling can thus fill an important niche in therapeutics by making drug discovery a faster and more systematic process.

Animals↗
PubMed1988

Inhibition of metabolic cooperation in vitro and enhancement of enzyme altered foci incidence in rat liver by the pyrethroid insecticide fenvalerate.

The synthetic pyrethroids cypermethrin, delta-methrin, fenvalerate, permethrin, and the fenvalerate metabolite p-chlorophenylisovaleric acid were investigated for inhibition of gap-junctional intercellular communication in vitro in the Chinese hamster lung fibroblast (V79) metabolic cooperation assay. Fenvalerate was furthermore studied for enhancement of gamma-glutamyl transpeptidase-positive enzyme altered foci incidence in partially hepatectomized, nitrosodiethylamine-initiated male Sprague Dawley rats. The in vitro studies showed that fenvalerate and p-chlorophenylisovaleric acid were inhibitors of intercellular communication at non-cytotoxic concentrations while cypermethrin, deltamethrin, and permethrin were inactive. In the in vivo study in rat liver, fenvalerate administered p.o. (75 mg/kg/day) 5 days a week for 10 weeks induced significantly more foci per cm3 and a larger percentage of liver tissue occupied by foci tissue compared to a vehicle control group. Analysis of size distributions of foci in fenvalerate- and vehicle-treated rats showed elevated foci incidences in fenvalerate-treated rats at all foci sizes. Fenvalerate induced no hepatotoxic effects as judged by plasma transaminase activities and histopathology. The results of this study suggest fenvalerate to be a potential tumour promoter.

Animals↗
PubMed2001

Sotalol: the mechanism of its antiarrhythmic-defibrillating effect.

This minireview deals with the role of intercellular communication and synchronization in the initiation and maintenance of ventricular fibrillation. It is proposed that myocardial cell junctions might represent a therapeutic substrate for the prevention of this fatal arrhythmia. This hypothesis is supported by the results of recent experimental studies involving elucidation of the mechanism of antiarrhythmic-defibrillating effects of sotalol. Enhancement of intercellular communication and myocardial synchronization are thought to play critical role in the mechanism of action of this drug.

Adrenergic beta-Antagonists↗
PubMed2000

Molecular recognition of disease at natural killer cell immune synapses.

An emerging theme in contemporary molecular immunology is that a knowledge of protein structures and the physical chemistry of soluble receptor/ligand pairs is insufficient to predict the outcome of intercellular communication. Cell surface receptors need to be considered as part of supramolecular complexes of proteins and lipids that facilitate specific receptor conformations and distinct distributions at cell surfaces. As cells of the immune system survey other cells for signatures of disease, proteins accumulate and organise in distinct patterns at the contact regions between the cells. The intercellular organisation of proteins by which a cell's state of health is relayed has been termed the immune or immunological synapse. That different arrangements of segregated protein domains can occur at immune synapses raises a number of important questions. For example does supramolecular organisation of the synapse influence the outcome of the intercellular communication and how is the organisation of protein at immune synapses biophysically controlled?

Antibody Formation↗
PubMed2003

Suicide gene therapy with Herpes simplex virus thymidine kinase and ganciclovir is enhanced with connexins to improve gap junctions and bystander effects.

Connexins are proteins that form gap junctions between cells in various mammalian tissues. Because of their role in intercellular communication, connexins are important in the bystander cell death seen in Herpes simplex virus-thymidine kinase (HSV-TK) gene therapy for brain tumors. A selective review of connexin transduction/transfection studies with particular emphasis to central nervous system tumor cells is presented. In addition, specific references to studies with cell types that demonstrate low gap junction intercellular communication are presented. Data are included with the HT-29 colorectal tumor cell line to support the concept that enhancing gap junction protein expression in otherwise low gap junction communicating HT-29 cells increases bystander cell death and reduces tumor burden beyond what might be expected from HSV-TK and ganciclovir (GCV) treatment alone. Maximum in vitro bystander cell death was always produced when GCV treated co-cultures of TK-transduced and non-TK-transduced HT-29 cell lines were also transduced with connexin-43. When connexin was present in only one group of cells in the co-culture, there was more bystander cell death observed with connexin transduced into the non-TK-transduced cells, rather than the TK-transduced cells. The data presented reinforces conclusions made from earlier findings from cell line mixing experiments in which the non-TK-transduced cell population determined the level of bystander cell death (Burrows et al., 2002).

Animals↗
PubMed2002

Nitric oxide drives skin repair: novel functions of an established mediator.

Wound healing of the skin represents a highly ordered process of important tissue movements that aims for a rapid closure of the wound site and a subsequent regeneration of the injured tissue. The factors ensuring the intercellular communication during repair are only known in part. However, although protein-type mediators are well-established players in this process, it has become evident that the diffusible, gaseous molecule nitric oxide (NO) participates in the orchestration of wound healing. The role of wound-derived NO that critically influences macrophage, fibroblast, and keratinocyte behaviour within the intercellular communication network during repair is subject of this review. Thus, cutaneous wound healing prototypically reflects processes that generally occur also in kidney injury and regeneration.

Arginine↗
PubMed1998

Cell-cell communication in carcinogenesis.

To explain the complex carcinogenic process by which a single normal cell in human beings can be converted to an invasive and metastatic cancer cell, a number of experimental findings, epidemiological observations and their associated hypothesis/theories have been integrated in this review. All cancers have been generally viewed as the result of a disruption of the homeostatic regulation of a cell's ability to respond appropriately to extra-cellular signals of the body which trigger intra-cellular signal transducting mechanisms which modulate gap junctional intercellular communication between the cells within a tissue. Normal homeostatic control of these three forms of cell communication determines whether: (a) the cell remains quiescent (Go); (b) enters into the cell proliferation phase; (c) is induced to differentiate; (d) is committed to apoptose; or (e) if it is already differentiated, it can adaptively respond. During the evolution from single cell organisms to multicellular organisms, new cellular/biological functions appeared, namely, the control of cell proliferation ("contact inhibition"), the appearance of the process of differentiation from committed stem cells of the various tissues and the need for programmed cell death or apoptosis. Interestingly, cancer cells have been characterized as cells: (a) having been derived from a stem-like cell; (b) without their ability to control cell growth or without the ability to contact inhibit; (c) which can not terminally differentiate under normal conditions; and (d) having altered ability to apoptosis under normal conditions. During that evolutionary transition from the single cell organism to the multicellular organism, many new genes appeared to accompany these new cellular functions. One of these new genes was the gene coding for a membrane associated protein channel (the gap junction) which between coupled cells, allowed the passive transfer on ions and small molecular weight molecules. A family of over a dozen of these highly evolutionarily-conserved genes (the connexin genes) coded for the connexin proteins. A hexameric unit of these connexins in one cell (a connexon) couples with a corresponding connexon in a contiguous cell to join the cytoplasms. This serves to synchronize either the metabolic or electrotonic functions of cells within a tissue. Most normal cells within solid tissues have functional gap junctional intercellular communication (GJIC) (exceptions are free-standing cells such as red blood cells, neutrophils, and several, if not all, the stem cells). On the other hand, the cancer cells of solid tissues appear to have either dysfunctional homologous or heterologous GJIC. Therefore, among the many differences between a cancer cell and its normal parental cell, the carcinogenic process involves the transition from a normal, GJIC-competent cell to one that is defective in GJIC. The review examines how GJIC can be either transiently or stably modulated by endogenous or exogenesis chemicals or by oncogenes and tumor suppressor genes at the transcriptional, translational, or posttranslational levels. It also uses the gap junction as the biological structure to facilitate cellular/tissue homeostasis to be the integrator for the "stem cell" theory, "disease of differentiation theory", "initiation/promotion/progression" concepts, nature and nurture concept of carcinogenesis, the mutation/ epigenetic theories of carcinogenesis, and the oncogene/ tumor suppressor gene theories of carcinogenesis. From this background, implications to cancer prevention and cancer therapy are generated.

Cell Communication↗
PubMed1999

[Effect of ATP on malignant phenotype of a human gastric cancer cell line].

OBJECTIVE: To study the effect of ATP on proliferation and differentiation of a human gastric cancer cell line. METHODS: M17, a subclone of human gastric cancer cell line MGC-803, was treated in vitro with ATP(0.23 mg/ml). After 48 hr, the following parameters were examined. (1) Proliferation of cells by daily cell counting. (2) Microvilli of the cells were observed by scanning EM. (3) Gap junction intercellular communication was examined by mechanical scraping and Lucifer dye transfer. (4) Microfilament of the cytoskeleton was studied with fluorescin-labeled phalloidin. (5) Vinculin adhesion plague was stained immunocytochemically with monoclonal antibodies. RESULTS: ATP significantly inhibited the in vitro growth of M17 cells. The ATP-treated M17 cells showed disappearance of microvilli on the cell surface, increased gap junction intercellular communication, improved organization of microfilament bundles and reappearance of vinculin adhesion plagues. CONCLUSION: ATP not only inhibits proliferation but also induces differentiation of a human gastric cancer cell line with reversion from malignant toward normal phenotype. The parameters examined could serve as useful biomarkers of human gastric cancer.

Actin Cytoskeleton↗
PubMed1999

Carcinogenesis and the plasma membrane.

Presented is a two-stage hypothesis of carcinogenesis based on: (1) plasma membrane defects that produce abnormal electron and proton efflux; and (2) electrical uncoupling of cells through loss of intercellular communication. These changes can be induced by a wide variety of stimuli including chemical carcinogens, oncoviruses, inherited and/or acquired genetic defects, and epigenetic abnormalities. The resulting loss of electron/proton homeostasis leads to decreased transmembrane potential, electrical microenvironment alterations, decreased extracellular pH, and increased intracellular pH. This produces a positive feedback loop to enhance and sustain the proton/electron efflux and loss of intercellular communication. Low transmembrane potential is functionally related to rapid cell cycling, changes in membrane structure, and malignancy. Intracellular alkalinization affects a variety of pH-sensitive systems including glycolysis, DNA synthesis, DNA transcription and DNA repair, and promotes genetic instability, accounting for the accumulation of genetic defects seen in malignancy. The abnormal microenvironment results in the selective survival and proliferation of malignant cells at the expense of contiguous normal cell populations.

Animals↗
PubMed1988

Specific viral oncogenes cause differential effects on cell-to-cell communication, relevant to the suppression of the transformed phenotype by normal cells.

We have studied growth regulation in mixed cultures of normal and oncogene-transformed 3T3 cells. The NIH 3T3 cells transformed by myc, src, and ras showed comparable cloning efficiency in semisolid medium. However, when they were plated on plastic with an excess of normal mouse embryo fibroblasts, BALB/c 3T3 ClA31-1-1, ras- and src-transformed cells were able to form distinct foci on the layer of density-arrested normal cells, whereas myc-transformed cells lacked this ability. In order to determine whether suppression or expression of the transformed phenotype could be correlated with the ability of the different cell populations to communicate, gap-junctional intercellular communication (IC) was measured by the Lucifer yellow dye transfer assay in coculture of normal and transformed cells. The dye was observed to spread from BALB/c 3T3 to myc-NIH 3T3 cells, indicating the presence of IC between these two cell types. In contrast no passage of Lucifer yellow was observed between src-NIH 3T3 or ras-NIH 3T3 and BALB/c 3T3. Addition of a phorbol ester tumor promoter, phorbol-12,13-didecanoate, efficiently rescued proliferation and focus formation by myc-transformed cells. The tumor promoter was able to inhibit IC in BALB/c 3T3 cells, although this response greatly varied among the different oncogene transformed clones. Tumorigenicity in nude mice strongly correlated with growth behavior in vitro: myc-transformed cells were either nontumorigenic or slowly tumorigenic, and src- and ras-transformed cells were highly tumorigenic. These data suggest an important role of IC in modulating abnormal growth behavior in vitro and in vivo.

Animals↗
PubMed2006

Experimental diabetes alters connexin43 derived gap junction permeability in short-term cultures of rat corporeal vascular smooth muscle cells.

PURPOSE: Intercellular communication through gap junctions was assessed in 8 to 10-week STZ diabetic rats to evaluate diabetes related effects on gap junctional conductance and permeability in short-term cultures of corporeal myocytes. MATERIALS AND METHODS: Rats were made diabetic by a single intraperitoneal injection of STZ. Eight to 10 weeks later erectile function was evaluated in vivo and corporeal tissue was harvested to isolate corporeal myocytes. Dual whole cell patch clamp studies of intercellular communication through connexin43 (Cx43) derived gap junction channels were done in short-term, ie passages 0 to 2, cultured corporeal myocytes excised from STZ diabetic rats with documented erectile impairment as well as in myocytes from age matched control rats. RESULTS: No differences in macroscopic junctional conductance, single channel conductance or open probability were detected between myocytes from age matched control and STZ diabetic rats, confirming the lack of diabetes related alterations in Cx43 gating or conductance. However, fluorescence dye transfer experiments revealed a marked 3-fold increase in Cx43 mediated junctional permeability in the absence of any detectable change in Cx43 protein expression. CONCLUSIONS: These data suggest that an alteration in the selectivity filter of Cx43 in diabetic animals affects the permeability of specifically sized and charged solutes. To our knowledge these studies provide the first evidence of a diabetes related increase in intercellular permselectivity in corporeal myocytes and, thus, they may have important implications for diabetes related erectile dysfunction.

Animals↗
PubMed1981

Intercellular junctions between femoral arterial smooth muscle cells of renal hypertensive rats.

Vascular smooth muscle from femoral arteries of hypertensive rats contract autorhythmically in vitro, whereas medial smooth muscle cells from normotensive animals are normally quiescent. This behavior suggests improved intercellular communication that permits pacemakers to control large numbers of cells. We used a transmission electron microscope to search for structural evidence of such change. In the medial arterial tissue of hypertensive rats, we found pedishaped projections extending from one cell and forming a close apposition with the smooth muscle surface of a neighboring cell. Comparable structures were not found in the normotensive controls. However, numerous other forms of close appositions were found in the tissues from the hypertensive and normotensive rats. The presence of the unique pedishaped projections in the hypertensive tissue suggest a physical means of intercellular communication permitting enhanced pacemaker influence. Perhaps these projections are formed in response to the hormonal environment seen prior to and during renal hypertension.

Animals↗
PubMed2000

Growth regulation of astrocytes and C6 cells by TGFbeta1: correlation with gap junctions.

Transforming growth factor (TGF) beta1 enhanced in vitro [3H]thymidine incorporation into C6 cells and reduced that of astrocytes in the presence of a high serum concentration. It concomitantly raised the gap junction intercellular communication (GJIC) in normal astrocytes but reduced the coupling of C6 cells, and respectively increased or decreased the proportion of P2-phosphorylated connexin (Cx) 43 isoform in these cells. Finally, octanol, which inhibited GJIC in both cell types, increased the thymidine incorporation in C6 cells, but neither altered the proliferation of astrocytes nor their response to TGFbeta1. These data indicate that an inhibition of gap junction intercellular communication, due to an altered phosphorylation of connexin 43, may contribute to the proliferative response of C6 glioblastoma cells to TGFbeta1.

Animals↗
PubMed1999

Identification of connexins in human oral mucosa and therapeutic effect of irsogladine maleate on aphthous stomatitis.

We identified connexins 26 and 32 in human oral mucosa. The presence of the connexins indicates the presence of gap junctions in this tissue. However, immunofluorescence study found no significant differences in the expression of the connexins between patients with aphthons stomatitis and controls. Irsogladine maleate, which reinforces gap junctional intercellular communication in vitro, was effective for the treatment of transient and relapsing aphthous stomatitis, as well as symptomatic and drug-induced aphthous stomatitis. It was also useful for prevention of episodes of relapsing aphthous stomatitis, with daily administration preverting recurrence of stomatitis for more than 4 years one patient. These findings suggest that irsogladine maleate accelerates the wound healing process in oral mucosa by reinforcing gap junctional intercellular communication among oral mucosal cells; and that it is useful for the treatment and prevention of aphthous stomatitis.

Adult↗
PubMed2001

Effects and neuro-toxic mechanisms of 2, 2', 4, 4', 5, 5'-hexachlorobiphenyl and endosulfan in neuronal stem cells.

Endocrine disrupters are exogenous compounds thought to mimic the action of estrogen or other hormones and influence endocrine activity in the body (Juberg, 2000). These chemicals have adverse effects not only in the reproductive system but also in the central nervous system during development and throughout life. Polychlorinated biphenyls (PCBs) are a class of environmentally persistent and widespread halogenated hydrocarbons. It has been reported that PCBs are potential neurotoxicants. Endosulfan is an organochlorine insecticide that is extensively used to control pests in vegetables, cotton, and fruits. To determine the effect of 2, 2', 4, 4', 5, 5',-hexachlorobiphenyl(2, 4, 5-HCB) and endosulfan on embryo nervous system, we isolated neural stem cells from rat brain at embryonic day 17. Isolated neural stem cells showed pluripotenty. Stem cells could differentiate into neurons and glia. Neurite formation in endosulfan and 2, 4, 5-HCB treated cells. And it appeared to be decreased as compared with that in untreated cells. In order to know the neuro-toxic mechanisms of 2, 4, 5-HCB and endosulfan in neuronal stem cells, we investigated mitogen-activated protein kinase activity (MAPK) and gap junctional intercellular communication (GJIC). Endosulfan decreased the MAPK activity in dose dependent manner. Endosulfan and 2, 4, 5-HCB inhibited GJIC compared to the untreated cell by scrape loading dye transfer (SL/DT). 2, 4, 5-HCB and endosulfan decreased the expression of connexin 43 in dose dependent manner. These results indicated that 2, 4, 5-HCB and endosulfan may inhibit differentiation and proliferation of neural stem cells and gap junctional intercellular communication which play a crucial role in the maintenance of cellular homeostasis.

Animals↗
PubMed1999

Gap junctional communication and regulation of the glycogenic response to insulin by cell density and glucocorticoids in cultured fetal rat hepatocytes.

Cell culture studies have revealed that metabolic functions of the adult hepatocyte are related to cell density. Development of the glycogenic response to insulin under glucocorticoid control was investigated in 15- and 18-day-old fetal rat hepatocytes plated at different cell densities. After culturing for 48 hours with glucocorticoids, the stimulatory effect of insulin on [14C]glucose incorporation into glycogen after 3 hours progressed from weak response (less than 1.4-fold) in sparse cultures to a maximal response in dense ones (3.0- to 4.5-fold), depending on the fetal stage. The response was always no more than 2.0-fold in the absence of glucocorticoids, even with dense cultures. Such a dual regulation pattern was not found for the glycogenolytic effect of glucagon similarly expressed regardless of culture conditions. When cells were clustered in limited circular regions of the dish, the insulin response was higher than for sparse cultures for a similar number of cells per culture. Using the scrape-loading technique with Lucifer Yellow CH, a positive dye transfer was obtained in clustered cultures providing that they were grown in the presence of glucocorticoids; insulin as well as glucagon stimulated twofold intercellular communication. Connexin32 (Cx32) and connexin26 (Cx26) protein levels were assayed by Western immunoblotting and developed according to age and exposure to glucocorticoids. Thus, glucocorticoids through development of gap junctions enabled establishment of intercellular communication that could be stimulated by insulin and glucagon in cultured fetal hepatocytes. Gap junction functioning and the biologic effect of insulin correlated closely.

Animals↗