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At least 307 records · Page 17Linked to original sources
PubMed2002

Modulating modulation: crosstalk between regulatory pathways of presynaptic calcium channels.

The activity of some voltage-gated calcium channels (VGCCs) can be inhibited by specific G protein beta subunits. Conversely, in the case of N-type VGCCs, protein kinase C can relieve Gbeta-dependent inhibition by phosphorylating at least one specific site on the calcium channel. A recent publication describes a newly identified method of intracellular regulation of specific VGCCs. Wu et al. have uncovered that VGCC activity can be regulated by phosphatidylinositol-4',5'-bisphosphate (PIP2). Whereas PIP2 is important for maintaining the activity (open state) of Cav2.1 (N-type) and Cav2.2 (P/Q-type) channels, the enzymatic breakdown of PIP2 leads to the inactivation of these channels. Additionally, PIP2 can cause changes in voltage-dependent activation of Cav2.2 (P/Q-type) channels that make it more difficult for these channels to open (from the closed state). Furthermore, protein kinase A activity can circumvent PIP2-mediated inhibition. Thus, the PIP2-mediated regulation of VGCCs is tightly controlled by the functions of kinases (and phosphatases), as well as phospholipases. Wu et al. stress that because PIP2 can be found at synapses, PIP2-dependent control of VGCCs "could have profound consequences on synaptic transmission and plasticity."

Animals↗
PubMed1973

Modulation of postural reflexes by voluntary movement. I. Modulation of the active limb.

Experiments were performed involving isometric activation/relaxation of the agonist-antagonist muscle groups about the ankle joint. It is shown that phasic changes of foot torque in the dorsal direction are associated with a transient inhibition of the soleus H-reflex which is independent of anterior tibial contraction. During phasic changes in foot torque in the plantar direction, facilitation, as opposed to disinhibition of the soleus H-reflex, is graded by soleus contraction. These results support the hypothesis that the sensitivity of the monosynaptic reflex arc is one of the controlled variables of the motor system. The stretch reflex of a shortening muscle is generally facilitated, while that of a lengthening muscle is inhibited. These hypotheses are in keeping with our present knowledge of the linkage between skeletomotor and fusimotor neurones for the organization of voluntary movements.

Ankle Joint↗
PubMed1973

Modulation of postural reflexes by voluntary movement. II. Modulation at an inactive joint.

We have observed that there is a brief, 400 msec period of widespread facilitation of both the Hoffmann and the tendon-jerk reflexes associated with the initiation of a variety of local, voluntary, isometric efforts. It is suggested that the site of this facilitation lies within the spinal cord. We have also observed that this period is followed, for the Hoffmann reflex, by a period of spinal inhibition. By contrast, the tendon-jerk is facilitated, at a reduced level, for at least another 500 msec by mechanisms probably working at the muscle spindle. These results are discussed in comparison with experiments involving activation of the reflex agonist and antagonist muscles. It is proposed that voluntary control of the locomotor system is organized through separate mechanisms for muscle recruitment and for regulation of the sensitivity of the myotatic reflex loop.

Ankle Joint↗
PubMed2002

Modulating the modulators: parasites, neuromodulators and host behavioral change.

Neuromodulators can resculpt neural circuits, giving an animal the behavioral flexibility it needs to survive in a complex changing world. This ability, however, provides parasites with a potential mechanism for manipulating host behavior. This paper reviews three invertebrate host-parasite systems to examine whether parasites can change host behavior by secreting neuromodulators. The parasitic wasp, Cotesia congregata, suppresses host feeding partly by inducing the host (Manduca sexta) to increase the octopamine concentration in its hemolymph. The increased octopamine concentration disrupts the motor pattern produced by the frontal ganglion, preventing the ingestion of food. Polymorphus paradoxus (Acanthocephalan) alters the escape behavior of its host, Gammarus lacustris (Crustacea), possibly through an effect on the host's serotonergic system. The trematode Trichobilharzia ocellata inhibits egg-laying in its snail host (Lymnaea stagnalis), partly by inducing the host to secrete schistosomin. Schistosomin decreases electrical excitability of the caudodorsal cells. The parasite also alters gene expression for some neuromodulators within the host's central nervous system. In at least two of these three examples, it appears that the host, not the parasite, produces the neuromodulators that alter host behavior. Producing physiologically potent concentrations of neuromodulators may be energetically expensive for many parasites. Parasites may exploit indirect less energetically expensive methods of altering host behavior. For example, parasites may induce the host's immune system to produce the appropriate neuromodulators. In many parasites, the ability to manipulate host behavior may have evolved from adaptations designed to circumvent the host's immune system. Immune-neural-behavioral connections may be pre-adapted for parasitic manipulation.

Animals↗
PubMed1997

Clinical application of biochemical modulation in cancer chemotherapy: biochemical modulation for 5-FU.

The addition of Uracil to Tegafur, a prodrug of 5-fluorouracil (5-FU), has been shown to enhance the antineoplastic effect of 5-FU while reducing the side effects attributed to 5-FU catabolism. Studies of 5-FU levels have shown that the 5-FU concentration in the tumor tissues of patients with head and neck cancer was 16.9 times greater than that in serum and approximately 2-6 times greater than in normal tissue. Similar observations have been made in tumor tissues of patients with breast cancer. The clinical efficacy of UFT, the combination of Uracil and Tegafur in a molar ratio of 4:1, has been studied in a variety of tumor types. An overall response rate of about 23% was obtained, with responses exceeding 30% in patients with head and neck, breast, and bladder cancer. Side effects are predominantly that of gastrointestinal toxicity. Hematologic toxicity is minimal and hepatotoxicity is rare. The UFT combination produces a good clinical effect in a variety of tumor types and is well tolerated.

Adolescent↗
PubMed1994

Modulating a modulator: biogenic amines at subthreshold levels potentiate peptide-mediated cardioexcitation of the heart of the tobacco hawkmoth Manduca sexta.

The central nervous system of the moth Manduca sexta contains a group of myoregulatory neuropeptides, the CAPs (Cardioacceleratory Peptides), which cause a physiologically important, dose-dependent increase in heart rate during wing inflation and flight in adult moths. We report here that the response of the adult heart to a subset of the CAPs, the CAP2S, is potentiated nearly twofold in the chronic presence of subthreshold levels of the biogenic amine octopamine or near-threshold levels of the biogenic amine serotonin. Subthreshold levels of the CAP2S fail to alter the response of the heart to octopamine. We have begun to investigate the molecular mechanisms underlying this potentiation. Previous work on the adult heart has shown that the CAP2s act through an inositol-1,4,5-trisphosphate second-messenger system. Here, we demonstrate that the cardioexcitatory effects of the two amines, in contrast to those of the CAP2S, are both mediated by cyclic AMP. Application to the heart of either 10(-5) moll-1 octopamine or 10(-6)moll-1 serotonin elicits a threefold increase in intracellular cyclic AMP levels. The CAP2S have no effect on cyclic AMP levels in the heart. These results illustrate a mechanism by which the effectiveness of a neurohormone can be increased with minimal cost to the animal. In Manduca sexta, subthreshold levels of octopamine are found in the haemolymph during wing inflation and flight. Thus, it is possible that octopamine up-regulates the effects of CAP2 via a cyclic-AMP-dependent mechanism during these activities.

Animals↗
PubMed2004

New developments on thromboxane and prostacyclin modulators part II: prostacyclin modulators.

Prostacyclin (PGI(2)) is a potent endogenous inhibitor of platelet function and possesses a strong vasodilator effect. Furthermore, prostacyclin is currently presented as the physiologic antagonist of thromboxane A(2)(TXA(2)), which exhibits pro-aggregatory and vasoconstrictor properties. So, the balance between PGI(2) and TXA(2) production is crucial for the cardiovascular system. Indeed, an imbalance in the production or effect of these products is deleterious for the circulatory system and can lead to characterized vascular diseases such as hypertension, stroke, atherosclerosis or myocardial infarction. Although the biological effects of PGI(2) are considered to be clinically useful, its use as therapeutic agent is largely limited by both its chemical and metabolic instability. Actually, several prostacyclin agonists have been synthesized and pharmacologically evaluated. Among these, some have been clinically evaluated as therapeutic agents in several vascular diseases. This review focuses on the latest chemical and pharmacological developments in the field of the prostacyclin agonists.

Cardiovascular System↗
PubMed2004

Down-modulation of heat shock protein 70 and up-modulation of Caspase-3 during schisandrin B-induced apoptosis in human hepatoma SMMC-7721 cells.

AIM: To investigate the effect of schisandrin B (Sch B) on proliferation and apoptosis of human hepatoma SMMC-7721 cells in vitro and regulation of Hsp70 and Caspases-3, 7, 9 expression by Sch B. METHODS: Human hepatoma cell line SMMC-7721 was cultured and treated with Sch B at various concentrations. Growth suppression was detected with MTT colorimetric assay. Cell apoptosis was confirmed by DNA ladder detection and flow cytometric analysis. The expression of Hsp70, Caspases-3, 7, 9 were analyzed by Western blot analysis. RESULTS: Sch B inhibited the growth of hepatoma SMMC-7721 cells in a dose-dependent manner, leading to a 50% decrease in cell number (LC50) value of 23.50 mg/L. Treatment with Sch B resulted in degradation of chromosomal DNA into small internucleosomal fragments, evidenced by the formation of a 180-200 bp DNA ladder on agarose gels. FCM analysis showed the peak areas of subdiploid at the increased concentration of Sch B. The results of Western bolt analysis showed that Hsp70 was down-regulated and Caspase-3 was up-regulated, while the activity of Caspases-7, -9 had no significant change. CONCLUSION: Sch B is able to inhibit the proliferation of human hepatoma SMMC-7721 cells and induce apoptosis, which goes through Caspase-3-dependent and Caspase-9-independent pathway accompanied with the down-regulation of Hsp70 protein expression at an early event.

Apoptosis↗
PubMed1992

Estrogen modulates Ca(2+)-independent lipid-stimulated kinase in the rabbit corpus luteum of pseudopregnancy. Identification of luteal estrogen-modulated lipid-stimulated kinase as protein kinase C delta.

Rabbit corpora lutea were tested for the presence of phosphorylative responses sensitive to estrogen. Luteal Ca(2+)-independent lipid-stimulated kinase activity was detected by phosphorylation of the endogenous substrate, p76. Estrogen treatment, by way of estradiol-17 beta implant, increased levels of the lipid-stimulated phosphoprotein 2-3-fold throughout pseudopregnancy. Midpseudopregnant rabbit luteal extracts were further evaluated to determine the identity of the lipid-stimulated kinase. Results of low pH-activated phosphorylation were consistent with the identification of p76 as an autophosphorylated member of the protein kinase C (PKC) family. Partial purification of the luteal lipid-stimulated kinase was performed using sequential DEAE-cellulose/hydroxylapatite chromatographies and using gel filtration. Western immunoblot with type-specific anti-PKC delta antiserum showed coelution of kinase p76 activity with immunoreactive PKC delta. Immunoblot analysis confirmed that luteal levels of PKC delta were increased by estrogen treatment.

Animals↗
PubMed1992

[Effects of modulators and cytostatics on catabolism of I-125 desoxyuridine in tumors (express-method of antineoplastic modulator screening)].

El-4 and P-815 murine tumor cells labelled by 125I-deoxyuridine or 51Cr were administered in 7-day subcutaneous syngeneic tumors or subcutaneously. At the same time different groups of mice were treated by LPS plus MDP, beta-C7H15-MDP, dexal-MDP, polyacrylamide-MDP-phosphatidylethanolamine, adriblastin or cyclophosphamide. It was shown that cytostatics and immunomodulators significantly delayed catabolism and withdrawing of 125I-deoxyuridine (that has not been incorporated in DNA) from tumor cells. This delay was correlated with the inhibition of tumor nodes growth rate. It is concluded that influence of cytostatics and immunomodulators on catabolism and withdrawing rate of 125I-deoxyuridine from tumor cells relates to their cytostatic effect and may be used at the earliest screening step of immunomodulator analysis.

Adjuvants, Immunologic↗