β3 Receptor Signaling in Pregnant Human Myometrium Suggests a Role for β3 Agonists as Tocolytics.

Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. At the present time, nothing can reliably halt labor once it begins. The knowledge that agonists of the β2 adrenergic receptor relax airway smooth muscle and are effective in the treatment of asthma led to the notion that β2 mimetics would prevent preterm birth by relaxing uterine smooth muscle.

β3 adrenergic receptor activation modulates connexin 43 activity to relax human myometrium.

Preterm labor, delivery prior to 37 completed weeks of gestation, is the leading cause of infant morbidity and mortality. β3 adrenergic receptor protein expression is increased in the myometrium during pregnancy, and the agonist, mirabegron, relaxes the myometrium making the β3 adrenergic receptor a potential therapeutic target in PTL. β3 adrenergic receptor has been shown to activate the tyrosine kinase, Src, which can down regulate connexin 43, a contractile associated protein which promotes the formation of gap junctions that create an electrical syncytium.

Novel identification and modulation of the mechanosensitive Piezo1 channel in human myometrium.

Approximately 10% of US births deliver preterm before 37 weeks of completed gestation. Premature infants are at risk for life-long debilitating morbidities and death, and spontaneous preterm labour explains 50% of preterm births. In all cases existing treatments are ineffective, and none are FDA approved.

Evolution of Medical Approaches and Prominent Therapies in Breast Cancer.

An examination of the origins of medical approaches to breast cancer marks this disease as one of the most difficult to manage. As the early identification, diagnosis and treatment of breast cancer evolve, we will move to a time when each patient and their cancer can be assessed to determine unique patient-specific (personalized) approaches to therapy. Humans have attempted to manage breast cancer for millennia.

Title: β3 Adrenergic Receptor Signaling in the Human Myometrium.

Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. Although β2 adrenergic agonists fail to provide adequate tocolysis, the expression of the β3 adrenergic receptor in myometrium and its unique signaling suggest a role for β3 agonist in the management of preterm labor. Western blot analysis showed that the β3 adrenergic receptor expression increased in human pregnancy myometrium compared to nonpregnant tissues (p < 0.

Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer.

Metastasis accounts for over 90% of cancer-related deaths, yet the mechanisms guiding this process remain unclear. Secreted nucleoside diphosphate kinase A and B (NDPK) support breast cancer metastasis. Proteomic evidence confirms their presence in breast cancer-derived extracellular vesicles (EVs).

Novel Tocolytic Strategy: Modulating Cx43 Activity by -Nitrosation.

Currently available tocolytics are ineffective at significantly delaying preterm birth. This is due in part to our failure to better understand the mechanisms that drive spontaneous preterm labor (sPTL). Cyclic nucleotides are not the primary contributors to myometrial quiescence, but instead nitric oxide (NO)-mediated protein -nitrosation (SNO) is integral to the relaxation of the tissue.

NF-κB/NKILA signaling modulates the anti-cancerous effects of EZH2 inhibition.

A wealth of evidence supports the broad therapeutic potential of NF-κB and EZH2 inhibitors as adjuvants for breast cancer treatment. We contribute to this knowledge by elucidating, for the first time, unique regulatory crosstalk between EZH2, NF-κB and the NF-κB interacting long non-coding RNA (NKILA). We define a novel signaling loop encompassing canonical and non-canonical actions of EZH2 on the regulation of NF-κB/NKILA homeostasis, with relevance to breast cancer treatment.

Hiding in Plain Sight: Nebivolol Exhibits Compelling Tocolytic Properties.

Preterm birth before 37 weeks of completed gestation results in numerous health consequences for the foetus. Preterm labour leads to preterm birth in over 50% of cases, and no FDA-approved treatment can prevent labour or help a foetus remain in the womb until term. Examination of nitric oxide mediated relaxation signaling in the uterine smooth muscle reveals a role for protein S-nitrosation.

Mechanical strain induced phospho-proteomic signaling in uterine smooth muscle cells.

Mechanical strain associated with the expanding uterus correlates with increased preterm birth rates. Mechanical signals result in a cascading network of protein phosphorylation events. These signals direct cellular activities and may lead to changes in contractile phenotype and calcium signaling.

S-Nitrosoglutathione Reductase Underlies the Dysfunctional Relaxation to Nitric Oxide in Preterm Labor.

Tocolytics show limited efficacy to prevent preterm delivery. In uterine smooth muscle cGMP accumulation following addition of nitric oxide (NO) has little effect on relaxation suggesting a role for protein S-nitrosation. In human myometrial tissues from women in labor at term (TL), or spontaneously in labor preterm (sPTL), direct stimulation of soluble guanylyl cyclase (sGC) fails to relax myometrium, while the same treatment relaxes vascular smooth muscle completely.

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy.

S-nitrosoglutathione reductase (GSNOR), or ADH5, is an enzyme in the alcohol dehydrogenase (ADH) family. It is unique when compared to other ADH enzymes in that primary short-chain alcohols are not its principle substrate. GSNOR metabolizes S-nitrosoglutathione (GSNO), S-hydroxymethylglutathione (the spontaneous adduct of formaldehyde and glutathione), and some alcohols.

Proteomic network analysis of human uterine smooth muscle in pregnancy, labor, and preterm labor.

The molecular mechanisms involved in human uterine quiescence during gestation and the induction of labor at term or preterm are not completely known. Preterm delivery is associated with major morbidity and mortality and current efforts to prevent delivery until term are largely ineffective. Identification and semi-quantification of proteomic changes in uterine smooth muscle during pregnancy will allow for targeted research into how quiescence is maintained and what changes are associated with induction of labor.

Blockade of extracellular NM23 or its endothelial target slows breast cancer growth and metastasis.

Background: Nucleoside Diphosphate Kinase (NDPK), described as NM23 a metastasis suppressor, is found in the culture medium of cancer cells lines suggesting that the kinase may have an extracellular role. We propose that extracellular NM23 released from breast cancers stimulates tumor cell migration, proliferation and endothelial cell angiogenesis in support of metastasis development.

Methods: NM23 in the bloodstream of immunocompromised mice carrying human triple-negative breast cancers or in breast cancer patients was measured by ELISA.

Alternatively Spliced Human TREK-1 Variants Alter TREK-1 Channel Function and Localization.

TREK-1, an outward-rectifying potassium channel activated by stretch, is found in the myometrium of pregnant women. Decreased expression of TREK-1 near term suggests that TREK-1 may contribute to uterine quiescence during gestation. Five alternatively spliced TREK-1 variants were identified in the myometrium of mothers who delivered spontaneously preterm (<37 wk), leading to the hypothesis that these TREK-1 variants could interfere with TREK-1 function or expression.

LC/MS/MS data analysis of the human uterine smooth muscle S-nitrosoproteome fingerprint in pregnancy, labor, and preterm labor.

The data described in this article is the subject of an article in the American Journal of Physiology: Cell Physiology, titled "The Human Uterine Smooth Muscle S-nitrosoproteome Fingerprint in Pregnancy, Labor, and Preterm Labor" (doi:10.1152/ajpcell.00198.

The human uterine smooth muscle S-nitrosoproteome fingerprint in pregnancy, labor, and preterm labor.

Molecular mechanisms involved in uterine quiescence during gestation and those responsible for induction of labor at term are incompletely known. More than 10% of babies born worldwide are premature and 1,000,000 die annually. Preterm labor results in preterm delivery in 50% of cases in the United States explaining 75% of fetal morbidity and mortality.

TREK-1 currents in smooth muscle cells from pregnant human myometrium.

The mechanisms governing maintenance of quiescence during pregnancy remain largely unknown. The current study characterizes a stretch-activated, tetraethylammonium-insensitive K(+) current in smooth muscle cells isolated from pregnant human myometrium. This study hypothesizes that these K(+) currents can be attributed to TREK-1 and that upregulation of this channel during pregnancy assists with the maintenance of a negative cell membrane potential, conceivably contributing to uterine quiescence until full term.

Integrin upregulation and localization to focal adhesion sites in pregnant human myometrium.

Focal adhesions are integrin-rich microdomains that structurally link the cytoskeleton to the extracellular matrix and transmit mechanical signals. In the pregnant uterus, increases in integrin expression and activation are thought to be critical for the formation of the mechanical syncytium required for labor. The aim of this study was to determine which integrins are upregulated and localized to focal adhesions in pregnant human myometrium.

Variants of stretch-activated two-pore potassium channel TREK-1 associated with preterm labor in humans.

Spontaneous preterm labor (PTL) is a uniquely human problem that results in preterm delivery of an underdeveloped fetus. The underlying cause remains elusive. The cost to societies in human suffering and treasure is enormous.

Extracellular NM23 Signaling in Breast Cancer: Incommodus Verum.

The notion that breast cancers can survive in an individual patient in a dormant state only to grow as metastatic disease in the future, is in our view incontrovertibly established. Convincing too is the evidence that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. Accepting that many deaths due to breast cancer might be averted were we to understand the cellular mechanisms underlying escape from dormancy, we have examined the extracellular signals produced by breast cancers derived from women with metastatic breast disease.

Uterine smooth muscle S-nitrosylproteome in pregnancy.

The molecular mechanisms involved in uterine quiescence during gestation and those responsible for induction of labor are not completely known. Nitric oxide relaxes uterine smooth muscle in a manner disparate from that for other smooth muscles because global elevation of cGMP after activation of soluble guanylyl cyclase does not relax the muscle. S-Nitrosylation, the covalent addition of an nitric oxide (NO) group to a cysteine thiol is a likely mechanism to explain the ability of NO to relax myometrium.

A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction.

Rates of premature birth are alarming and threaten societies and healthcare systems worldwide. Premature labor results in premature birth in over 50% of cases. Preterm birth accounts for three-quarters of infant morbidity and mortality.

Expression of stretch-activated two-pore potassium channels in human myometrium in pregnancy and labor.

Background: We tested the hypothesis that the stretch-activated, four-transmembrane domain, two pore potassium channels (K2P), TREK-1 and TRAAK are gestationally-regulated in human myometrium and contribute to uterine relaxation during pregnancy until labor.

Methodology: We determined the gene and protein expression of K2P channels in non-pregnant, pregnant term and preterm laboring myometrium. We employed both molecular biological and functional studies of K2P channels in myometrial samples taken from women undergoing cesarean delivery of a fetus.

Agonist-specific compartmentation of cGMP action in myometrium.

Nitric oxide relaxes myometrium in a cGMP-independent manner. Although cGMP activates its cognate kinase, this is not required for the inhibitory effect of nitric oxide. Thus, nitric oxide-mediated cGMP elevation does not enjoy the same set of substrates as it does in other smooth muscles.