Possible actions of cannabidiol in obsessive-compulsive disorder by targeting the WNT/ß-catenin pathway.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by recurrent and distinctive obsessions and/or compulsions. The etiologies remain unclear. Recent findings have shown that oxidative stress, inflammation, and glutamatergic pathways play key roles in the causes of OCD. However, first-line therapies include cognitive-behavioral therapy but only 40% of the patients respond to this first-line therapy. Research for new treatment is mandatory. This review focuses on the potential effects of cannabidiol (CBD), as a potential therapeutic strategy, on OCD and some of the presumed mechanisms by which CBD provides its benefit properties. CBD medication downregulates GSK-3ß, the main inhibitor of the WNT/ß-catenin pathway. The activation of the WNT/ß-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway and circadian rhythms dysregulation in OCD. Future prospective clinical trials could focus on CBD and its different and multiple interactions in OCD.

WNT/ß-catenin Pathway: a Possible Link Between Hypertension and Alzheimer's Disease.

PURPOSE OF REVIEW: Recent research has shown that older people with high blood pressure (BP), or hypertension, are more likely to have biomarkers of Alzheimer's disease (AD). Essential hypertension represents the most common cardiovascular disease worldwide and is thought to be responsible for about 13% of all deaths. People with essential hypertension who regularly take prescribed BP medications are half as likely to develop AD as those who do not take them. What then is the connection? RECENT FINDINGS: We know that high BP can damage small blood vessels in the brain, affecting those parts that are responsible for memory and thinking. However, the link between AD and hypertension remains unclear. Recent advances in the field of molecular and cellular biology have revealed a downregulation of the canonical WNT/ß-catenin pathway in both hypertension and AD. In AD, the glutamate transport function is decreased, a decrease that is associated with a loss of synapse and neuronal death. ß-catenin signaling appears to act as a major regulator of glutamate transporters (EAAT and GS) expression and can be harnessed to remove excess glutamate in AD. This review focuses on the possible link between hypertension and AD through the decreased WNT/ß-catenin which interacts with the glutamatergic pathway.

Friction in Myocardial Anoxia Leads to Negative Excess Entropy Production, Self-Organization, and Dissipative Structures.

Contraction of the heart is caused by actin filaments sliding along myosin filaments. This generates a frictional force inducing wear of the contractile apparatus. We postulated that this process could be exacerbated when the heart was submitted to severe anoxia. Anoxia induced dramatic abnormalities in the molecular properties of actin-myosin crossbridges. We applied the formalism of far-from-equilibrium thermodynamics to the left ventricular papillary muscles (LVPMs) of mammalian rat hearts which had been subjected to a prolonged anoxia (3 h). We showed that when subjected to prolonged anoxia, the heart operated far-from-equilibrium as evidenced by the non-linearity between thermodynamic force (F/T: Frictional force/Kelvin temperature) and thermodynamic flow (v0: myofilament sliding velocity). The rate of entropy production (EPR) was the product of (F/T) and v0. The excess entropy production (EEP) was equal to ∂δ2S∂t = ∂FTδvo; (S: entropy). The tribological system remained stable when EEP was positive and became unstable when EEP became negative, thus characterizing instability of the system and reflecting the occurrence of self-organization and possibly dissipative structures. After 3 h anoxia, re-oxygenation induced significant reversibility. About 20% of the myosin heads did not recover despite re-oxygenation. These results may be of importance in the context of heart transplantation where the delay between the time of sampling from the donor and the time of the graft installation in the recipient should be as short as possible.

Cardiac Neural Crest Cells: Their Rhombomeric Specification, Migration, and Association with Heart and Great Vessel Anomalies.

Outflow tract abnormalities are the most frequent congenital heart defects. These are due to the absence or dysfunction of the two main cell types, i.e., neural crest cells and secondary heart field cells that migrate in opposite directions at the same stage of development. These cells directly govern aortic arch patterning and development, ascending aorta dilatation, semi-valvular and coronary artery development, aortopulmonary septation abnormalities, persistence of the ductus arteriosus, trunk and proximal pulmonary arteries, sub-valvular conal ventricular septal/rotational defects, and non-compaction of the left ventricle. In some cases, depending on the functional defects of these cells, additional malformations are found in the expected spatial migratory area of the cells, namely in the pharyngeal arch derivatives and cervico-facial structures. Associated non-cardiovascular anomalies are often underestimated, since the multipotency and functional alteration of these cells can result in the modification of multiple neural, epidermal, and cervical structures at different levels. In most cases, patients do not display the full phenotype of abnormalities, but congenital cardiac defects involving the ventricular outflow tract, ascending aorta, aortic arch and supra-aortic trunks should be considered as markers for possible impaired function of these cells. Neural crest cells should not be considered as a unique cell population but on the basis of their cervical rhombomere origins R3-R5 or R6-R7-R8 and specific migration patterns: R3-R4 towards arch II, R5-R6 arch III and R7-R8 arch IV and VI. A better understanding of their development may lead to the discovery of unknown associated abnormalities, thereby enabling potential improvements to be made to the therapeutic approach.

Cannabidiol and the Canonical WNT/ß-Catenin Pathway in Glaucoma.

Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the WNT/ß-catenin pathway in glaucoma, associated with overactivation of the GSK-3ß signaling. WNT/ß-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa plant which possesses many therapeutic properties across a range of neuropsychiatric disorders. Since few years, CBD presents an increased interest as a possible drug in anxiolytic disorders. CBD administration is associated with increase of the WNT/ß-catenin pathway and decrease of the GSK-3ß activity. CBD has a lower affinity for CB1 but can act through other signaling in glaucoma, including the WNT/ß-catenin pathway. CBD downregulates GSK3-ß activity, an inhibitor of WNT/ß-catenin pathway. Moreover, CBD was reported to suppress pro-inflammatory signaling and neuroinflammation, oxidative stress and glutamatergic pathway. Thus, this review focuses on the potential effects of cannabidiol, as a potential therapeutic strategy, on glaucoma and some of the presumed mechanisms by which this phytocannabinoid provides its possible benefit properties through the WNT/ß-catenin pathway.

Mechanical and Thermodynamic Properties of Non-Muscle Contractile Tissues: The Myofibroblast and the Molecular Motor Non-Muscle Myosin Type IIA.

Myofibroblasts are contractile cells found in multiple tissues. They are physiological cells as in the human placenta and can be obtained from bone marrow mesenchymal stem cells after differentiation by transforming growth factor-ß (TGF-ß). They are also found in the stroma of cancerous tissues and can be located in non-muscle contractile tissues. When stimulated by an electric current or after exposure to KCl, these tissues contract. They relax either by lowering the intracellular Ca2+ concentration (by means of isosorbide dinitrate or sildenafil) or by inhibiting actin-myosin interactions (by means of 2,3-butanedione monoxime or blebbistatin). Their shortening velocity and their developed tension are dramatically low compared to those of muscles. Like sarcomeric and smooth muscles, they obey Frank-Starling's law and exhibit the Hill hyperbolic tension-velocity relationship. The molecular motor of the myofibroblast is the non-muscle myosin type IIA (NMIIA). Its essential characteristic is the extreme slowness of its molecular kinetics. In contrast, NMIIA develops a unitary force similar to that of muscle myosins. From a thermodynamic point of view, non-muscle contractile tissues containing NMIIA operate extremely close to equilibrium in a linear stationary mode.

Possible Treatment of Myocardial Infarct Based on Tissue Engineering Using a Cellularized Solid Collagen Scaffold Functionalized with Arg-Glyc-Asp (RGD) Peptide.

Currently, the clinical impact of cell therapy after a myocardial infarction (MI) is limited by low cell engraftment due to low cell retention, cell death in inflammatory and poor angiogenic infarcted areas, secondary migration. Cells interact with their microenvironment through integrin mechanoreceptors that control their survival/apoptosis/differentiation/migration and proliferation. The association of cells with a three-dimensional material may be a way to improve interactions with their integrins, and thus outcomes, especially if preparations are epicardially applied. In this review, we will focus on the rationale for using collagen as a polymer backbone for tissue engineering of a contractile tissue. Contractilities are reported for natural but not synthetic polymers and for naturals only for: collagen/gelatin/decellularized-tissue/fibrin/Matrigel™ and for different material states: hydrogels/gels/solids. To achieve a thick/long-term contractile tissue and for cell transfer, solid porous compliant scaffolds are superior to hydrogels or gels. Classical methods to produce solid scaffolds: electrospinning/freeze-drying/3D-printing/solvent-casting and methods to reinforce and/or maintain scaffold properties by reticulations are reported. We also highlight the possibility of improving integrin interaction between cells and their associated collagen by its functionalizing with the RGD-peptide. Using a contractile patch that can be applied epicardially may be a way of improving ventricular remodeling and limiting secondary cell migration.

PPARγ agonists: potential treatment for autism spectrum disorder by inhibiting the canonical WNT/ß-catenin pathway.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by a deficit in social interactions and communication with repetitive and restrictive behavior. No curative treatments are available for ASD. Pharmacological treatments do not address the core ASD behaviors, but target comorbid symptoms. Dysregulation of the core neurodevelopmental pathways is associated with the clinical presentation of ASD, and the canonical WNT/ß-catenin pathway is one of the major pathways involved. The canonical WNT/ß-catenin pathway participates in the development of the central nervous system, and its dysregulation involves developmental cognitive disorders. In numerous tissues, the canonical WNT/ß-catenin pathway and peroxisome proliferator-activated receptor gamma (PPARγ) act in an opposed manner. In ASD, the canonical WNT/ß-catenin pathway is increased while PPARγ seems to be decreased. PPARγ agonists present a beneficial effect in treatment for ASD children through their anti-inflammatory role. Moreover, they induce the inhibition of the canonical WNT/ß-catenin pathway in several pathophysiological states. We focus this review on the hypothesis of an opposed interplay between PPARγ and the canonical WNT/ß-catenin pathway in ASD and the potential role of PPARγ agonists as treatment for ASD.

Molecular Mechanisms Underlying the Circadian Rhythm of Blood Pressure in Normotensive Subjects.

PURPOSE OF REVIEW: Blood pressure (BP) follows a circadian rhythm (CR) in normotensive subjects. BP increases in the morning and decreases at night. This review aims at providing an up-to-date overview regarding the molecular mechanisms underlying the circadian regulation of BP. RECENT FINDINGS: The suprachiasmatic nucleus (SCN) is the regulatory center for CRs. In SCN astrocytes, the phosphorylated glycogen synthase kinase-3ß (pGSK-3ß) also follows a CR and its expression reaches a maximum in the morning and decreases at night. pGSK-3ß induces the ß-catenin migration to the nucleus. During the daytime, the nuclear ß-catenin increases the expression of the glutamate excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). In SCN, EAAT2 removes glutamate from the synaptic cleft of glutamatergic neurons and transfers it to the astrocyte cytoplasm where GS converts glutamate into glutamine. Thus, glutamate decreases in the synaptic cleft. This decreases the stimulation of the glutamate receptors AMPA-R and NMDA-R located on glutamatergic post-synaptic neurons. Consequently, activation of NTS is decreased and BP increases. The opposite occurs at night. Despite several studies resulting from animal studies, the circadian regulation of BP appears largely controlled in normotensive subjects by the canonical WNT/ß-catenin pathway involving the SCN, astrocytes, and glutamatergic neurons.

Curcumin and Endometriosis.

Endometriosis is one of the main common gynecological disorders, which is characterized by the presence of glands and stroma outside the uterine cavity. Some findings have highlighted the main role of inflammation in endometriosis by acting on proliferation, apoptosis and angiogenesis. Oxidative stress, an imbalance between reactive oxygen species and antioxidants, could have a key role in the initiation and progression of endometriosis by resulting in inflammatory responses in the peritoneal cavity. Nevertheless, the mechanisms underlying this disease are still unclear and therapies are not currently efficient. Curcumin is a major anti-inflammatory agent. Several findings have highlighted the anti-oxidant, anti-inflammatory and anti-angiogenic properties of curcumin. The purpose of this review is to summarize the potential action of curcumin in endometriosis by acting on inflammation, oxidative stress, invasion and adhesion, apoptosis and angiogenesis.

Circadian Rhythms in Exudative Age-Related Macular Degeneration: The Key Role of the Canonical WNT/ß-Catenin Pathway.

Age-related macular degeneration (AMD) is considered as the main worldwide cause of blindness in elderly adults. Exudative AMD type represents 10 to 15% of macular degeneration cases, but is the main cause of vision loss and blindness. Circadian rhythm changes are associated with aging and could further accelerate it. However, the link between circadian rhythms and exudative AMD is not fully understood. Some evidence suggests that dysregulation of circadian functions could be manifestations of diseases or could be risk factors for the development of disease in elderly adults. Biological rhythms are complex systems interacting with the environment and control several physiological pathways. Recent findings have shown that the dysregulation of circadian rhythms is correlated with exudative AMD. One of the main pathways involved in exudative AMD is the canonical WNT/ß-catenin pathway. Circadian clocks have a main role in some tissues by driving the circadian expression of genes involved in physiological and metabolic functions. In exudative AMD, the increase of the canonical WNT/ß-catenin pathway is enhanced by the dysregulation of circadian rhythms. Exudative AMD progression is associated with major metabolic reprogramming, initiated by aberrant WNT/ß-catenin pathway, of aerobic glycolysis. This review focuses on the interest of circadian rhythm dysregulation in exudative AMD through the aberrant upregulation of the canonical WNT/ß-catenin pathway.

Metabolic reprogramming in atherosclerosis: Opposed interplay between the canonical WNT/ß-catenin pathway and PPARγ.

Atherosclerosis, a chronic inflammatory and age-related disease, is a complex mechanism presenting a dysregulation of vessel structures. During this process, the canonical WNT/ß-catenin pathway is increased whereas PPARγ is downregulated. The two systems act in an opposite manner. This paper reviews the opposing interplay of these systems and their metabolic-reprogramming pathway in atherosclerosis. Activation of the WNT/ß-catenin pathway enhances the transcription of targets involved in inflammation, endothelial dysfunction, the proliferation of vascular smooth muscle cells, and vascular calcification. This complex mechanism, which is partly controlled by the WNT/ß-catenin pathway, presents several metabolic dysfunctions. This phenomenon, called aerobic glycolysis (or the Warburg effect), consists of a shift in ATP production from mitochondrial oxidative phosphorylation to aerobic glycolysis, leading to the overproduction of intracellular lactate. This mechanism is partially due to the injury of mitochondrial respiration and an increase in the glycolytic pathway. In contrast, PPARγ agonists downregulate the WNT/ß-catenin pathway. Therefore, the development of therapeutic targets, such as PPARγ agonists, for the treatment of atherosclerosis could be an interesting and innovative way of counteracting the canonical WNT pathway.

Hypothesis of Opposite Interplay Between the Canonical WNT/beta-catenin Pathway and PPAR Gamma in Primary Central Nervous System Lymphomas.

Primary central nervous system lymphomas (PCNSLs) are angiocentric neoplasia which present dense monoclonal lymphocyte proliferation, and occur in brain parenchyma in 90% of the cases. Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL) subtype represents more than 90% of PCNSLs and is the most aggressive subtype with a cure rate of only 40%. One of the characteristics of ABC-DLBCL subtype is neuroinflammation through the activation of NF-kappaB pathway. c-Myc alterations and protein expression have been shown in aggressive DLBCL. c-Myc is considered as a key prognostic and predictive biomarker for survival in DLBCL, its expression is associated with worst survival rates. Although mRNA of c-Myc is increased by low levels gains of c-Myc, several studies have shown that c-Myc protein expression is overexpressed without c-Myc abnormalities. These high levels of c-Myc protein in DLBCL without genetic abnormalities suggest that c-Myc protein expression may be also increased by other mechanisms or signaling pathways which regulate its expression. In PCNSLs, the canonical WNT/beta- catenin pathway is upregulated while PPAR gamma is downregulated. The opposite interplay between WNT/beta-catenin pathway and PPAR gamma is reviewed here. Activation of WNT/beta-catenin pathway leads to the transcription of genes involved in cell proliferation, mitochondrial metabolism, protein synthesis, and tumor growth, such as c-Myc. PPAR gamma agonists induce the inhibition of several signaling pathways such as NF-kappaB, STAT, PI3K/Akt and WNT/beta-catenin pathway. Activation of PPAR gamma agonists may have a major negative key role in the regulation of PCNSLs progression.

Circadian Rhythms and Energy Metabolism Reprogramming in Parkinson's Disease.

Entropy rate is increased by several metabolic and thermodynamic abnormalities in neurodegenerative diseases (NDs). Changes in Gibbs energy, heat production, ionic conductance or intracellular acidity are irreversible processes impelling modifications of the entropy rate. The present review focuses on the thermodynamic implications in the reprogramming of cellular energy metabolism enabling in Parkinson's disease (PD) through the contrasting interplay of the molecular signaling pathways WNT/ ß-catenin and PPARγ. In PD, WNT/ß-catenin pathway is downregulated while PPARγ is upregulated. Thermodynamic behaviors of metabolic enzymes are modified by dysregulation of the canonical WNT/ß-catenin pathway. Downregulation of WNT/ß-catenin pathway leads to hypometabolism, oxidative stress and cell death through inactivation of glycolytic enzymes such as Glut, PKM2, PDK1, MCT-1, LDH-A but also to activation of PDH. In addition, in NDs, PPARγ is dysregulated even though it contributes to the regulation of several key circadian genes. PD processes may be considered as dissipative structures that exchange energy or matter with their environment far-from the thermodynamic equilibrium. Far-from-equilibrium thermodynamics are notions driven by circadian rhythms, which directly contribute to regulation of the molecular pathways WNT/ß-catenin and PPARγ involved in the reprogramming of cellular energy metabolism enabling in Parkinson's disease.

Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis.

Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.

Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches.

Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/ß-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/ß-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4⁺ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/ß-catenin pathway. Upregulation of WNT/ß-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/ß-catenin signaling and demyelinating processes by inducing dysfunction of CD4⁺ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4⁺ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/ß-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.

Effects of cannabidiol interactions with Wnt/ß-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease, in which the primary etiology remains unknown. AD presents amyloid beta (Aß) protein aggregation and neurofibrillary plaque deposits. AD shows oxidative stress and chronic inflammation. In AD, canonical Wingless-Int (Wnt)/ß-catenin pathway is downregulated, whereas peroxisome proliferator-activated receptor γ (PPARγ) is increased. Downregulation of Wnt/ß-catenin, through activation of glycogen synthase kinase-3ß (GSK-3ß) by Aß, and inactivation of phosphatidylinositol 3-kinase/Akt signaling involve oxidative stress in AD. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid from Cannabis sativa plant. In PC12 cells, Aß-induced tau protein hyperphosphorylation is inhibited by CBD. This inhibition is associated with a downregulation of p-GSK-3ß, an inhibitor of Wnt pathway. CBD may also increase Wnt/ß-catenin by stimulation of PPARγ, inhibition of Aß and ubiquitination of amyloid precursor protein. CBD attenuates oxidative stress and diminishes mitochondrial dysfunction and reactive oxygen species generation. CBD suppresses, through activation of PPARγ, pro-inflammatory signaling and may be a potential new candidate for AD therapy.

Thermodynamic Aspects and Reprogramming Cellular Energy Metabolism during the Fibrosis Process.

Fibrosis is characterized by fibroblast proliferation and fibroblast differentiation into myofibroblasts, which generate a relaxation-free contraction mechanism associated with excessive collagen synthesis in the extracellular matrix, which promotes irreversible tissue retraction evolving towards fibrosis. From a thermodynamic point of view, the mechanisms leading to fibrosis are irreversible processes that can occur through changing the entropy production rate. The thermodynamic behaviors of metabolic enzymes involved in fibrosis are modified by the dysregulation of both transforming growth factor ß (TGF-ß) signaling and the canonical WNT/ß-catenin pathway, leading to aerobic glycolysis, called the Warburg effect. Molecular signaling pathways leading to fibrosis are considered dissipative structures that exchange energy or matter with their environment far from the thermodynamic equilibrium. The myofibroblastic cells arise from exergonic processes by switching the core metabolism from oxidative phosphorylation to glycolysis, which generates energy and reprograms cellular energy metabolism to induce the process of myofibroblast differentiation. Circadian rhythms are far-from-equilibrium thermodynamic processes. They directly participate in regulating the TGF-ß and WNT/ß-catenin pathways involved in energetic dysregulation and enabling fibrosis. The present review focusses on the thermodynamic implications of the reprogramming of cellular energy metabolism, leading to fibroblast differentiation into myofibroblasts through the positive interplay between TGF-ß and WNT/ß-catenin pathways underlying in fibrosis.

Lung Cancers: Parenchymal Biochemistry and Mechanics.

Parenchyma of pulmonary cancers acquires contractile properties that resemble those of muscles but presents some particularities. These non-muscle contractile tissues could be stimulated either electrically or chemically (KCl). They present the Frank-Starling mechanism, the Hill hyperbolic tension-velocity relationship, and the tridimensional time-independent tension-velocity-length relationship. Relaxation could be obtained by the inhibition of crossbridge molecular motors or by a decrease in the intracellular calcium concentration. They differ from muscles in that their kinetics are ultraslow as evidenced by their low shortening velocity and myosin ATPase activity. Contractility is generated by non-muscle myosin type II A and II B. The activation of the ß-catenin/WNT pathway is accompanied by the high level of the non-muscle myosin observed in lung cancers.

Thermodynamic bifurcation in anoxic heart: A far-from-equilibrium dissipative structure.

Thermodynamic consequences of a three-hour long anoxia were investigated on the isolated mammalian rat myocardium. The anoxic heart operated in a far-from-equilibrium manner as attested by the non-linearity between the thermodynamic force and the thermodynamic flow. When subjected to slight fluctuations due to anoxia, the open far-from-equilibrium cardiac system presented a thermodynamic bifurcation at ~ 60 minutes of anoxia. The bifurcation was characterized by a sudden change of direction in the bifurcation diagram of a one-dimensional nonlinear differential equation with one parameter and occurred at a non-hyperbolic fixed point at which moment the heart lost its thermodynamic stability. The parameter of the differential equation was the single force of the myosin molecular motor. These results helped to reflect a self-organized process and the occurrence of a dissipative structure. This offers valuable insights into our understanding of myocardial protection and could be of considerable interest, especially for heart transplants where the recipient must benefit from the donor's heart in the shortest possible time.