Cardioprotective effect of notoginsenoside R1 in a rabbit lung remote ischemic postconditioning model via activation of the TGF-ß1/TAK1 signaling pathway.

Pharmacological postconditioning using cardioprotective agents is able to reduce myocardial infarct size. Notoginsenoside R1 (NG-R1), a phytoestrogen isolated from Panax notoginseng saponins (PNS), is considered to have anti-oxidative and anti-apoptotic properties. However, its cardioprotective properties and underlying mechanisms remain largely unknown. The aim of the present study was to determine the cardioprotective and anti-apoptotic effects of NG-R1 in an ischemia-reperfusion (IR)-induced myocardial injury rabbit model. A total of 45 Japanese big-ear rabbits were equally randomized to three groups: Control group, remote ischemic postconditioning (RIP) group and NG-R1 intervention group. At the endpoint of the experiment, the animals were sacrificed to remove myocardial tissues for the detection of transforming growth factor (TGF)-ß1-TGF-ß activated kinase 1 (TAK1) pathway-related proteins by immunohistochemistry and western blot analysis, the activities of caspase-3, -8 and -9 in myocardial cells by fluorometric assay, and the apoptosis of myocardial cells by terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling. Right and left lung tissues were stained with hematoxylin and eosin (H&E) to observe the severity of injury. NG-R1 treatment reduced the activity of superoxide dismutase, increased the content of malondialdehyde, reduced the activities of caspase-3, -8 and -9, and inhibited the apoptosis of myocardial cells in rabbits undergoing RIP. In addition, the expression of TGF-ß1-TAK1 signaling pathway-related proteins was downregulated following NG-R1 intervention. H&E staining of bilateral lung tissues showed that cell morphology was generally intact without significant alveolar congestion, and there was no significant difference among the three groups. These results indicate that NG-R1 protects the heart against IR injury, possibly by inhibiting the activation of the TGF-ß1-TAK1 signaling pathway and attenuating apoptotic stress in the myocardium.

Calorie-induced ER stress suppresses uroguanylin satiety signaling in diet-induced obesity.

BACKGROUND/OBJECTIVES: The uroguanylin-GUCY2C gut-brain axis has emerged as one component regulating feeding, energy homeostasis, body mass and metabolism. Here, we explore a role for this axis in mechanisms underlying diet-induced obesity (DIO). SUBJECTS/METHODS: Intestinal uroguanylin expression and secretion, and hypothalamic GUCY2C expression and anorexigenic signaling, were quantified in mice on high-calorie diets for 14 weeks. The role of endoplasmic reticulum (ER) stress in suppressing uroguanylin in DIO was explored using tunicamycin, an inducer of ER stress, and tauroursodeoxycholic acid (TUDCA), a chemical chaperone that inhibits ER stress. The impact of consumed calories on uroguanylin expression was explored by dietary manipulation. The role of uroguanylin in mechanisms underlying obesity was examined using Camk2a-Cre-ER(T2)-Rosa-STOP(loxP/loxP)-Guca2b mice in which tamoxifen induces transgenic hormone expression in brain. RESULTS: DIO suppressed intestinal uroguanylin expression and eliminated its postprandial secretion into the circulation. DIO suppressed uroguanylin through ER stress, an effect mimicked by tunicamycin and blocked by TUDCA. Hormone suppression by DIO reflected consumed calories, rather than the pathophysiological milieu of obesity, as a diet high in calories from carbohydrates suppressed uroguanylin in lean mice, whereas calorie restriction restored uroguanylin in obese mice. However, hypothalamic GUCY2C, enriched in the arcuate nucleus, produced anorexigenic signals mediating satiety upon exogenous agonist administration, and DIO did not impair these responses. Uroguanylin replacement by transgenic expression in brain repaired the hormone insufficiency and reconstituted satiety responses opposing DIO and its associated comorbidities, including visceral adiposity, glucose intolerance and hepatic steatosis. CONCLUSIONS: These studies reveal a novel pathophysiological mechanism contributing to obesity in which calorie-induced suppression of intestinal uroguanylin impairs hypothalamic mechanisms regulating food consumption through loss of anorexigenic endocrine signaling. The correlative therapeutic paradigm suggests that, in the context of hormone insufficiency with preservation of receptor sensitivity, obesity may be prevented or treated by GUCY2C hormone replacement.

It's a bear market: evolutionary and ecological effects of predation on two wild sockeye salmon populations.

Predation can affect both phenotypic variation and population productivity in the wild, but quantifying evolutionary and demographic effects of predation in natural environments is challenging. The aim of this study was to estimate selection differentials and coefficients associated with brown bear (Ursus arctos) predation in wild sockeye salmon (Oncorhynchus nerka) populations spawning in pristine habitat that is often subject to intense predation pressure. Using reconstructed genetic pedigrees, individual reproductive success (RS) was estimated in two sockeye salmon populations for two consecutive brood years with very different predation intensities across brood years. Phenotypic data on individual adult body length, body depth, stream entry timing and reproductive lifespan were used to calculate selection coefficients based on RS, and genetic variance components were estimated using animal models. Bears consistently killed larger and more recently arrived adults, although selection differentials were small. In both populations, mean RS was higher in the brood year experiencing lower predation intensity. Selection coefficients were similar across brood years with different levels of predation, often indicating stabilizing selection on reproductive lifespan as well as directional selection for longer reproductive lifespan. Despite these selection pressures, genetic covariation of morphology, phenology and lifespan appears to have maintained variation in spawner body size and stream entry timing in both populations. Our results therefore suggest considerable demographic but limited evolutionary effects of bear predation in the two study populations.

Antiobesity pharmacotherapy: new drugs and emerging targets.

Obesity is a growing pandemic, and related health and economic costs are staggering. Pharmacotherapy, partnered with lifestyle modifications, forms the core of current strategies to reduce the burden of this disease and its sequelae. However, therapies targeting weight loss have a significant history of safety risks, including cardiovascular and psychiatric events. Here, evolving strategies for developing antiobesity therapies, including targets, mechanisms, and developmental status, are highlighted. Progress in this field is underscored by Belviq (lorcaserin) and Qsymia (phentermine/topiramate), the first agents in more than 10 years to achieve regulatory approval for chronic weight management in obese patients. On the horizon, novel insights into metabolism and energy homeostasis reveal guanosine 3',5'-cyclic monophosphate (cGMP) signaling circuits as emerging targets for antiobesity pharmacotherapy. These innovations in molecular discovery may elegantly align with practical off-the-shelf approaches, leveraging existing approved drugs that modulate cGMP levels for the management of obesity.

Central and peripheral molecular targets for antiobesity pharmacotherapy.

Obesity has emerged as one of the principal worldwide health concerns of the modern era, and there exists a tremendous unmet clinical need for safe and effective therapies to combat this global pandemic. The prevalence of obesity and its associated comorbidities, including cardiovascular and metabolic diseases, has focused the attention of those in drug discovery and development on generating effective modalities for the treatment and prevention of obesity. Early efforts in the field of obesity pharmacotherapy centered on the development of agents with indeterminate mechanisms of action. This led to treatment paradigms characterized by significant off-target effects. In the past two decades, new insights have been made into the physiologic regulation of energy balance and the subordinate central and peripheral circuits coordinating appetite, metabolism, and lipogenesis. These studies have revealed previously unrecognized molecular targets for controlling appetite and managing weight from which has emerged a new wave of targeted pharmacotherapies to prevent and control obesity.

Can colorectal cancer be prevented or treated by oral hormone replacement therapy?

Guanylyl cyclase C (GCC) is the receptor specifically expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin and diarrheagenic bacterial heat-stable enterotoxins. This tissue-specific receptor coordinates lineage-dependent regulation of epithelial homeostasis, and its disruption contributes to intestinal tumorigenesis. It coordinates regenerative and metabolic circuits by restricting the cell cycle and proliferation and programming metabolic transitions central to organizing the dynamic crypt-surface axis. Further, mice deficient in GCC signaling are more susceptible to colon cancer induced by Apc mutations or the carcinogen azoxymethane. Moreover, guanylin and uroguanylin are gene products most commonly lost, early, in colon cancer in animals and humans. The role of GCC as a tumor suppressing receptor regulating proliferation and metabolism, together with the universal loss of guanylin and uroguanylin in tumorigenesis, suggests a model in which colorectal cancer is a paracrine hormone deficiency syndrome. In that context, activation of GCC reverses the tumorigenic phenotype by limiting growth of colorectal cancer cells by restricting progression through the G1/S transition and reprogramming metabolic circuits from glycolysis to oxidative phosphorylation, limiting bioenergetic support for rapid proliferation. These observations suggest a pathophysiological hypothesis in which GCC is a lineage-dependent tumor suppressing receptor coordinating proliferative homeostasis whose dysregulation through hormone loss contributes to neoplasia. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands.

GCC signaling in colorectal cancer: Is colorectal cancer a paracrine deficiency syndrome?

Guanylyl cyclase C (GCC) is the receptor expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin that coordinate mucosal homeostasis and its silencing contributes to intestinal transformation. It orchestrates proliferative and metabolic circuits by limiting the cell cycle and programming metabolic transitions central to regeneration along the crypt-villus axis. Mice deficient in GCC are more susceptible to colon cancer induced by germline mutations or carcinogens. Moreover, guanylin and uroguanylin are the most commonly lost gene products in colon cancer. The role of GCC as a tumor suppressor and the universal loss of its hormones in transformation suggest a paradigm in which colorectal cancer is a disease of paracrine hormone insufficiency. Indeed, GCC signaling reverses the tumorigenic phenotype of human colon cancer cells by regulating proliferation and metabolism. These data suggest a pathophysiological hypothesis in which GCC is a tumor suppressor coordinating proliferative homeostasis whose silencing through hormone loss initiates transformation. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral hormone replacement therapy employing GCC ligands.

Colorectal cancer is a paracrine deficiency syndrome amenable to oral hormone replacement therapy.

The most commonly lost gene products in colorectal carcinogenesis include the paracrine hormones guanylin and uroguanylin, the endogenous ligands for guanylyl cyclase C (GCC), the intestinal receptor for diarrheagenic bacterial enterotoxins. Recently, GCC-cGMP signaling has emerged as a principal regulator of proliferation, genetic integrity and metabolic programming in normal human enterocytes and colon cancer cells. Elimination of GCC in mice produced hyperplasia of the proliferating compartment associated with increases in rapidly cycling progenitor cells, and reprogrammed enterocyte metabolism, with a shift from oxidative phosphorylation to glycolysis. In addition, in colons of mice carrying mutations in Apc (Apc(Min) (/+)) or exposed to the carcinogen azoxymethane, elimination of GCC increased tumor initiation and promotion by disrupting genomic integrity and releasing cell cycle restriction. These previously unrecognized roles for GCC as a fundamental regulator of intestinal homeostasis and as an intestinal tumor suppressor suggest that receptor dysregulation reflecting paracrine hormone insufficiency is a key event during the initial stages of colorectal tumorigenesis. Together with the uniform over-expression of GCC in human tumors, these novel roles for GCC underscore the potential of oral replacement with GCC ligands for targeted prevention and therapy of colorectal cancer.

The paracrine hormone hypothesis of colorectal cancer.

Colorectal carcinogenesis originates in the context of dysregulated epithelial cell homeostasis, wherein hyperproliferation, hypodifferentiation, metabolic reprogramming, and mesenchymal remodeling reflect recursive mutually reinforcing mechanisms contributing to progressive genomic instability. Although genotypic and phenotypic elements characterizing the terminal integration of these pathophysiological processes defining cancer are well enumerated, events initiating, coordinating, and sustaining this hierarchical maladaptive systems evolution remain elusive for most tumors. In the intestine, guanylyl cyclase C (GCC) and its paracrine ligands organize and regulate the homeostatic integrity of the crypt-villus axis, forming a hormonal tumor suppressor signaling sequence, whose dysfunction defines the initiation of neoplastic transformation and creates a permissive niche for tumor progression.

Guanylyl cyclase is an ATP sensor coupling nitric oxide signaling to cell metabolism.

Defending cellular integrity against disturbances in intracellular concentrations of ATP ([ATP](i)) is predicated on coordinating the selection of substrates and their flux through metabolic pathways (metabolic signaling), ATP transfer from sites of production to utilization (energetic signaling), and the regulation of processes consuming energy (cell signaling). Whereas NO and its receptor, soluble guanylyl cyclase (sGC), are emerging as key mediators coordinating ATP supply and demand, mechanisms coupling this pathway with metabolic and energetic signaling remain undefined. Here, we demonstrate that sGC is a nucleotide sensor whose responsiveness to NO is regulated by [ATP](i). Indeed, ATP inhibits purified sGC with a K(i) predicting >60% inhibition of NO signaling in cells maintaining physiological [nucleotide](i). ATP inhibits sGC by interacting with a regulatory site that prefers ATP > GTP. Moreover, alterations in [ATP](i), by permeabilization and nucleotide clamping or inhibition of mitochondrial ATP synthase, regulate NO signaling by sGC. Thus, [ATP](i) serves as a "gain control" for NO signaling by sGC. At homeostatic [ATP](i), NO activation of sGC is repressed, whereas insults that reduce [ATP](i,) derepress sGC and amplify responses to NO. Hence, sGC forms a key synapse integrating metabolic, energetic, and cell signaling, wherein ATP is the transmitter, allosteric inhibition the coupling mechanism, and regulated accumulation of cGMP the response.

[Exploration of nursing diagnosis with a cognitive reasoning model].

One of the important topics in theoretic studies on nursing diagnosis, still a new concept in China, is to explore the logical reasoning process from collecting data to making diagnoses. This paper introduced an epistemological model which mentions every step in detail on how to make a nursing diagnosis. The model was built on the basis of analyzing the knowledge structure of nursing diagnosis and applying the methodology of cognitive psychology.

Effect of adsorbents on degradation of toxic organic compounds by coimmobilized systems.

The use of coimmobilized systems for treatment of toxic organic compounds has been proposed. The proposed approach combines the use of adsorbents and laboratory identified microorganisms immobilized in a protective permeable barrier to achieve a greater degree of control over the remediation process. This study was launched to understand the effect of adsorbents and changes in adsorption on the degradation of toxic compounds by coimmobilized systems. The specific case studied involved the degradation of pentachlorophenol (PCP) by Arthrobacter (ATCC 33790) coimmobilized with powdered activated carbon within calcium alginate capsules.The design parameters studied included adsorbent content and type as well as the effect of solution pH and surfactant concentration on adsorption and biodegradation. It was found that the equilibrium adsorption behavior of PCP was strongly influenced by solution pH and surfactant concentration. A mathematical model was developed that combined the physical processes of mass transfer and adsorption with biological degradation of PCP. The model was used to predict the effect of various parameters on the degradation of PCP. Based on model predictions, the degradation of PCP. Based on model predictions, the degradation of PCP was strongly dependent on variations in adsorbent capacity and affinity for this contaminant.

Use of coimmobilized biological systems to degrade toxic organic compounds.

The concept of coimmobilizing cell mass (and/or enzyme) and adsorbent in a hydrogel matrix for biodegradation of toxic organic chemicals was introduced. Under defined experimental conditions, the coimmobilized system using activated carbon and Phanerochaete chrysosporium was compared with nonimmobilized systems for the degradation of pentachlorophenol (PCP). It was demonstrated that the coimmobilized system degraded PCP more effectively than the nonimmobilized system. A solid substrate included in the coimmobilized system could support the biodegradation. Isolation of the degrading agents from a model interrupting microorganism by the coimmobilized capsule membrane reduced the interference on the biodegradation. In simulated contaminated soil extract and sand, the coimmobilized system also exhibited higher degradative ability and stability than the nonimmobilized systems.

Degradation kinetics of pentachlorophenol by Phanerochaete chrysosporium.

The extracellular enzymes and cell mass from the pregrown Phanerochaete chrysosporium cultures were used for the degradation of PCP. The use of both extracellular enzymes and cell mass resulted in extensive mineralization of PCP, while the action of only the crude extracellular enzymes led to the formation of a degradation intermediate (TCHD). A kinetic model, which describes the relationship among PCP degradation, initial PCP concentration, dosage of extracellular enzymes, and cell mass concentration, was developed. Based on this model, various effects of initial PCP concentration, dosage of extracellular enzymes, and cell mass concentration were evaluated experimentally. It was found that when initial PCP concentration is lower than 12 mumol/L, the model of a parallel-series first-order reaction is sufficient to describe the degradation process. PCP disappearance and mineralization were enhanced by increasing either the extracellular enzyme concentration or the cell mass concentration. As high as 70% of PCP mineralization could be obtained by using a higher dosage of extracellular enzymes and cell mass. Various parameters of the kinetic model were determined and the model was verified experimentally. Simulation using this model provided the criteria needed to choose rational dosages of extracellular enzymes and cell mass for the degradation of PCP. Data reported allow some insight into the function of the extracellular enzymes and cell mass of P. chrysosporium in degradation processes of toxic pollutants and assist in the design and evaluation of practical bioremediation methods.

Carpal tunnel syndrome in paraplegic patients.

Median nerve compression at the wrist (Carpal Tunnel Syndrome) is commonly associated with local trauma around the flexor retinaculum. Repeated manual activity also exacerbates the disease severity. We undertook a prospective study of the incidence of Carpal Tunnel Syndrome (CTS) in 47 paraplegic patients who have used their hands extensively for daily activity. Since surgical decompression generally provides excellent relief of symptoms, early detection of CTS will be particularly important in these patients. Of the 47 patients studied, 19 had clinical CTS (40%). A total of 91 hands (nerves) were tested with motor and sensory nerve conduction of the median and ulnar nerves. Electrophysiological evidence of CTS was noted in 57 hands (63%). The incidence of CTS appears to be related to the duration of Spinal Cord Injury. Concurrent ulnar neuropathy at the elbow was noted in 19 patients (40%). There was no predisposing factor such as diabetes mellitus in any of these patients, and the compressive neuropathy appears to be purely mechanical.