Ginger metabolites and metabolite-inspired synthetic products modulate intracellular calcium and relax airway smooth muscle

Asthma affects millions of people worldwide and its prevalence is increasing. It is characterized by chronic airway inflammation, airway remodeling, and pathologic bronchoconstriction, and it poses a continuous treatment challenge with very few new therapeutics available. Thus, many asthmatics turn to plant-based complementary products, including ginger, for better symptom control, indicating an unmet needed for novel therapies. Previously, we demonstrated that 6-shogaol (6S), the primary bioactive component of ginger, relaxes human airway smooth muscle (hASM) likely by inhibition of phosphodiesterases (PDEs) in the b-adrenergic (cyclic nucleotide PDEs) and muscarinic (phospholipase C, PLC) receptor pathways. However, oral 6S is extensively metabolized and it is unknown if the resulting metabolites remain bioactive. Here we screened all the known human metabolites of 6S and several metabolite-based synthetic derivatives to better understand their mechanism of action and structure-function relationships. We demonstrate that several metabolites and metabolite-based synthetic derivatives are able to prevent Gq-coupled stimulation of intracellular calcium [Ca2+]i and inositol triphosphate (IP3) synthesis by inhibiting PLC, similar to the parent compound 6S. We also show that these compounds prevent re-contraction of ASM after b-agonist relaxation likely by inhibiting PDEs. Furthermore, they potentiate isoproterenol-induced relaxation. Importantly, moving beyond cell-based assays, metabolites also retain the functional ability to relax Gq-coupled-contractions in upper (human) and lower (murine) airways. The current study indicates that, although oral ginger may be metabolized rapidly, it retains physiologic activity through its metabolites. Moreover, we are able to use naturally occurring metabolites as inspiration to develop novel therapeutics for brochoconstrictive diseases.

First bioimpedance assessment for detecting effects caused by environmental stimuli on Grapevine ( Vitis vinifera L.): preliminary results

Plants comprise biological tissues where bioimpedance could be measured. Changes in values of these impedance parameters within tissues are the result of changes in the chemical composition of the sap, cellular depolarization, and ion transport in response to external stimuli such as water availability, diseases, and photosynthesis activity, among others. Therefore, the environmental effects on the plant change its morphology and physiology would be related to bioimpedance. In this way, bioimpedance could become a novel and powerful technique used to analyze, in-situ and in real-time, the physiologic activity and status. In this study, we assess the Evaluation Board AD5933EBZ as a bioimpedance low-cost measurement device to perform observations of module and phase of the bioimpedance, aimed to correlate them with the effects of environmental stimuli such as irrigation, CO2 concentration, sun exposure and temperature level in the grapevine.

The Physiologic Activity and Mechanism of Quercetin-Like Natural Plant Flavonoids

The term “vitamin P” is an old but interesting concept. Most substances in this category belong to the family of flavonoids. “Vitamin P” has also been used to define the activity of some flavonoids, including quercetin, myricetin, and rutin. According to experimental studies, the “quercetin-like natural plant flavonoids” are beneficial to the body due to their various physiological and pharmacological activities in large doses (5 μM in vitro, 50 mg/kg in mice and 100 mg/kg in rats). The physiologically achievable concentration is 10 to 100 nM, which is quite high and hard to achieve from a normal diet. Thus, the physiologic activity and mechanism of "vitamin P" are still not clear. It should be noted that the quercetin-like natural plant flavonoids are physiological co-factors of cyclooxygenases (COXs), which are the rate-limiting key enzymes of prostaglandins. These quercetin-like natural plant flavonoids can strongly stimulate prostaglandin levels at lower doses (10 nM in vitro and in 0.1 mg/kg in vivo in rats). Although these "vitamin P" substances are not original substances in the body, their physiological functions affect the body. This review is focused on the most compelling evidence regarding the physiologic role and mechanism of quercetin-like natural plant flavonoids, which may be useful in understanding the physiological functions of "vitamin P", with the goal of focusing on the role of flavonoids in human physiological health.

Phosphonopeptides containing free phosphonic groups: recent advances

Chemistry and physiologic activity of peptide mimetics containing phosphonic acid moiety in their structures was reviewed.

Native and engineered sensors for Ca2+ and Zn2+: lessons from calmodulin and MTF1

Ca2+ and Zn2+ dynamics have been identified as important drivers of physiological processes. In order for these dynamics to encode function, the cell must have sensors that transduce changes in metal concentration to specific downstream actions. Here we compare and contrast the native metal sensors: calmodulin (CaM), the quintessential Ca2+ sensor and metal-responsive transcription factor 1 (MTF1), a candidate Zn2+ sensor. While CaM recognizes and modulates the activity of hundreds of proteins through allosteric interactions, MTF1 recognizes a single DNA motif that is distributed throughout the genome regulating the transcription of many target genes. We examine how the different inorganic chemistries of these two metal ions may shape these different mechanisms transducing metal ion concentration into changing physiologic activity. In addition to native metal sensors, scientists have engineered sensors to spy on the dynamic changes of metals in cells. The inorganic chemistry of the metals shapes the possibilities in the design strategies of engineered sensors. We examine how different strategies to tune the affinities of engineered sensors mirror the strategies nature developed to sense both Ca2+ and Zn2+ in cells.

Physiologic Activity of Bisphosphonates – Recent Advances

Background: Bisphosphonates are drugs commonly used for the medication and prevention of diseases caused by decreased mineral density. Despite such important medicinal use, they display a variety of physiologic activities, which make them promising anti-cancer, anti-protozoal, antibacterial and antiviral agents. Objective: To review physiological activity of bisphosphonates with special emphasis on their ongoing and potential applications in medicine and agriculture. Method: Critical review of recent literature data. Results: Comprehensive review of activities revealed by bisphosphonates. Conclusion: although bisphosphonates are mostly recognized by their profound effects on bone physiology their medicinal potential has not been fully evaluated yet. Literature data considering enzyme inhibition suggest possibilities of far more wide application of these compounds. These applications are, however, limited by their low bioavailability and therefore intensive search for new chemical entities overcoming this shortage are carried out.

Abstract 13189: CV-Ecosystem Model: Workplace Wellness With Individualized Medicine

Introduction: At-work stress is rapidly becoming a significant contributory cause of occupational disease, while sedentary work and dietary indiscretion, taken together, have contributed to cardiovascular disease, known to be associated with substantial morbidity and mortality. The aim of the CV-Ecosystem Model is to provide an individual approach by systematic environmental modification of the work site. Methods and Results: Our model which we term the CV-Ecosystem Model includes two basic tenets: 1) Workstation technologic design 2) Flexible physiologic activity. Workstation technologic design utilizes the services of a certified Ergonomist to engineer a comfortable, safe, and effective work environment. It is tailored to the unique physiologic needs of the worker while enhancing productivity within different environments. Computer aided design software would evaluate ergonomics to maximally mitigate the risk and incidence of eye strain, musculoskeletal disorders, repetitive movement disorders such as Carpal Tunnel Syndrome, etc unique to that work activity. Flexible physiologic activity would permit a worker to actively focus on basic needs during work time, on site; this would include exercise activity and food intake, channeled into healthy options. Exercise time would provide a sense of calm during stressful projects and enhance emotional well-being. In this regard, a three hour period of time, weekly, could be allocated to fitness or meditation. Conveniently located food stations could provide a variety of healthy, plant-based, fresh food options. Both would come with flexible, relative control and scheduling of these activities, within a social environment and context. Conclusions: The CV Ecosystem Model, due to its simple technology and relative low cost, could be successfully implemented in a number of enterprises, including all healthcare facilities, with benefit to employee health, wellbeing, and favorable to the business bottom line.

Coagulation potential of immobilised factor VIII in flow-dependent fibrin generation on platelet surfaces

SummaryCoagulation factor VIII (FVIII) plays an essential role in haemostasis. To date, physiologic activity of FVIII circulating in the bloodstream (S-FVIII) is evaluated by classic coagulation assays. However, the functional relevance of FVIII (-von Willebrand factor complex) immobilised on thrombogenic surfaces (I-FVIII) remains unclear. We used an in vitro perfusion chamber system to evaluate the function of I-FVIII in the process of mural thrombus formation under whole blood flow conditions. In perfusion of either control or synthetic haemophilic blood, the intra-thrombus fibrin generation on platelet surfaces significantly increased as a function of I-FVIII, independent of S-FVIII, under high shear rate conditions. This I-FVIII effect was unvarying regardless of anti-FVIII inhibitor levels in synthetic haemophilic blood. Thus, our results illustrate coagulation potentials of immobilised clotting factors, distinct from those in the bloodstream, under physiologic flow conditions and may give a clue for novel therapeutic approaches for haemophilic patients with anti-FVIII inhibitors.