Reviews of Physiology Biochemistry and Pharmacology最新文献

{"title":"Chronobiology and Pharmacologic Modulation of the Renin-Angiotensin-Aldosterone System in Dogs: What Have We Learned?","authors":"Jonathan P Mochel,&nbsp;Meindert Danhof","doi":"10.1007/112_2015_27","DOIUrl":"https://doi.org/10.1007/112_2015_27","url":null,"abstract":"<p><p>Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides in spontaneous cases of canine CHF. If such a link could be established, profiling of these biomarkers could support determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes. </p>","PeriodicalId":21169,"journal":{"name":"Reviews of Physiology Biochemistry and Pharmacology","volume":"169 ","pages":"43-69"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/112_2015_27","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34122476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Piezo Mechanosensitive Ion Channels: May the Force Be with You!","authors":"Eric Honoré,&nbsp;Joana Raquel Martins,&nbsp;David Penton,&nbsp;Amanda Patel,&nbsp;Sophie Demolombe","doi":"10.1007/112_2015_26","DOIUrl":"https://doi.org/10.1007/112_2015_26","url":null,"abstract":"<p><p>Piezo1 and Piezo2 are critically required for nonselective cationic mechanosensitive channels in mammalian cells. Within the last 5 years, tremendous progress has been made in understanding the function of Piezo1/2 in embryonic development, physiology, and associated disease states. A recent breakthrough was the discovery of a chemical opener for Piezo1, indicating that mechanosensitive ion channels can be opened independently of mechanical stress. We will review these new exciting findings, which might pave the road for the identification of novel therapeutic strategies. </p>","PeriodicalId":21169,"journal":{"name":"Reviews of Physiology Biochemistry and Pharmacology","volume":"169 ","pages":"25-41"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/112_2015_26","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34005920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards Understanding the Role of the Na²⁺-Ca²⁺ Exchanger Isoform 3.","authors":"Lauriane Y M Michel,&nbsp;Joost G J Hoenderop,&nbsp;René J M Bindels","doi":"10.1007/112_2015_23","DOIUrl":"https://doi.org/10.1007/112_2015_23","url":null,"abstract":"<p><p>The Na²⁺-Ca²⁺ exchanger (NCX) is critical for Ca²⁺ homeostasis throughout the body. Of the three isoforms in the NCX family, NCX1 has been extensively studied, providing a good basis for understanding the molecular aspects of the NCX family, including structural resemblances, stoichiometry, and mechanism of exchange. However, the tissue expression of the third isoform of the family, NCX3, together with its proposed involvement in the Ca²⁺ fluxes of the endoplasmic reticulum and the mitochondria suggests a distinctive role for this isoform. Investigations of the exchanger revealed the involvement of NCX3 in diverse processes such as bone formation, TNF-α production, slow-twitch muscle contraction, and long-term potentiation in the hippocampus. Furthermore, the study of its posttranslational modification, its cleavage by the Ca²⁺-sensitive protease, calpain, and its upregulation in numerous stress conditions linked NCX3 to the aberrant Ca²⁺ influx seen during neuronal excitotoxicity in Alzheimer's disease, brain stroke, and neuronal injuries. Hence, beyond its role in calcium homeostasis, NCX3 plays an important role in stress conditions, neuronal excitotoxicity, and metabolism and is thereby a key element in many cell types. The present review aims to survey the knowledge on NCX3, focusing on the recent discoveries on its functional and structural properties, and discusses the implications of NCX3 in both physiological and pathological conditions.</p>","PeriodicalId":21169,"journal":{"name":"Reviews of Physiology Biochemistry and Pharmacology","volume":"168 ","pages":"31-57"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/112_2015_23","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33196476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Secretion and Action of Brush Border Enzymes in the Mammalian Small Intestine.","authors":"Diane Hooton,&nbsp;Roger Lentle,&nbsp;John Monro,&nbsp;Martin Wickham,&nbsp;Robert Simpson","doi":"10.1007/112_2015_24","DOIUrl":"https://doi.org/10.1007/112_2015_24","url":null,"abstract":"<p><p>Microvilli are conventionally regarded as an extension of the small intestinal absorptive surface, but they are also, as latterly discovered, a launching pad for brush border digestive enzymes. Recent work has demonstrated that motor elements of the microvillus cytoskeleton operate to displace the apical membrane toward the apex of the microvillus, where it vesiculates and is shed into the periapical space. Catalytically active brush border digestive enzymes remain incorporated within the membranes of these vesicles, which shifts the site of BB digestion from the surface of the enterocyte to the periapical space. This process enables nutrient hydrolysis to occur adjacent to the membrane in a pre-absorptive step. The characterization of BB digestive enzymes is influenced by the way in which these enzymes are anchored to the apical membranes of microvilli, their subsequent shedding in membrane vesicles, and their differing susceptibilities to cleavage from the component membranes. In addition, the presence of active intracellular components of these enzymes complicates their quantitative assay and the elucidation of their dynamics. This review summarizes the ontogeny and regulation of BB digestive enzymes and what is known of their kinetics and their action in the peripheral and axial regions of the small intestinal lumen. </p>","PeriodicalId":21169,"journal":{"name":"Reviews of Physiology Biochemistry and Pharmacology","volume":"168 ","pages":"59-118"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/112_2015_24","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34049976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperforin: To Be or Not to Be an Activator of TRPC(6).","authors":"Kristina Friedland,&nbsp;Christian Harteneck","doi":"10.1007/112_2015_25","DOIUrl":"https://doi.org/10.1007/112_2015_25","url":null,"abstract":"<p><p>Meantime, it is well accepted that hyperforin, the chemical instable phloroglucinol derivative of Hypericum perforatum, St. John's wort, is the pharmacophore of St. John's wort extracts. With the decline of this scientific discussion, another controversial aspect has been arisen, the question regarding the underlying mechanism leading to the pharmacological profile of the plant extract used in therapy of depression. We will summarize the different concepts described for hyperforin's antidepressive activity. Starting with unspecific protein-independent mechanisms due to changes in pH, we will summarize data of protein-based concepts beginning with concepts based on involvement of a variety of proteins and will finally present concepts based on the modulation of a single protein. </p>","PeriodicalId":21169,"journal":{"name":"Reviews of Physiology Biochemistry and Pharmacology","volume":"169 ","pages":"1-24"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/112_2015_25","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34015367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Properties of the Urothelium that Establish the Blood-Urine Barrier and Their Implications for Drug Delivery.","authors":"Eva Lasič,&nbsp;Tanja Višnjar,&nbsp;Mateja Erdani Kreft","doi":"10.1007/112_2015_22","DOIUrl":"https://doi.org/10.1007/112_2015_22","url":null,"abstract":"<p><p>The primary function of the urinary bladder is to store and periodically release urine. How the urothelium prevents permeation of water, ions, solutes, and noxious agents back into the bloodstream and underlying tissues as well as serving as a sensor and transducer of physiological and nociceptive stimuli is still not completely understood, and thus its unique functional complexity remains to be fully elucidated. This article reviews the permeation routes across urothelium as demonstrated in extensive morphological and electrophysiological studies on in vivo and in vitro urothelia. We consider the molecular and morphological structures of urothelium and how they contribute to the impermeability of the blood-urine barrier. Based on the available data, the extremely low permeability properties of urothelium can be postulated. This remarkable impermeability is necessary for the normal functioning of all mammals, but at the same time represents limitations regarding the uptake of drugs. Therefore, the current progress to overcome this most resilient barrier in our body for drug therapy purposes is also summarized in this review. </p>","PeriodicalId":21169,"journal":{"name":"Reviews of Physiology Biochemistry and Pharmacology","volume":"168 ","pages":"1-29"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/112_2015_22","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33196474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glial calcium signalling in Alzheimer's disease.","authors":"Dmitry Lim,&nbsp;Virginia Ronco,&nbsp;Ambra A Grolla,&nbsp;Alexei Verkhratsky,&nbsp;Armando A Genazzani","doi":"10.1007/112_2014_19","DOIUrl":"https://doi.org/10.1007/112_2014_19","url":null,"abstract":"<p><p>The most accredited (and fashionable) hypothesis of the pathogenesis of Alzheimer Disease (AD) sees accumulation of β-amyloid protein in the brain (in both soluble and insoluble forms) as a leading mechanism of neurotoxicity. How β-amyloid triggers the neurodegenerative disorder is at present unclear, but growing evidence suggests that a deregulation of Ca(2+) homeostasis and deficient Ca(2+) signalling may represent a fundamental pathogenic factor. Given that symptoms of AD are most likely linked to synaptic dysfunction (at the early stages) followed by neuronal loss (at later and terminal phases of the disease), the effects of β-amyloid have been mainly studied in neurones. Yet, it must be acknowledged that neuroglial cells, including astrocytes, contribute to pathological progression of most (if not all) neurological diseases. Here, we review the literature pertaining to changes in Ca(2+) signalling in astrocytes exposed to exogenous β-amyloid or in astrocytes from transgenic Alzheimer disease animals models, characterized by endogenous β-amyloidosis. Accumulated experimental data indicate deregulation of Ca(2+) homeostasis and signalling in astrocytes in AD, which should be given full pathogenetic consideration. Further studies are warranted to comprehend the role of deficient astroglial Ca(2+) signalling in the disease progression. </p>","PeriodicalId":21169,"journal":{"name":"Reviews of Physiology Biochemistry and Pharmacology","volume":"167 ","pages":"45-65"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/112_2014_19","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32427651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRP channels coordinate ion signalling in astroglia.","authors":"Alexei Verkhratsky,&nbsp;Reno C Reyes,&nbsp;Vladimir Parpura","doi":"10.1007/112_2013_15","DOIUrl":"https://doi.org/10.1007/112_2013_15","url":null,"abstract":"<p><p>Astroglial excitability is based on highly spatio-temporally coordinated fluctuations of intracellular ion concentrations, among which changes in Ca(2+) and Na(+) take the leading role. Intracellular signals mediated by Ca(2+) and Na(+) target numerous molecular cascades that control gene expression, energy production and numerous homeostatic functions of astrocytes. Initiation of Ca(2+) and Na(+) signals relies upon plasmalemmal and intracellular channels that allow fluxes of respective ions down their concentration gradients. Astrocytes express several types of TRP channels of which TRPA1 channels are linked to regulation of functional expression of GABA transporters, whereas TRPV4 channels are activated following osmotic challenges and are up-regulated in ischaemic conditions. Astrocytes also ubiquitously express several isoforms of TRPC channels of which heteromers assembled from TRPC1, 4 and/or 5 subunits that likely act as stretch-activated channels and are linked to store-operated Ca(2+) entry. The TRPC channels mediate large Na(+) fluxes that are associated with the endoplasmic reticulum Ca(2+) signalling machinery and hence coordinate Na(+) and Ca(2+) signalling in astroglia. </p>","PeriodicalId":21169,"journal":{"name":"Reviews of Physiology Biochemistry and Pharmacology","volume":"166 ","pages":"1-22"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/112_2013_15","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31520123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of mTORC1 in regulating protein synthesis and skeletal muscle mass in response to various mechanical stimuli.","authors":"Craig A Goodman","doi":"10.1007/112_2013_17","DOIUrl":"https://doi.org/10.1007/112_2013_17","url":null,"abstract":"<p><p>Skeletal muscle plays a fundamental role in mobility, disease prevention, and quality of life. Skeletal muscle mass is, in part, determined by the rates of protein synthesis, and mechanical loading is a major regulator of protein synthesis and skeletal muscle mass. The mammalian/mechanistic target of rapamycin (mTOR), found in the multi-protein complex, mTORC1, is proposed to play an essential role in the regulation of protein synthesis and skeletal muscle mass. The purpose of this review is to examine the function of mTORC1 in relation to protein synthesis and cell growth, the current evidence from rodent and human studies for the activation of mTORC1 signaling by different types of mechanical stimuli, whether mTORC1 signaling is necessary for changes in protein synthesis and skeletal muscle mass that occur in response to different types of mechanical stimuli, and the proposed molecular signaling mechanisms that may be responsible for the mechanical activation of mTORC1 signaling. </p>","PeriodicalId":21169,"journal":{"name":"Reviews of Physiology Biochemistry and Pharmacology","volume":"166 ","pages":"43-95"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/112_2013_17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32043739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The TRPA1 channel in inflammatory and neuropathic pain and migraine.","authors":"Romina Nassini,&nbsp;Serena Materazzi,&nbsp;Silvia Benemei,&nbsp;Pierangelo Geppetti","doi":"10.1007/112_2014_18","DOIUrl":"https://doi.org/10.1007/112_2014_18","url":null,"abstract":"<p><p>The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, is primarily localized to a subpopulation of primary sensory neurons of the trigeminal, vagal, and dorsal root ganglia. This subset of nociceptors produces and releases the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), which mediate neurogenic inflammatory responses. TRPA1 is activated by a number of exogenous compounds, including molecules of botanical origin, environmental irritants, and medicines. However, the most prominent feature of TRPA1 resides in its unique sensitivity for large series of reactive byproducts of oxidative and nitrative stress. Here, the role of TRPA1 in models of different types of pain, including inflammatory and neuropathic pain and migraine, is summarized. Specific attention is paid to TRPA1 as the main contributing mechanism to the transition of mechanical and cold hypersensitivity from an acute to a chronic condition and as the primary transducing pathway by which oxidative/nitrative stress produces acute nociception, allodynia, and hyperalgesia. A series of migraine triggers or medicines have been reported to modulate TRPA1 activity and the ensuing CGRP release. Thus, TRPA1 antagonists may be beneficial in the treatment of inflammatory and neuropathic pain and migraine. </p>","PeriodicalId":21169,"journal":{"name":"Reviews of Physiology Biochemistry and Pharmacology","volume":"167 ","pages":"1-43"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/112_2014_18","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32207511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}