Acta Physiologica最新文献

{"title":"Did you know? Is there a reserve in myocardial work via the Frank-Starling mechanism in healthy humans?","authors":"Meihan Guo, David Montero","doi":"10.1111/apha.14230","DOIUrl":"https://doi.org/10.1111/apha.14230","url":null,"abstract":"","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":" ","pages":"e14230"},"PeriodicalIF":5.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138685","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 pattern of CNI nephrotoxicity differs between treatments","authors":"Jenny Nyström, Kerstin Ebefors","doi":"10.1111/apha.14227","DOIUrl":"10.1111/apha.14227","url":null,"abstract":"<p>Immunosuppressants have greatly improved the outcomes of organ transplantation and calcineurin inhibitors (CNI) have been used extensively to prevent graft rejection since their development over 40 years ago.<span><sup>1</sup></span> The most commonly used CNIs are cyclosporine A (CsA) and tacrolimus (Tac), and in the United States, Tac is the most commonly prescribed immunosuppressant (in combination with mycophenolate agents and/or steroids) after kidney transplantation in adults.<span><sup>2</sup></span> CsA was approved by the FDA for immunosuppression following transplantation in 1983, and Tac in 1994. But like many great drugs, there are drawbacks. For CNIs, one of the major adverse effects is nephrotoxicity, which has been investigated extensively and it is known that CsA and Tac in part have a different side effect pattern, but details are still lacking.<span><sup>3</sup></span> In this issue of Acta Physiologica, Demirci et al. have investigated how CsA and Tac affect the renal compartments, and if there are differences in the mechanisms behind the nephrotoxicity caused by CNIs.<span><sup>4</sup></span> A recent review by Attachaipanich et al. in Acta Physiologica regarding cardiotoxicity after CNI treatment indicate that the cardiovascular toxicity profiles between CsA and Tac differ substantially,<span><sup>5</sup></span> implying that this could be true for other organs as well. Understanding the differences in CsA and Tac nephrotoxicity could improve patient treatment, allowing adapted treatment for each patient and hopefully reducing allograft damage caused by CNIs, alongside careful consideration of the non-renal side effects of the two drugs as well.</p><p>Although both CsA and Tac have immunosuppressive properties through the inhibition of the calcineurin/NFAT pathway, the compounds are quite different. CsA is a lipophilic cyclic peptide and Tac is a macrolide antibiotic and they are both derived from fungi. CsA binds to cyclophilins and Tac to FK-binding proteins present in the cytoplasm and both the complexes inhibit calcineurin. Calcineurin is regulated by calcium and calmodulin and activates transcription factors in the NFAT family inducing an immune response with proliferation of T lymphocytes. Calcineurin is not only expressed by lymphocytes but also other cells in the body; hence, the effects of CNIs are not exclusive for lymphocytes. Calcineurin is, for example, involved in regulating the renal potassium and sodium transport in the kidneys, which is reviewed in this number of Acta Physiologica.<span><sup>6</sup></span></p><p>To give further insight into the different effects of CsA and Tac on the kidneys, Demirci et al. has explored the effects of CsA and Tac in a rat model, and after 4 weeks of treatment investigating the early chronic phase of nephrotoxicity. The histopathology of the rats has been investigated in great detail in combination with omics techniques (RNA sequencing, global proteomics and phosphoproteomi","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131268","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":"Cytokine relay from the peripheral to the central: Secrets behind fever","authors":"Xianshu Bai","doi":"10.1111/apha.14225","DOIUrl":"10.1111/apha.14225","url":null,"abstract":"<p>Fever is often triggered by infections or inflammatory conditions, primarily mediated by the immune system. Immune cells like macrophages and dendritic cells detect pathogens through pathogen-associated molecular patterns, such as lipopolysaccharides (LPS).<span><sup>1</sup></span> In response, these immune cells release a significant number of inflammatory factors or cytokines, which travel through the bloodstream to the hypothalamus, the body's thermoregulatory center. Once in the hypothalamus, these cytokines stimulate various cells, including microglia—the innate immune cell in the central nervous system.<span><sup>2</sup></span> This stimulation initiates a complex cascade that raises body temperature. However, the precise mechanisms by which hypothalamic microglia interact with peripheral immune cells to induce fever remain unclear.<span><sup>3</sup></span></p><p>In this issue of <i>Acta Physiologica</i>, Yu et al. elucidate the molecular mechanisms of fever driven by interactions between peripheral macrophages and preoptic anterior hypothalamus (POAH) microglia.<span><sup>4</sup></span> In this study, they administered 20 μg/kg of LPS via the tail vein, which triggered a characteristic biphasic fever at 2 and 6 hours post-injection (hpi). At each time point, the levels of key pro-inflammatory cytokines involved in fever development, including IL-1β, IL-18, interferon (IFN)-β, and TNF-α, were measured. At 2 hpi, there was a slight but not significant increase in the number of macrophages in the blood and in the levels of cytokines in the serum. However, by 6 hpi, there was a significant increase in both peripheral macrophages and CNS microglia, accompanied by a dramatic rise in PGE2 and IL-1β levels in the blood and POAH region. Importantly, this was not due to LPS entering the brain, as neither Evans blue nor FITC-LPS applied peripherally was detected in the brain, indicating that microglia activation was not a direct result of LPS exposure. As these sets of cytokines are mainly expressed by macrophages and microglia, authors hypothesized that the activation of microglia is due to the entry of cytokines derived from macrophages.</p><p>To further investigate, the authors selectively depleted peripheral macrophages by administering clodronate-liposome via tail-vein injection 24 h before LPS treatment. In the absence of macrophages, even after 6 h of LPS injection, neither the microglia number nor the body temperature changed. Depleting macrophages also suppressed the LPS-induced increase in cytokine levels in both serum and the POAH region, suggesting that peripheral macrophages play a key role in fever development. Conversely, when POAH microglia were depleted using the same drug injected directly into the POAH region, cytokine levels in the serum were similarly elevated but remained low in the PO/AH region even after LPS treatment. Although body temperature was significantly reduced in comparison to LPS-treated control mice, it remained","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102335","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":"Evolutionary physiology","authors":"Pontus B. Persson, Anja Bondke Persson","doi":"10.1111/apha.14221","DOIUrl":"10.1111/apha.14221","url":null,"abstract":"<p>Evolution, a “process of heritable change in populations of organisms over multiple generations […] through mechanisms including natural selection, sexual selection and genetic drift,”<span><sup>1</sup></span> is the unifying framework that explains the diversity of life, guiding our understanding of biological processes, species interactions, and the development of new medical and biotechnological innovations. Evolutionary physiology is a multidisciplinary field that explores how organisms adapt their physiological functions to changing environmental conditions. Some authors attribute the development or emergence of evolutionary physiology as a subspecialty to the late 1980s<span><sup>2</sup></span> as a field which integrates perspectives from genetics, ecology, and evolutionary biology to understand the origins, adaptability and maintenance of physiological diversity. Svante Pääbo, so-called “reader of the Neanderthal genome,”<span><sup>3</sup></span> may be seen as a prime example who opened the door to ancient genomics. However, for a study to touch upon evolutionary physiology, it does not necessarily have to focus primarily on elucidating developments from eons past. In this paper, we take a closer look at recent publications, which aim to investigate the physiological adaptations and trade-offs that have arisen through natural selection, shedding light on evolutionary pathways, outcomes and perspectives.</p><p>Recent developments, including climate change, are increasingly recognized as significant drivers of evolutionary processes in various species. These environmental changes create new selective pressures, leading to adaptations that can alter genetic diversity and influence species' survival and reproduction.<span><sup>4</sup></span> The study by Sokolova et al. sheds light on the impact of environmental temperature changes on energy metabolism and thus on the mitochondrial function.</p><p>Mitochondria, usually introduced in Bio 101 classes as cellular power plants, are in themselves almost bizarre examples of evolutionary development. Other entities within the mammalian organism are also of questionable descent, such as retrovirus-like Gag Protein Arc1, which—and we do not know why—bears a domain which resembles retroviral/retrotransposon -like proteins, which multimerize into a capsid that packages viral RNA.<span><sup>5</sup></span> Most likely, once upon a time, mitochondria started out as α-Proteobacteria. Until recently, the most common theory was an endosymbiont hypothesis, that is, an incorporation of bacterial cell compounds into eukaryotic cells. Recently, however, evidence has emerged which prompts the question of whether the mitochondrion really emerged after the eukaryotic cell, or if this organelle even originated simultaneously with the cell that contains it.<span><sup>6</sup></span> Nevertheless, mitochondrial bacterial characteristics, such as cytosine-phosphate-guanosine, the membrane lipid cardiolipin, N-formyla","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14221","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102336","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":"Modulation of olfactory bulb activity by serotoninergic inputs in odor-associative learning","authors":"Yue Hao, Zheng Wang, Qian Li","doi":"10.1111/apha.14222","DOIUrl":"10.1111/apha.14222","url":null,"abstract":"<p>Olfaction is critical for animal survival, enabling them to discern complex environmental cues such as food, mates, and predators. This sensory modality can trigger innate animal behaviors through detecting distinct odorants and activating hardwired neural circuits. In addition, the olfactory system mediates odor-associative learning, allowing animals to link odors with beneficial or harmful contexts and form long-term memories. Several olfactory cortical regions including piriform cortex, anterior olfactory nucleus, and lateral entorhinal cortex have been implicated in the formation of odor-associative learning and memory.<span><sup>1-3</sup></span> Surprisingly, the olfactory bulb (OB)—the first relay station in the olfactory system—also exhibits neuronal plasticity during odor learning, suggesting that the OB is able to encode odor values in addition to basic odor information.<span><sup>4, 5</sup></span> However, it is still not fully understood how the odor values are encoded in the OB neurons and how the neuronal plasticity is shaped during odor learning.</p><p>In the current issue of Acta Physiologica, Jing et al. elucidate the serotonergic inputs from the dorsal raphe nucleus (DRN) to the OB as the neural mechanisms underlying plasticity of odor response in the OB during odor-associative learning.<span><sup>6</sup></span> Odors are initially detected by olfactory receptors on olfactory sensory neurons and transmitted to the OB, where the olfactory information is integrated. This information is then relayed by secondary neurons in the OB, mainly mitral and tufted (M/T) cells, to higher brain regions, including the piriform cortex, olfactory tubercle, and anterior olfactory nucleus. Beyond direct projections from olfactory sensory neurons, the OB is modulated by feedback from the olfactory cortex and centrifugal inputs from systems such as serotonergic, cholinergic, and noradrenergic pathways. These higher central inputs are believed to regulate OB responses to odors and play a role in odor-associative learning and memory, though direct evidence has been limited. The authors focused on serotonergic inputs to the OB that are mainly originated from the DRN (Figure 1A). Previous studies have indicated that the DRN modulates OB neural activity and odor response. The DRN neurons activated by optogenetics and electrical stimulation can release serotonin, regulate synaptic activity in the OB, and modulate outputs of M/T cells.<span><sup>7, 8</sup></span> However, there is limited evidence connecting this neural regulation to olfactory perception and discrimination under physiological conditions such as odor-associative learning process.</p><p>Using GCaMP to detect DRN neuronal activity, the authors found that the serotoninergic neurons in DRN is specifically activated during odor-associative tasks with a reward (both go/go task and go/no-go tasks) but not during passive odor recognition. However, during early learning stage of the go/no go task,","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071479","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":"Lessons from Klotho mouse models to understand mineral homeostasis","authors":"Teodora V. Grigore,&nbsp;Malou Zuidscherwoude,&nbsp;Hannes Olauson,&nbsp;Joost G. Hoenderop","doi":"10.1111/apha.14220","DOIUrl":"10.1111/apha.14220","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Klotho, a key component of the endocrine fibroblast growth factor receptor—fibroblast growth factor axis, is a multi-functional protein that impacts renal electrolyte handling. The physiological significance of Klotho will be highlighted in the regulation of calcium, phosphate, and potassium metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this review, we compare several murine models with different renal targeted deletions of Klotho and the insights into the molecular and physiological function that these models offer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In vivo, Klotho deficiency is associated with severely impaired mineral metabolism, with consequences on growth, longevity and disease development. Additionally, we explore the perspectives of Klotho in renal pathology and vascular events, as well as potential Klotho treatment options.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This comprehensive review emphasizes the use of Klotho to shed light on deciphering the renal molecular in vivo mechanisms in electrolyte handling, as well as novel therapeutic interventions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034617","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 human AMPKγ3 R225W mutation negatively impacts site-1 nucleotide binding and does not enhance basal AMPKγ3-associated activity nor glycogen production in human or mouse skeletal muscle","authors":"Nicolas O. Eskesen,&nbsp;Rasmus Kjøbsted,&nbsp;Jesper Bratz Birk,&nbsp;Nicolai S. Henriksen,&nbsp;Nicoline R. Andersen,&nbsp;Stine Ringholm,&nbsp;Henriette Pilegaard,&nbsp;Jørgen F. P. Wojtaszewski","doi":"10.1111/apha.14213","DOIUrl":"10.1111/apha.14213","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>AMP-activated protein kinase (AMPK) is activated during cellular energy perturbation. AMPK complexes are composed of three subunits and several variants of AMPK are expressed in skeletal muscle. The regulatory AMPKγ3 subunit is predominantly expressed in fast-twitch muscle fibers. A human AMPKγ3 R225W mutation has been described. The mutation increases the total pool of AMPK activity in cells cultured from R225W carrier muscle and is associated with increased glycogen levels in mature skeletal muscle. This led to the idea of AMPKγ3 being involved in the regulation of skeletal muscle glycogen levels. Evidence for this causative link remains to be provided.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We studied muscle biopsies from human carriers of the AMPKγ3 R225W mutation and we developed a novel AMPKγ3 R225W knock-in mouse model (KI HOM). Through in vitro, in situ, and ex vivo techniques, we investigated AMPK activity, AMPK function, and glycogen levels in skeletal muscle of humans and mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In human carriers, the basal AMPKγ3-associated activity was reduced when assayed in the absence of exogenous AMP. No difference was observed when assayed under AMP saturation, which was supported by findings in muscle of KI HOM mice. Furthermore, effects of AICAR/muscle contraction on AMPKγ3-associated activity were absent in KI HOM muscle. Muscle glycogen levels were not affected by the mutation in human carriers or in KI HOM mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The AMPKγ3 R225W mutation does not impact the AMPK-associated activity in human skeletal muscle and the mutation is not linked to glycogen accumulation. The R225W mutation ablates the AMPKγ3-associated activation by AICAR/muscle contractions, presumably due to loss of nucleotide binding in the CBS 1 domain of AMPKγ3.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142015654","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":"How to visualize high-dimensional data","authors":"Ralf Mrowka,&nbsp;Ralf Schmauder","doi":"10.1111/apha.14219","DOIUrl":"10.1111/apha.14219","url":null,"abstract":"&lt;p&gt;Recently, a colleague asked after a lecture about a fancy diagram where the axis designation was not clear to him and the discussion about that raised a few interesting thoughts about that specific matter. Physiological knowledge is often taught at university seminars and in textbooks with the help of diagrams. A very important first step when discussing diagrams is to clarify which physical, physiological variable at what scale and unit is represented on which axis. Examples of typical classical low dimensional diagrams in physiology publications in Acta Physiologica might be blood pressure over time,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; infarct size as percentage of Left ventricular mass depending on genotype&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; or urine excretion in volume per time depending on diet.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Not knowing the axes of the classical diagrams, they might as well be “just” pieces of fancy modern art.&lt;/p&gt;&lt;p&gt;We strongly believe that graphical representation of complex data—for example, as diagrams—is essential in communicating them. However, for specific types of diagrams, the understanding and interpretation of their content is more complex, and requires more explanation than classical diagrams. Specifically, we refer to the graphical representation of high-dimensional data, which have, in recent years, played an increasing role in new understandings of physiological processes.&lt;/p&gt;&lt;p&gt;To visualize data a reduction of dimensionality is often applied. A simple example is a black/white photograph of a colorful moving three dimensional object. The snapshot “eliminated” the dimension time and the optical projection on a plane in the camera eliminated one dimension in space and the gray values just reduced the spectral information to an intensity value on the photograph. Although the photograph does not represent the compete “dataset” it gives us in most cases a good impression about the situation captured by the photographer.&lt;/p&gt;&lt;p&gt;Times have changed.&lt;/p&gt;&lt;p&gt;To describe the “amount” of data obtained for a study in the 1960s one physiologist for example referred to the length of the paper of plots of curved of blood pressure measurements he was analyzing for one particular study. Compared with that amount of data back then we are nowadays faced with a completely new situation. With the development of technology we have to handle a huge amount of data today. For example, in recent studies with single RNAseq data scientists obtained with thousands of expression values for single genes for each of thousands of single cells at multiple experimental points and possibly for multiple interventions. Obviously you cannot produce a meaningful simple classical plot with thousands of dimensions.&lt;/p&gt;&lt;p&gt;In order to make sense out of the hugely dimensional data, researches can employ methods for the reduction of dimensionality. One classical methods would be to employ the so called principal component analysis (PCA). This linear method projects the data onto a","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14219","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998964","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":"Rapid restoration of intracellular pH in erythrocytes protects oxygen transport","authors":"Tobias Wang,&nbsp;Michael Berenbrink","doi":"10.1111/apha.14218","DOIUrl":"10.1111/apha.14218","url":null,"abstract":"&lt;p&gt;In the current issue of &lt;i&gt;Acta Physiologica&lt;/i&gt;, Harter et al.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; provide novel evidence for soluble adenylyl cyclase (sAC), a ubiquitous regulatory enzyme present in the cytosol of almost all cells, acting as a sensor for intracellular pH (pHi) in fish red blood cells. Harter and coworkers also propose an acid–base sensing mechanism that acts to protect adequate oxygen delivery in face of alkalosis or acidosis, and therefore may be of considerable functional importance.&lt;/p&gt;&lt;p&gt;Erythrocytes are very specialized cells, packed with hemoglobin, that provide for oxygen delivery to the tissues. In humans and other mammals, the nucleus and mitochondria are lost as the erythrocytes mature, and ATP is mostly derived from glycolysis.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; This is not the case in other vertebrates where the red blood cells from birds, reptiles, amphibians, and fish retain their nucleus and capacity for mitochondrial respiration. In contrast to the other vertebrates, the mammalian red blood cell is therefore often viewed as a simple cell, a bag of hemoglobin. However, there is mounting evidence that mammalian red blood cells can rapidly restore pHi upon acid–base disturbances by activating the chloride-bicarbonate exchanger (or anion exchanger, AE1).&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; In addition to safeguarding the metabolic processes within the erythrocyte, the protection of pHi has important implications for oxygen delivery as oxygen affinity of the hemoglobin is sensitive to pHi through the Bohr effect.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; This is the case for all vertebrates, but perhaps particularly so in fish. In addition to having rather large Bohr effects, fish are endowed with the so-called Root effect, named after its discoverer Raymond W. Root, who demonstrated that acidosis not only right-shifts the blood oxygen equilibrium curve, that is, lowers oxygen affinity, but also reduces the capacity for oxygen binding, such that part of the hemoglobin is unable to bind oxygen.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The Root effect may, at least at first, seem maladaptive, but provides for the possibility of creating very high partial pressures of oxygen when local acidification forces the oxygen to separate from the hemoglobin. This is exploited in the swim bladder of many fish species where local acidification of the blood in a specialized gas gland with a &lt;i&gt;rete mirabile&lt;/i&gt; elicits extraordinarily high partial pressures of oxygen that then fills the swim-bladder and enables exquisite control of buoyancy.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Moreover, the Root effect also plays an important role in delivering oxygen to the eyes of numerous groups of fishes.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Here, specialized mechanisms for acidification provide partial pressures of oxygen in excess of 500 mmHg that enable diffusion into the avascular retina.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; To allow fish to exploit the Root effect in these specialized structures, it is essential that the acidifi","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986836","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":"Beneficial effects of MGL-3196 and BAM15 combination in a mouse model of fatty liver disease","authors":"Mingyan Zhou,&nbsp;Catherine Li,&nbsp;Frances L. Byrne,&nbsp;Calum S. Vancuylenburg,&nbsp;Ellen M. Olzomer,&nbsp;Adam Hargreaves,&nbsp;Lindsay E. Wu,&nbsp;Nicholas A. Shackel,&nbsp;Webster L. Santos,&nbsp;Kyle L. Hoehn","doi":"10.1111/apha.14217","DOIUrl":"10.1111/apha.14217","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aim</h3>\u0000 \u0000 <p>Metabolic dysfunction-associated steatohepatitis (MASH) is a metabolic disorder with limited treatment options. The thyroid hormone receptor (THR)-β agonist resmetirom/MGL-3196 (MGL) increases liver fat oxidation and has been approved for treating adult MASH. However, over 60% of patients receiving MGL treatment do not achieve MASH resolution. Therefore, we investigated the potential for combination therapy of MGL with the mitochondrial uncoupler BAM15 to improve fatty liver disease outcomes in the GAN mouse model of MASH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>C57BL/6J male mice were fed GAN diet for 38 weeks before stratification and randomization to treatments including MGL, BAM15, MGL + BAM15, or no drug control for 8 weeks. Treatments were admixed in diet and mice were pair-fed to control for drug intake. Treatment effectiveness was assessed by body weight, body composition, energy expenditure, glucose tolerance, tissue lipid content, and histological analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MGL + BAM15 treatment resulted in better efficacy versus GAN control mice than either monotherapy in the context of energy expenditure, liver fat loss, glucose control, and fatty liver disease activity score. Improvements in ALT, liver mass, and plasma cholesterol were primarily driven by MGL, while improvements in body fat were primarily driven by BAM15. No treatments altered liver fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>MGL + BAM15 treatment had overall better efficacy to improve metabolic outcomes in mice fed GAN diet than either monotherapy alone. These data warrant further investigation into combination therapies of THR-β agonists and mitochondrial uncouplers for the potential treatment of disorders related to fatty liver, obesity, and insulin resistance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 10","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14217","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994829","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}