Function (Oxford, England)最新文献

{"title":"Oxidation Driven Reversal of PIP₂-dependent Gating in GIRK2 Channels.","authors":"Sun-Joo Lee, Shoji Maeda, Jian Gao, Colin G Nichols","doi":"10.1093/function/zqad016","DOIUrl":"10.1093/function/zqad016","url":null,"abstract":"<p><p>Physiological activity of G protein gated inward rectifier K⁺ (GIRK, Kir3) channel, dynamically regulated by three key ligands, phosphoinositol-4,5-bisphosphate (PIP₂), Gβγ, and Na⁺, underlies cellular electrical response to multiple hormones and neurotransmitters in myocytes and neurons. In a reducing environment, matching that inside cells, purified GIRK2 (Kir3.2) channels demonstrate low basal activity, and expected sensitivity to the above ligands. However, under oxidizing conditions, anomalous behavior emerges, including rapid loss of PIP₂ and Na⁺-dependent activation and a high basal activity in the absence of any agonists, that is now paradoxically inhibited by PIP₂. Mutagenesis identifies two cysteine residues (C65 and C190) as being responsible for the loss of PIP₂ and Na⁺-dependent activity and the elevated basal activity, respectively. The results explain anomalous findings from earlier studies and illustrate the potential pathophysiologic consequences of oxidation on GIRK channel function, as well as providing insight to reversed ligand-dependence of Kir and KirBac channels.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad016"},"PeriodicalIF":5.1,"publicationDate":"2023-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/47/88/zqad016.PMC10165546.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9753469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision Medicine in Pancreatitis: The Future of Acute Pancreatitis Care.","authors":"Andras Garami, Peter Hegyi","doi":"10.1093/function/zqad015","DOIUrl":"10.1093/function/zqad015","url":null,"abstract":"<p><p>Acute pancreatitis (AP) continues to present a substantial burden to patients and healthcare personnel. Despite its occasionally severe progression and high mortality rate, there is no specific therapy that could be routinely applied in patients with AP. Here, we review treatment possibilities in AP, describe how the treatment approaches have changed in pancreatic cancer as an analogy, and point out potential causes for the failure of clinical trials on AP. We highlight that instead of attempting to discover generalized treatment options that could be used in any AP patient, it is time for a paradigm shift in the treatment of AP, which would help to focus more on individual patients or specific patient subpopulations when designing clinical trials and therapeutic approaches (similarly as in pancreatic cancer). Since the recruitment of specific patient subpopulations with AP could take excessive time if clinical centers work separately, the development of precision medicine in AP would require to establish an expert committee, eg, Pancreatitis Precision Medicine Interest Group, which could organize and coordinate the activities of the joined centers. With the joined forces of expert clinicians and leading centers, a new era could start in the treatment of AP, in which personalized treatment options could be discovered and introduced to efficiently reduce the burden of the disease on patients and healthcare workers.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad015"},"PeriodicalIF":0.0,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9f/1d/zqad015.PMC10165548.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival.","authors":"Peter Bailey, Xu Zhou, Jingyu An, Teresa Peccerella, Kai Hu, Christoph Springfeld, Markus Büchler, John P Neoptolemos","doi":"10.1093/function/zqad011","DOIUrl":"10.1093/function/zqad011","url":null,"abstract":"<p><p>Pancreatic cancer is one of the most lethal cancers worldwide, most notably in Europe and North America. Great strides have been made in combining the most effective conventional therapies to improve survival at least in the short and medium term. The start of treatment can only be made once a diagnosis is made, which at this point, the tumor volume is already very high in the primary cancer and systemically. If caught at the earliest opportunity (in circa 20% patients) surgical resection of the primary followed by combination chemotherapy can achieve 5-year overall survival rates of 30%-50%. A delay in detection of even a few months after symptom onset will result in the tumor having only borderline resectabilty (in 20%-30% of patients), in which case the best survival is achieved by using short-course chemotherapy before tumor resection as well as adjuvant chemotherapy. Once metastases become visible (in 40%-60% of patients), cure is not possible, palliative cytotoxics only being able to prolong life by few months. Even in apparently successful therapy in resected and borderline resectable patients, the recurrence rate is very high. Considerable efforts to understand the nature of pancreatic cancer through large-scale genomics, transcriptomics, and digital profiling, combined with functional preclinical models, using genetically engineered mouse models and patient derived organoids, have identified the critical role of the tumor microenvironment in determining the nature of chemo- and immuno-resistance. This functional understanding has powered fresh and exciting approaches for the treatment of this cancer.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad011"},"PeriodicalIF":5.1,"publicationDate":"2023-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9b/ed/zqad011.PMC10165547.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle.","authors":"Adam J Amorese, Everett C Minchew, Michael D Tarpey, Andrew T Readyoff, Nicholas C Williamson, Cameron A Schmidt, Shawna L McMillin, Emma J Goldberg, Zoe S Terwilliger, Quincy A Spangenburg, Carol A Witczak, Jeffrey J Brault, E Dale Abel, Joseph M McClung, Kelsey H Fisher-Wellman, Espen E Spangenburg","doi":"10.1093/function/zqad012","DOIUrl":"10.1093/function/zqad012","url":null,"abstract":"<p><p>The various functions of skeletal muscle (movement, respiration, thermogenesis, etc.) require the presence of oxygen (O₂). Inadequate O₂ bioavailability (ie, hypoxia) is detrimental to muscle function and, in chronic cases, can result in muscle wasting. Current therapeutic interventions have proven largely ineffective to rescue skeletal muscle from hypoxic damage. However, our lab has identified a mammalian skeletal muscle that maintains proper physiological function in an environment depleted of O₂. Using mouse models of <i>in vivo</i> hindlimb ischemia and <i>ex vivo</i> anoxia exposure, we observed the preservation of force production in the flexor digitorum brevis (FDB), while in contrast the extensor digitorum longus (EDL) and soleus muscles suffered loss of force output. Unlike other muscles, we found that the FDB phenotype is not dependent on mitochondria, which partially explains the hypoxia resistance. Muscle proteomes were interrogated using a discovery-based approach, which identified significantly greater expression of the transmembrane glucose transporter GLUT1 in the FDB as compared to the EDL and soleus. Through loss-and-gain-of-function approaches, we determined that GLUT1 is necessary for the FDB to survive hypoxia, but overexpression of GLUT1 was insufficient to rescue other skeletal muscles from hypoxic damage. Collectively, the data demonstrate that the FDB is uniquely resistant to hypoxic insults. Defining the mechanisms that explain the phenotype may provide insight towards developing approaches for preventing hypoxia-induced tissue damage.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad012"},"PeriodicalIF":5.1,"publicationDate":"2023-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/80/55/zqad012.PMC10165545.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10130679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Do Endogenously Produced and Dietary ω-3 Fatty Acids Act Differently?","authors":"Philip C Calder","doi":"10.1093/function/zqad009","DOIUrl":"10.1093/function/zqad009","url":null,"abstract":"Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are a family of fatty acids distinguished by the presence of the double bond closest to the methyl terminus of the acyl chain being on carbon number 3 counting from the methyl terminal carbon. There are several members of the ω-3 PUFA family. Usually, the most common ω-3 PUFA in the human diet is α-linolenic acid (ALA; 18:3ω-3), an essential fatty acid made in plants from the ω-6 PUFA linoleic acid (LA; 18:2ω-3) by an enzymatic conversion catalyzed by delta-15 desaturase (Figure 1). Animals do not possess the latter enzyme, so they cannot make ALA. Nevertheless, once consumed in the diet, ALA can be converted by animals into long-chain, more unsaturated ω-3 PUFAs, including eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA: 22:6ω-3) (Figure 1). EPA and DHA are biologically active, influencing cell membrane structure, intracellular signaling pathways, gene expression, and lipid mediator synthesis.1 DPA is less well studied but seems to have similar actions to EPA and DHA. Amongst dietary sources, EPA and DHA are found in the highest amounts in fatty fish; they are also present in fish oil-type supplements. EPA and DHA are linked to many health benefits, including reducing the risk of cardiovascular disease and mortality2; these effects are due to beneficial modification of a number of risk factors.3 There is also evidence that EPA and DHA might reduce the risk of developing nonalcoholic fatty liver disease, through effects on hepatic carbohydrate and fat metabolism and on inflammation.4 In general, case-control studies and longitudinal cohort studies provide stronger evidence for the benefits of EPA and DHA on disease outcomes, with findings from randomized controlled trials in patients at risk of, or already with, disease being inconsistent. Circulating and cell and tissue EPA, DPA, and DHA could come directly from the diet or from endogenous biosynthesis starting with ALA as substrate and using the pathway shown in Figure 1. In people with very low or no intake of seafood and not using supplements that contain EPA, DPA, and DHA, it seems likely that much of the body’s EPA, DPA, and DHA are produced through endogenous biosynthesis.5 Thus, a major role of ALA is as a precursor to its more bioactive ω-3 PUFA derivatives. Endogenous biosynthesis is likely to be downregulated when there is more EPA, DPA, and DHA in the diet.6 However, the relative contributions of diet and endogenous biosynthesis to EPA, DPA, and DHA levels in any compartment or pool within the body are not known. Furthermore, whether the origin of these fatty acids affects their biological action is not well studied. A recent paper published in Function starts to address these questions using murine models.7 Daniel et al.7 use wild-type C57Bl/6 mice and fat-1 mice. The latter are transgenic mice expressing the fat-1 gene from Caenorhabditis elegans, which encodes an enzyme with ","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad009"},"PeriodicalIF":0.0,"publicationDate":"2023-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMAL1 in the Adrenal Gland: It's About Time-A Perspective on \"Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior\".","authors":"Brittni N Moore, Jennifer L Pluznick","doi":"10.1093/function/zqad008","DOIUrl":"10.1093/function/zqad008","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 2","pages":"zqad008"},"PeriodicalIF":5.1,"publicationDate":"2023-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9972345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9115352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Gut Microbiome-Endocannabinoidome Axis: A New Way of Controlling Metabolism, Inflammation, and Behavior.","authors":"Cristoforo Silvestri, Vincenzo Di Marzo","doi":"10.1093/function/zqad003","DOIUrl":"10.1093/function/zqad003","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 2","pages":"zqad003"},"PeriodicalIF":5.1,"publicationDate":"2023-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10799506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adrenal-Specific KO of the Circadian Clock Protein BMAL1 Alters Blood Pressure Rhythm and Timing of Eating Behavior.","authors":"Hannah M Costello, G Ryan Crislip, Kit-Yan Cheng, I Jeanette Lynch, Alexandria Juffre, Phillip Bratanatawira, Annalisse Mckee, Ryanne S Thelwell, Victor M Mendez, Charles S Wingo, Lauren G Douma, Michelle L Gumz","doi":"10.1093/function/zqad001","DOIUrl":"10.1093/function/zqad001","url":null,"abstract":"<p><p>Brain and muscle ARNT-like 1 (BMAL1) is a core circadian clock protein and transcription factor that regulates many physiological functions, including blood pressure (BP). Male global <i>Bmal1</i> knockout (KO) mice exhibit ∼10 mmHg reduction in BP, as well as a blunting of BP rhythm. The mechanisms of how BMAL1 regulates BP remains unclear. The adrenal gland synthesizes hormones, including glucocorticoids and mineralocorticoids, that influence BP rhythm. To determine the role of adrenal BMAL1 on BP regulation, adrenal-specific <i>Bmal1</i> (<i>AS^Cre/+</i> ::<i>Bmal1</i>) KO mice were generated using aldosterone synthase Cre recombinase to KO <i>Bmal1</i> in the adrenal gland zona glomerulosa. We confirmed the localization and efficacy of the KO of BMAL1 to the zona glomerulosa. Male <i>AS^Cre/+</i> ::<i>Bmal1</i> KO mice displayed a shortened BP and activity period/circadian cycle (typically 24 h) by ∼1 h and delayed peak of BP and activity by ∼2 and 3 h, respectively, compared with littermate Cre- control mice. This difference was only evident when KO mice were in metabolic cages, which acted as a stressor, as serum corticosterone was increased in metabolic cages compared with home cages. <i>A</i>S <i>^Cre/+</i> ::<i>Bmal1</i> KO mice also displayed altered diurnal variation in serum corticosterone. Furthermore, these mice have altered eating behaviors where they have a blunted night/day ratio of food intake, but no change in overall food consumed compared with controls. Overall, these data suggest that adrenal BMAL1 has a role in the regulation of BP rhythm and eating behaviors.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 2","pages":"zqad001"},"PeriodicalIF":5.1,"publicationDate":"2023-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/20/c0/zqad001.PMC9909366.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10822439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial Cell Metabolism and Vascular Function: A Paradigm Shift?","authors":"Osama F Harraz","doi":"10.1093/function/zqad002","DOIUrl":"10.1093/function/zqad002","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 2","pages":"zqad002"},"PeriodicalIF":5.1,"publicationDate":"2023-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b4/d2/zqad002.PMC9909363.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10799993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Watching Ion Channels on the Move.","authors":"Luis A Pardo","doi":"10.1093/function/zqac072","DOIUrl":"https://doi.org/10.1093/function/zqac072","url":null,"abstract":"Ion channels remain fascinating molecular machines implicated in virtually every cellular function. Their activity can be studied in deep detail using biophysical techniques down to the single-molecule level. However, as large hydrophobic proteins embedded in a lipidic environment, their structure has traditionally been very difficult to study. Cryo-EM approaches have boosted our knowledge in the last few years, expanding the collection of resolved structures almost on a weekly basis. Yet, there are still open questions regarding the structure-function of the channels that are now starting to find answers. Ion channels react rapidly to a wide range of stimuli, opening a pathway for the flow of ions across the membrane. The coupling of the stimulus to the opening of the gate can be studied in ligand-gated channels by comparing the structures of the ligand-bound and unbound channels. Still, such a comparison is more difficult to achieve when the channel responds to physical rather than chemical stimuli, as is the case of voltage-gated channels. The molecular principles of voltage-dependent gating of ion channels have been known for four decades. The mechanism consists, in essence, of the movement of some parts of the protein (the voltage-sensing domains) relative to others. The displacement results in a conformational change that produces the opening of the gate, but the intimate molecular mechanisms linking both events remain only partly known in many cases. Although the problem might appear like an academic discussion for experts at first glance, it has many practical implications. On the one hand—mainly","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac072"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10740532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}