Function (Oxford, England)最新文献

{"title":"Cardiac Timeless Trans-Organically Regulated by miR-276 in Adipose Tissue Modulates Cardiac Function.","authors":"Chao Tang, Qiufang Li, Xiaoya Wang, Zhengwen Yu, Xu Ping, Yi Qin, Yang Liu, Lan Zheng","doi":"10.1093/function/zqad064","DOIUrl":"10.1093/function/zqad064","url":null,"abstract":"<p><p>The interconnection between cardiac function and circadian rhythms is of great importance. While the role of the biological clock gene Timeless (Tim) in circadian rhythm has been extensively studied, its impact on cardiac function remains largely been unexplored. Previous research has provided experimental evidence for the regulation of the heart by adipose tissue and the targeting of miR-276a/b on Timeless. However, the extent to which adipose tissue regulates cardiac Timeless genes trans-organically through miR-276a/b, and subsequently affects cardiac function, remains uncertain. Therefore, the objective of this study was to investigate the potential trans-organ modulation of the Timeless gene in the heart by adipose tissue through miR-276a/b. We found that cardiac-specific Timeless knockdown and overexpression resulted in a significant increase in heart rate (HR) and a significant decrease in Heart period (HP), diastolic intervals (DI), systolic intervals (SI), diastolic diameter (DD), and systolic diameter (SD). miR-276b systemic knockdown resulted in a significant increase in DI, arrhythmia index (AI), and fractional shortening (FS) significantly increased and SI, DD and SD significantly decreased. Adipose tissue-specific miR-276a/b knockdown and miR-276a overexpression resulted in a significant increase in HR and a significant decrease in DI and SI, which were improved by exercise intervention. This study presents a novel finding that highlights the significance of the heart circadian clock gene Timeless in heart function. Additionally, it demonstrates that adipose tissue exerts trans-organ modulation on the expression of the heart Timeless gene via miR-276a/b.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138500701","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":"Overcoming Confounding to Characterize the Effects of Calcium Channel Blockers.","authors":"Sudarshan Rajagopal, Paul B Rosenberg","doi":"10.1093/function/zqad054","DOIUrl":"10.1093/function/zqad054","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41241712","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":"A Reappraisal of the Effects of L-type Ca²⁺ Channel Blockers on Store-Operated Ca²⁺ Entry and Heart Failure.","authors":"Gary S Bird, Diane D'Agostin, Safaa Alsanosi, Stefanie Lip, Sandosh Padmanabhan, Anant B Parekh","doi":"10.1093/function/zqad047","DOIUrl":"10.1093/function/zqad047","url":null,"abstract":"<p><p>Dihydropyridines such as amlodipine are widely used as antihypertensive agents, being prescribed to ∼70 million Americans and >0.4 billion adults worldwide. Dihydropyridines block voltage-gated Ca²⁺ channels in resistance vessels, leading to vasodilation and a reduction in blood pressure. Various meta-analyses show that dihydropyridines are relatively safe and effective in reducing hypertension. The use of dihydropyridines has recently been called into question as these drugs appear to activate store-operated Ca²⁺ entry in fura-2-loaded nonexcitable cells, trigger vascular remodeling, and increase heart failure, leading to the questioning of their clinical use. Given that hypertension is the dominant \"silent killer\" across the globe affecting ∼1.13 billion people, removal of Ca²⁺ channel blockers as antihypertensive agents has major health implications. Here, we show that amlodipine has marked intrinsic fluorescence, which further increases considerably inside cells over an identical excitation spectrum as fura-2, confounding the ability to measure cytosolic Ca²⁺. Using longer wavelength Ca²⁺ indicators, we find that concentrations of Ca²⁺ channel blockers that match therapeutic levels in serum of patients do not activate store-operated Ca²⁺ entry. Antihypertensive Ca²⁺ channel blockers at pharmacological concentrations either have no effect on store-operated channels, activate them indirectly through store depletion or inhibit the channels. Importantly, a meta-analysis of published clinical trials and a prospective real-world analysis of patients prescribed single antihypertensive agents for 6 mo and followed up 1 yr later both show that dihydropyridines are not associated with increased heart failure or other cardiovascular disorders. Removal of dihydropyridines for treatment of hypertension cannot therefore be recommended.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41241710","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":"How Do We Clean Up the Scientific Record?","authors":"Alexei Verkhratsky,&nbsp;Ole H Petersen","doi":"10.1093/function/zqad055","DOIUrl":"10.1093/function/zqad055","url":null,"abstract":"© t a he famous phrase “Errar e human um est, sed in errare perseerar e dia bolicum” (“To err is human, but to persist in error is iabolical”), which is attributed to the Roman philosopher and rator Lucius Annaeus Seneca ( ∼4 bce to 65 ce ), is as r elev ant oday as it al w ays w as. It is particularl y important for science. e all make mistakes, but we should be careful not to persist in rror and, most importantly, do everything we can to correct our rrors and do so as quickly as possible. Otherwise, our scientific ecord will be unreliable and therefore not a secure basis for furher work and rational decision making. In the worst cases, real arm is done to the care of patients. The pr ob lem is often dealt with under the heading of irr e pr oucibility, but it is r eall y a question of getting it right. There are any examples of incorrect findings that wer e perfectl y r e pr ouced by r e peating the mistakes or wrong assumptions others ad made. In extreme cases, fraud or glaring errors, published apers are usually retracted and the scientific record is therefore leaned up. Howev er, ther e ar e unfortunatel y many mor e cases n which seriously flawed articles remain uncorrected. Although e w papers ma y appear that corr ect err oneous articles pr eviusl y pub lished, the wr ong papers usuall y r emain part of the iterature and may continue to cause confusion. In this issue of FUNCTION , Anant Parekh and colleagues rom NIH/NIEHS, North Carolina, publish a salient paper 1 that orrects a serious error in a previously published article 2 that as important consequences for the treatment of hypertenion, the leading cause of death globally, accounting for > 10 illion deaths ann uall y. 3 The issue concerns the mechanism f action of amlodipine, a dih ydrop yridine blocker of voltageated L-type Ca 2 + channels, a first-line choice for the treatent of hypertension. 3 It has for a long time been generally ccepted that amlodipine specifically inhibits opening of L-type a 2 + channels, ther eby r educing the cytosolic Ca 2 + concentraion in vascular smooth muscles, which, in turn, will relax and","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41241711","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":"Breathing and Oxygen Carrying Capacity in Ts65Dn and Down Syndrome.","authors":"Lara R DeRuisseau, Candace N Receno, Caitlin Cunningham, Melissa L Bates, Morgan Goodell, Chen Liang, Brianna Eassa, Jessica Pascolla, Keith C DeRuisseau","doi":"10.1093/function/zqad058","DOIUrl":"10.1093/function/zqad058","url":null,"abstract":"<p><p>Individuals with Down syndrome (Ds) are at increased risk of respiratory infection, aspiration pneumonia, and apnea. The Ts65Dn mouse is a commonly used model of Ds, but there have been no formal investigations of awake breathing and respiratory muscle function in these mice. We hypothesized that breathing would be impaired in Ts65Dn vs. wild-type (WT), and would be mediated by both neural and muscular inputs. Baseline minute ventilation was not different at 3, 6, or 12 mo of age. However, <i>V_T/T_i</i>, a marker of the neural drive to breathe, was lower in Ts65Dn vs. WT and central apneas were more prevalent. The response to breathing hypoxia was not different, but the response to hypercapnia was attenuated, revealing a difference in carbon dioxide sensing, and/or motor output in Ts65Dn. Oxygen desaturations were present in room air, demonstrating that ventilation may not be sufficient to maintain adequate oxygen saturation in Ts65Dn. We observed no differences in arterial <i>P</i>_O2 or <i>P</i>_CO2, but Ts65Dn had lower hemoglobin and hematocrit. A retrospective medical record review of 52,346 Ds and 52,346 controls confirmed an elevated relative risk of anemia in Ds. We also performed eupneic in-vivo electromyography and in-vitro muscle function and histological fiber typing of the diaphragm, and found no difference between strains. Overall, conscious respiration is impaired in Ts65Dn, is mediated by neural mechanisms, and results in reduced hemoglobin saturation. Oxygen carrying capacity is reduced in Ts65Dn vs. WT, and we demonstrate that individuals with Ds are also at increased risk of anemia.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89721633","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":"Breast Milk Epidermal Growth Factor Confers Paracellular Calcium Absorption in the Infant Small Intestine.","authors":"Andreanna Burman, Izumi Kaji","doi":"10.1093/function/zqad057","DOIUrl":"10.1093/function/zqad057","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1a/d5/zqad057.PMC10583193.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49685762","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":"Striatal Dopamine Signals and Reward Learning.","authors":"Pol Bech,&nbsp;Sylvain Crochet,&nbsp;Robin Dard,&nbsp;Parviz Ghaderi,&nbsp;Yanqi Liu,&nbsp;Meriam Malekzadeh,&nbsp;Carl C H Petersen,&nbsp;Mauro Pulin,&nbsp;Anthony Renard,&nbsp;Christos Sourmpis","doi":"10.1093/function/zqad056","DOIUrl":"10.1093/function/zqad056","url":null,"abstract":"Abstract We are constantly bombarded by sensory information and constantly making decisions on how to act. In order to optimally adapt behavior, we must judge which sequences of sensory inputs and actions lead to successful outcomes in specific circumstances. Neuronal circuits of the basal ganglia have been strongly implicated in action selection, as well as the learning and execution of goal-directed behaviors, with accumulating evidence supporting the hypothesis that midbrain dopamine neurons might encode a reward signal useful for learning. Here, we review evidence suggesting that midbrain dopaminergic neurons signal reward prediction error, driving synaptic plasticity in the striatum underlying learning. We focus on phasic increases in action potential firing of midbrain dopamine neurons in response to unexpected rewards. These dopamine neurons prominently innervate the dorsal and ventral striatum. In the striatum, the released dopamine binds to dopamine receptors, where it regulates the plasticity of glutamatergic synapses. The increase of striatal dopamine accompanying an unexpected reward activates dopamine type 1 receptors (D1Rs) initiating a signaling cascade that promotes long-term potentiation of recently active glutamatergic input onto striatonigral neurons. Sensorimotor-evoked glutamatergic input, which is active immediately before reward delivery will thus be strengthened onto neurons in the striatum expressing D1Rs. In turn, these neurons cause disinhibition of brainstem motor centers and disinhibition of the motor thalamus, thus promoting motor output to reinforce rewarded stimulus-action outcomes. Although many details of the hypothesis need further investigation, altogether, it seems likely that dopamine signals in the striatum might underlie important aspects of goal-directed reward-based learning.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10572094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41241713","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":"Elucidating a Complex Mechanism.","authors":"Victor Wray","doi":"10.1093/function/zqad051","DOIUrl":"10.1093/function/zqad051","url":null,"abstract":"ur understanding of the complex dynamic system dri v en by onformational change during adenosine triphosphate (ATP) ydr ol ysis by F 1 -ATPase is of fundamental biochemical imporance. 1 , 2 Cr yo-electr on micr oscopy (Cr yo-EM) studies 3 −5 have ontributed v alua b le structural information on how the F 1 TPase functions, although, in themselves, these have not led o a definiti v e mechanism. The F 1 -ATPase is a multi-subunit sysem containing 3 β-catalytic sites that have been studied by biohysical single-molecule experiments based on direct visualizaion of the rotation of its central γ -subunit. 6 However, it is difcult to esta b lish which interconverting site or sites contribute nergy for the observ ed r otation, gi v en that a site can perform he elementary chemical steps of ATP binding, ATP hydr ol ytic ond cleav a ge, and pr oduct (Pi and adenosine diphosphate, ADP) elease. 7 Originally, the molecular mechanism of ATP syntheis/hydr ol ysis w as studied using classical biochemical pproaches that provided a wealth of fundamental data. A i-site Boyer’s binding change mechanism of ATP syntheis/hydr ol ysis (Nobel Prize for Chemistry, 1997) was postulated etween 1973 and 1993 based on biochemical unisite/multisite atalysis and oxygen exchange experiments. 8 An alternati v e ri-site Nath’s torsional mechanism of energy transduction nd ATP synthesis/hydr ol ysis w as first pr oposed in 1999 and ev eloped ov er the next 25 yr using a nov el m ultidisciplinar y pproac h, 9 whic h inte gr ated physics, c hemistry, bioc hemistry, nd engineering. The dir ect measur ements by Senior and oworkers of the fluorescence quenching of tryptophan probes","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10548849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41164820","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":"Correction to: Do Endogenously Produced and Dietary ω-3 Fatty Acids Act Differently?","authors":"","doi":"10.1093/function/zqad052","DOIUrl":"10.1093/function/zqad052","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/function/zqad009.].</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10532101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41172212","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":"Inactivation of TRPM7 Kinase Targets AKT Signaling and Cyclooxygenase-2 Expression in Human CML Cells.","authors":"Birgit Hoeger,&nbsp;Wiebke Nadolni,&nbsp;Sarah Hampe,&nbsp;Kilian Hoelting,&nbsp;Marco Fraticelli,&nbsp;Nadja Zaborsky,&nbsp;Anna Madlmayr,&nbsp;Viktoria Sperrer,&nbsp;Laura Fraticelli,&nbsp;Lynda Addington,&nbsp;Dirk Steinritz,&nbsp;Vladimir Chubanov,&nbsp;Roland Geisberger,&nbsp;Richard Greil,&nbsp;Andreas Breit,&nbsp;Ingrid Boekhoff,&nbsp;Thomas Gudermann,&nbsp;Susanna Zierler","doi":"10.1093/function/zqad053","DOIUrl":"10.1093/function/zqad053","url":null,"abstract":"<p><p>Cyclooxygenase-2 (COX-2) is a key regulator of inflammation. High constitutive <i>COX-2</i> expression enhances survival and proliferation of cancer cells, and adversely impacts antitumor immunity. The expression of <i>COX-2</i> is modulated by various signaling pathways. Recently, we identified the melastatin-like transient-receptor-potential-7 (TRPM7) channel-kinase as modulator of immune homeostasis. TRPM7 protein is essential for leukocyte proliferation and differentiation, and upregulated in several cancers. It comprises of a cation channel and an atypical α-kinase, linked to inflammatory cell signals and associated with hallmarks of tumor progression. A role in leukemia has not been established, and signaling pathways are yet to be deciphered. We show that inhibiting TRPM7 channel-kinase in chronic myeloid leukemia (CML) cells results in reduced constitutive <i>COX-2</i> expression. By utilizing a CML-derived cell line, HAP1, harboring CRISPR/Cas9-mediated TRPM7 knockout, or a point mutation inactivating TRPM7 kinase, we could link this to reduced activation of AKT serine/threonine kinase and mothers against decapentaplegic homolog 2 (SMAD2). We identified AKT as a direct in vitro substrate of TRPM7 kinase. Pharmacologic blockade of TRPM7 in wildtype HAP1 cells confirmed the effect on <i>COX-2</i> via altered AKT signaling. Addition of an AKT activator on TRPM7 kinase-dead cells reconstituted the wildtype phenotype. Inhibition of TRPM7 resulted in reduced phosphorylation of AKT and diminished <i>COX-2</i> expression in peripheral blood mononuclear cells derived from CML patients, and reduced proliferation in patient-derived CD34⁺ cells. These results highlight a role of TRPM7 kinase in AKT-driven <i>COX-2</i> expression and suggest a beneficial potential of TRPM7 blockade in COX-2-related inflammation and malignancy.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6d/e8/zqad053.PMC10541797.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41160752","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}