Acta Physiol (Oxf)
· 2026 Feb · PMID 41521165
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AIM: Acyl-CoA binding protein plays a vital role in lipid metabolism by mediating the intracellular flux and utilization of long-chain acyl-CoAs. We generated an adipocyte-wide ACBP knockout mouse and a brown adipose tis...AIM: Acyl-CoA binding protein plays a vital role in lipid metabolism by mediating the intracellular flux and utilization of long-chain acyl-CoAs. We generated an adipocyte-wide ACBP knockout mouse and a brown adipose tissue-specific ACBP knockout mouse to investigate ACBP function in adipose tissue. METHODS: Male mice with conditional targeting of the Acbp gene in adipose tissue (Adipoq-Acbp) or brown adipose tissue (Ucp1-Acbp) were generated by crossing Acbp mice with transgenic mice expressing Cre recombinase under the control of the adiponectin (Adipoq-Cre) or uncoupling protein 1 (Ucp1-Cre) promoter, respectively. Systemic energy expenditure was assessed by indirect calorimetry. Body composition was examined using nuclear magnetic resonance. Primary brown and white preadipocytes were isolated to examine their ability to differentiate to mature adipocytes. Lipid composition of adipose tissues was examined by lipidomics. Global changes in gene expression in adipose tissues were examined by RNA sequencing. Tissue respiration was determined using high-resolution respirometry. RESULTS: We demonstrate that loss of ACBP in adipose tissue does not affect body weight, fat and lean mass, food intake and systemic energy expenditure, even under cold stress. Global gene expression analysis shows only minor changes in gene expression, whereas lipidomic profiling reveals a subtle increase in acyl-carnitine levels in brown adipose tissue. Lipolytic activity in white adipose tissue as well as plasma glycerol, nonesterified fatty acid and triacylglycerol levels remained unaffected. In addition, no changes in mitochondrial respiration in BAT were observed. CONCLUSION: Our findings suggest that ACBP is dispensable for adipose tissue function and systemic energy metabolism.
van der Kolk BW, Heinonen S, White JW
… +14 more, Wagner A, Karppinen JE, Saari S, Muniandy M, Metsikkö S, Dillon ET, Groop PH, Saarinen T, Le Roux CW, Virtanen KA, Docherty NG, Pirinen E, Juuti A, Pietiläinen KH
Acta Physiol (Oxf)
· 2026 Feb · PMID 41507695
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AIM: We investigated how weight loss induced by bariatric surgery or lifestyle intervention affects skeletal muscle mitochondrial metabolism. METHODS: We studied two weight-loss cohorts: RYSA (BMI ≥ 35 kg/m; n = 39, incl...AIM: We investigated how weight loss induced by bariatric surgery or lifestyle intervention affects skeletal muscle mitochondrial metabolism. METHODS: We studied two weight-loss cohorts: RYSA (BMI ≥ 35 kg/m; n = 39, including 18 with diabetes) undergoing bariatric surgery, and CRYO (BMI ≥ 30 kg/m; n = 19) undergoing a lifestyle intervention with a low-calorie diet. Assessments were performed at 5-6 and 12 months and included muscle proteome (LC-MS/MS), mitochondrial biogenesis by mtDNA amount (qPCR), number and morphology (transmission electron microscopy) in both cohorts, and mitochondrial oxidative capacity (high-resolution respirometry) in the surgery cohort. RESULTS: Both cohorts achieved clinically meaningful weight loss, greater following surgery (24.4% vs 9.0% at 12 months). Per 1% weight loss, bariatric surgery was associated with significant downregulation of glycolysis pathways at 12 months. OXPHOS complex subunit proteins were associated with upregulation in individuals without diabetes but downregulation in those with diabetes. Lifestyle intervention was associated with downregulated OXPHOS complex subunits at 5 months. Mitochondrial morphology remained unchanged, while mtDNA amount correlated negatively with weight loss percentage in both cohorts. In the surgery cohort, complex I and complex I + II-mediated respiration increased 3.2- and 2.9-fold at 12 months, reflecting improved oxidative capacity. CONCLUSION: Bariatric surgery was associated with increased skeletal muscle mitochondrial respiration despite unchanged morphology and reduced mtDNA amount, whereas lifestyle-induced weight loss showed a transient downregulation of OXPHOS-related proteins with other mitochondrial markers remaining stable. Surgery-induced weight loss may reflect improved mitochondrial efficiency in skeletal muscle, potentially influenced by diabetes status. Long-term functional mitochondrial adaptations after weight loss require future studies. TRIAL REGISTRATION:RYSA: ClinicalTrials.gov ID NCT02882685; CRYO: ClinicalTrials.gov ID NCT01312090.
Acta Physiol (Oxf)
· 2026 Feb · PMID 41498431
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BACKGROUND AND AIMS: Colonic bicarbonate secretion is mediated by the chloride/bicarbonate exchanger SLC26A3 and the cystic fibrosis transmembrane conductance regulator (CFTR). Dysfunction of either causes luminal acidos...BACKGROUND AND AIMS: Colonic bicarbonate secretion is mediated by the chloride/bicarbonate exchanger SLC26A3 and the cystic fibrosis transmembrane conductance regulator (CFTR). Dysfunction of either causes luminal acidosis, altered mucus properties, and inflammation. While physical and functional interactions have been demonstrated in heterologous systems, their relationship in native epithelium is not fully established. We investigated the distinct roles of SLC26A3 and CFTR using human intestinal organoids with inducible SLC26A3 overexpression. METHODS: Human colonic and rectal organoids from healthy controls and cystic fibrosis patients with F508del mutations were studied in the proliferative state with high endogenous CFTR expression and inducible SLC26A3 overexpression. Real-time surface pH measurements, electrophysiological analysis, forskolin-induced swelling assays, and confocal microscopy were employed. RESULTS: Steady-state surface pH was lower in CF versus healthy organoids (7.23 ± 0.03 vs. 7.34 ± 0.03). SLC26A3 overexpression normalized surface pH in CF organoids and CFTR-inhibited organoids, equalizing responses between genotypes. SLC26A3 overexpression corrected abnormal morphology and significantly improved intracellular MUC2 distribution in CF organoids. However, SLC26A3 did not restore fluid secretion in CF organoids or enhance CFTR-mediated electrogenic anion secretion in Ussing chambers. CONCLUSIONS: SLC26A3 and CFTR perform distinct yet complementary functions. SLC26A3 dominates surface pH regulation and maintains bicarbonate efflux independently of CFTR, while CFTR drives agonist-stimulated fluid secretion. SLC26A3's ability to restore pH homeostasis and normalize mucin intracellular distribution in CF organoids demonstrates its critical importance for maintaining colonic mucosal health.
AIM: Urinary tract infections (UTIs) are common and frequently caused by uropathogenic Escherichia coli (UPEC). Whether urinary pH has any influence on the development and progression of UTIs is still widely debated. In...AIM: Urinary tract infections (UTIs) are common and frequently caused by uropathogenic Escherichia coli (UPEC). Whether urinary pH has any influence on the development and progression of UTIs is still widely debated. In this study, we systematically address whether urinary pH affected progression and dissemination of UTIs. METHODS: To assess the effect of urine pH on the development of UTI in vivo, 8-10-week-old female Balb/cJRj mice were randomized to 100 mM NHCl (acid-load), 100 mM NaHCO (base-load), or demineralised water as drinking water intervention 24 h before UTI was induced via installation of either UPEC or vehicle in the urinary bladder. RESULTS: Acid load lowered urinary pH by 0.8-1.0 pH points (p < 0.0001), decreased [HCO ] (p = 0.0002), and increased [titratable acid] (TA, p = 0.0007), [NH ] (p < 0.0001) and net acid concentration (NAC, p < 0.0001), while base load raised urinary pH by 0.3-0.7 pH points (p = 0.0154), increased [HCO ] (p = 0.0358), and decreased [TA] (p = 0.0154), [NH ] (p = 0.0121) and NAC (p = 0.0064). The UPEC infection did not affect urine acid/base parameters. Compared to control, acid load led to elevated urinary levels of tumor necrosis factor α (TNF-α), keratinocyte chemoattractant (KC), interleukin 1β (IL-1β) and IL-6, and reduced bacterial burden in urine (737.6 ± 1315.0 CFU mL vs. 29.5 ± 53.3 CFU mL, p = 0.0030) and kidney (2.39 ± 5.94 CFU mg vs. 0.06 ± 0.14 CFU mg, p = 0.0054). The opposite tendency was observed with base load (2204.0 ± 3135.0 CFU mL urine, 2.23 ± 2.95 CFU mg kidney). CONCLUSION: Thus, increased urine acid excretion reduced UPEC burden in urine and decreased risk of pyelonephritis while enhancing the urinary excretion of proinflammatory cytokines.
AIM: Sensory gating is a neurological mechanism that filters out irrelevant sensory input, protecting cognitive processing from sensory overload. Patients with schizophrenia usually lack sensory gating, which severely af...AIM: Sensory gating is a neurological mechanism that filters out irrelevant sensory input, protecting cognitive processing from sensory overload. Patients with schizophrenia usually lack sensory gating, which severely affects normal cognitive functions due to an overload of irrelevant information. Sensory gating and cognitive tasks have been found to need moderate activity in the medial prefrontal cortex (mPFC). However, the specific control mechanisms of the mPFC remain unknown. We assume that the "Excitation-Inhibition" imbalance in the mPFC can induce schizophrenia-like sensory gating and cognitive defects. METHODS: The current study utilized chemogenetics and FloxP-Cre techniques to examine the distinct roles of glutamatergic and GABAergic neurons in the mPFC in regulating sensory gating and cognitive functions, both in healthy and schizophrenia-like mouse models. RESULTS: Manipulation of neural activity in the mPFC, specifically inhibiting GABAergic neurons or stimulating glutamatergic neurons in the mPFC, caused schizophrenia-like sensory gating deficits, disturbances in temporal order and long-term recognition memory, and hyperlocomotion. Conversely, activating GABAergic neurons or inhibiting glutamatergic neurons mitigated these schizophrenia-like symptoms, including sensory gating deficits, temporal order memory impairments, and hyperlocomotion. CONCLUSIONS: We discovered that a disturbance in the "Excitation-Inhibition" balance in the mPFC significantly contributes to schizophrenia-like sensory gating deficits, cognitive impairments, and hyperlocomotion. Remarkably, correcting this imbalance in schizophrenia-like mice alleviated these deficits, providing profound insights into the regulatory functions of glutamatergic and GABAergic neurons in the mPFC.
Lian J, Lin X, Shi J
… +17 more, Jia M, Zhang W, Yan X, Lu S, Xie D, Zhou J, Zhu Z, Fan Z, He Y, Wu Y, Dong J, Zhang W, Huang K, Zhu M, Wang Y, Huang Z, Teng H
OBJECTIVES: Ependymal cell-derived perilesional glial borders may play a beneficial role in neural regeneration after spinal cord injury (SCI). Yes-associated protein (YAP), a key transcriptional cofactor, is involved in...OBJECTIVES: Ependymal cell-derived perilesional glial borders may play a beneficial role in neural regeneration after spinal cord injury (SCI). Yes-associated protein (YAP), a key transcriptional cofactor, is involved in the control of body organ size by regulating cell differentiation, proliferation, growth, and apoptosis; however, it remains unclear whether the roles and underlying mechanisms of YAP signaling regulate the ependymal cell-derived perilesional glial borders after SCI. METHODS: We established a dorsal cord incision injury mouse model. The YAP; FoxJ1-CreERT2 (YAP-CKO) mice and YAP; FoxJ1-CreERT2; Rosa26 mice were generated to examine the roles of ependymal YAP signaling in SCI. The RNA-seq, western blot, immunostaining, and cell-fate tracing tools were used to investigate the underlying mechanisms of YAP signaling in the regulation of ependymal cell-derived perilesional glial borders after SCI. RESULTS: YAP was activated in ependymal cells after SCI. Interestingly, YAP deletion in ependymal cells (YAP-CKO mice) aggravated the neuronal loss and impaired the formation of perilesional glial borders and then inhibited the functional recovery after SCI. Furthermore, YAP deletion inhibited the proliferation and differentiation of ependymal cells to astrocytes and oligodendrocytes and reduced the secretion of neurotrophic factors after SCI. Mechanically, RNA-seq revealed that the expression of Colorectal Neoplasia Differentially Expressed (CRNDE) was downregulated in YAP-CKO mice. Furthermore, we found downregulation of P300 and β-catenin and upregulation of GSK-3β in YAP ependymal cells after SCI. CONCLUSION: Ependymal YAP signaling promotes the formation of ependymal cell-derived perilesional glial borders in mice through the P300-CRNDE-Wnt/β-catenin pathway after SCI, which provides a novel target for SCI.
AIM: Collagen VI has recently been strongly linked to poor outcomes in heart failure through increased endotrophin, a collagen VI-derived signaling molecule linked to fibrotic remodeling in cardiovascular disease. The mu...AIM: Collagen VI has recently been strongly linked to poor outcomes in heart failure through increased endotrophin, a collagen VI-derived signaling molecule linked to fibrotic remodeling in cardiovascular disease. The mutation of collagen VI can result in Ullrich congenital muscular dystrophy and Bethlem myopathy, pointing to a critical function in muscle physiology. However, the functional role of collagen VI in the heart is poorly understood. In human heart failure with reduced ejection fraction, collagen VI is increased within the remodeled T-tubules, suggesting a possible role in tubular structure and Ca dynamics. METHODS: To investigate this hypothesis, a global knockout of the collagen VI alpha 1 gene (Col6a1) was generated in the rat. RESULTS: T-tubule structure and ryanodine receptor cluster organization were unchanged, but echocardiography demonstrated reduced systolic function. Consistent with this, isolated trabeculae from Col6a1 hearts generated significantly less peak stress, confirming impaired contractile force at the tissue level. Paradoxically, isolated cardiomyocytes from the Col6a1 rat had increased Ca transient amplitude and increased sarcoplasmic reticulum Ca load that would be expected to increase force. β-adrenergic stimulation further increased Ca transient amplitude and was associated with diastolic Ca release events in Col6a1 cardiomyocytes. Furthermore, β-adrenergic stimulation of Col6a1 trabeculae exhibited spontaneous contractions, indicating an increased susceptibility to arrhythmic activity. CONCLUSION: Together, these results indicate collagen VI has a role in both force transduction and Ca cycling in the heart.
Thakur M, Quillard T, Angliker N
… +11 more, Siegrist M, Jansen Y, Yan Y, Wollenhaupt J, Goettsch C, Maegdefessel L, Sachs N, Schindewolf M, Kotelis D, Noels H, Döring Y
Acta Physiol (Oxf)
· 2026 Jan · PMID 41399911
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AIM: Lower-extremity arterial disease (LEAD) is a manifestation of atherosclerotic cardiovascular disease, affecting 230 million people worldwide with increasing prevalence. Medial arterial calcification (MAC) is common...AIM: Lower-extremity arterial disease (LEAD) is a manifestation of atherosclerotic cardiovascular disease, affecting 230 million people worldwide with increasing prevalence. Medial arterial calcification (MAC) is common in LEAD patients and contributes to disease-related mortality. However, therapeutic strategies targeting femoral MAC are lacking, and its underlying mechanisms remain unclear. This study aimed to identify molecular drivers of femoral MAC in LEAD. METHODS & RESULTS: Calcium deposits and pro-calcifying markers were analyzed in human patient samples using von Kossa staining, immunofluorescence, and gene expression analysis. Femorals showed significantly more calcification and pro-calcifying gene expression than carotids. Given MAC abundance in LEAD, we assessed medial calcification in Apoe-/- mice fed a WD for 4/21 weeks. Digital PCR revealed upregulation of Ddr1 and Bmp2 in femoral versus carotid arteries after 21 weeks of WD. DDR1 expression positively correlated with calcification in human femoral samples. In vitro experiments with mouse femoral vs. carotid vascular smooth muscle cells (VSMCs) confirmed a significantly higher prevalence of calcifying proteins (DDR1, BMP2, and RUNX2) in femoral VSMCs. Additionally, calcification analyses in murine and human VSMCs showed that DDR1 inhibition reduced, while DDR1 activation increased, calcium deposition. Transcriptomic analysis revealed elevated NF-κB expression in human femoral arteries, matching data in femoral VSMCs. DDR1 stimulation activated NF-κB, and its inhibition blocked DDR1-induced calcification. CONCLUSION: This study identifies DDR1 as a key driver of calcification in LEAD, operating through NF-κB activation and the expression of calcifying proteins. Targeting DDR1 may offer a novel therapeutic approach to prevent MAC in LEAD.
Acta Physiol (Oxf)
· 2026 Jan · PMID 41395799
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AIM: We have previously described an important role of skeletal muscle tone in body temperature regulation, muscle tone defined as the tonic motor unit activity recorded between movements. Here, we study muscle tone in a...AIM: We have previously described an important role of skeletal muscle tone in body temperature regulation, muscle tone defined as the tonic motor unit activity recorded between movements. Here, we study muscle tone in an extensive sample of new muscles outside (external muscles) and inside (internal muscles) the body core. METHODS: Skeletal muscles of adult, male Wistar rats were chronically implanted with EMG electrodes, and EMG was recorded during exposures to changes in ambient temperatures between 30°C and 5°C. Every consecutive period between movements (M) was identified as one of rest (R), whether the rat was awake or asleep. The amount of tonic motor unit impulse activity, or muscle tone, within (R) was then measured by root mean square analysis of the raw EMG. RESULTS: Muscle tone in external muscles depended strictly on ambient temperature, rising and falling with falling and rising ambient temperatures. In contrast, muscle tone in internal iliacus and psoas muscles showed no relation to ambient temperature but increased markedly during recovery from hypothermia caused by general anesthesia. Mean tonic motor unit firing rates varied between 10 and 75 Hz. CONCLUSION: All examined muscles, except iliopsoas, participated in moment-to-moment regulation of body temperature by heat-producing muscle tone during rest. Iliopsoas appeared to have an emergency function coming into play when the body temperature fell below some critical value, as during anesthesia. The wide range of tonic firing rates indicated that not only slow but also fast, fatigue-resistant motor units contributed to heat-producing muscle tone during rest.
Tognozzi A, Carli F, Abdelkarim S
… +12 more, Cornuti S, Damiani F, Giuliano MG, Miniati A, Nasisi M, De Benedictis L, Ashtiani KC, Scabia G, Maffei M, Baldi P, Gastaldelli A, Tognini P
AIM: Obesity significantly impacts the central nervous system (CNS), increasing the risks of neuropsychiatric disorders and dementia. Intermittent fasting (IF) shows promise for improving peripheral and CNS health, but i...AIM: Obesity significantly impacts the central nervous system (CNS), increasing the risks of neuropsychiatric disorders and dementia. Intermittent fasting (IF) shows promise for improving peripheral and CNS health, but its mechanisms are unclear. METHODS: Using a diet-induced obesity mouse model [10 weeks high fat diet (HFD), then 4 weeks intervention], we compared HFD, HFD-IF, ad libitum control chow (CC), and CC-IF groups. RESULTS: Switching to CC or IF reduced body weight, fat mass, and improved glucose tolerance. Notably, CC-IF uniquely enhanced exploration and reduced anxiety-like behavior. Transcriptomics revealed HFD-induced hippocampal neuroinflammation, whereas metabolomics identified a specific succinate signature in CC-IF mice: plasma concentration decreased, whereas liver and brown adipose tissue (BAT) levels increased. Succinate supplementation mimicked CC-IF metabolic and behavioral benefits and reduced hippocampal inflammation. CONCLUSION: These findings suggest that regulating plasma succinate and its metabolism in liver and BAT may represent a novel biochemical correlate underlying the metabolic, neuroinflammatory, and behavioral improvements induced by IF.
AIM: The mechanism of pulmonary venous remodeling (PVR) remains unclear. We tested the role of the calcium sensing receptor (CaSR) in PVR in pulmonary hypertension (PH). METHODS: PVR was investigated in two PH models, mo...AIM: The mechanism of pulmonary venous remodeling (PVR) remains unclear. We tested the role of the calcium sensing receptor (CaSR) in PVR in pulmonary hypertension (PH). METHODS: PVR was investigated in two PH models, monocrotaline (MCT)-induced PH (MCT-PH) and hypoxia-induced PH (HPH). Human pulmonary venous smooth muscle cells (PVSMCs) were subjected to hypoxia. We examined whether CaSR is involved in the enhanced Ca influx and proliferation in PVSMCs and whether CaSR mediates PVR. RESULTS: PVR presented in distal pulmonary veins (PV) in MCT-PH and HPH rats, accompanied by upregulated CaSR expression in PVSMCs from PH rats. Hypoxia promoted human PVSMCs proliferation with increased CaSR and HIF-1α expression in hypoxic cells. Extracellular Ca restoration induced a huge increase in [Ca] in MCT-PH PVSMCs and human hypoxic PVSMCs, which was significantly higher than that in normal cells. Both the basal [Ca] and proliferate rate in MCT-PH PVSMCs and human hypoxic PVSMCs were higher than in normal PVSMCs. Spermine or R568 enhanced, whereas both NPS2143 or NPS2390 and siCaSR attenuated the extracellular Ca-induced [Ca] increase in rat MCT-PH PVSMCs and human hypoxic PVSMCs and hypoxia-induced human PVSMCs proliferation. Blockade of CaSR with NPS2143 attenuated the increases in basal [Ca] in PVSMCs, right ventricular systolic pressure, and Fulton index in PH rats and prevented PVR and PH development in rats injected with MCT or exposed to hypoxia. CONCLUSIONS: Upregulated CaSR mediating excessive PVSMCs proliferation through enhanced CaSR function and increased intracellular Ca signaling is an important pathogenic mechanism underlying the development of PVR in PH.
AIM: Insulin resistance and pancreatic β-cell failure are key characteristics of type 2 diabetes (T2D). Impaired β-cell function is associated with loss of β-cell identity, resulting in β-cell dedifferentiation or trans-...AIM: Insulin resistance and pancreatic β-cell failure are key characteristics of type 2 diabetes (T2D). Impaired β-cell function is associated with loss of β-cell identity, resulting in β-cell dedifferentiation or trans-differentiation to other endocrine cells. We have shown that β-cell dedifferentiation can be reversed, restoring insulin secretion. The aim of this study was to investigate whether semaglutide or tirzepatide treatment can reverse early stages of β-cell dedifferentiation in db/db mice independent of their effect on body weight. METHODS: After 4 weeks of treatment, 12-week-old db/db mice were assessed by oral glucose tolerance test and immunofluorescence to evaluate glucose clearance capacity and effects on pancreatic β-cell. Body weight, fasting blood glucose, and plasma insulin levels were monitored weekly. Bulk RNA sequencing from islets was performed to identify potential targets. RESULTS: At the doses employed, tirzepatide stabilized, whereas semaglutide was unable to reverse the weight gain of db/db mice. After a 4-week course, both groups showed comparable glucose lowering and increased insulin levels. However, both treatments failed to reverse pancreatic β-cell dedifferentiation, as assessed by either the percentage of cells expressing the dedifferentiation marker ALDH1A3 or FOXO1 translocation. Furthermore, the number of β-cells expressing low levels of PDX1 was higher in both treatment groups than in controls. Gene expression analyses showed a muted transcriptional response in overlapping patterns in islets treated with either compound but no obvious candidate target genes. CONCLUSION: The findings highlight that the early glucose-lowering effects of semaglutide and tirzepatide in db/db mice occur independently of changes to β-cell identity.
Acta Physiol (Oxf)
· 2026 Jan · PMID 41314247
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AIM: The circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) is resistant to glucocorticoids (GC) in adults but responds to dexamethasone (DEX) during the fetal stage. Previously, this resistance of t...AIM: The circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) is resistant to glucocorticoids (GC) in adults but responds to dexamethasone (DEX) during the fetal stage. Previously, this resistance of the adult SCN clock was attributed to a developmental loss of the glucocorticoid receptor (GR). The aim of our study was to re-examine the mechanism underlying SCN clock resistance. METHODS: We detected GR in the adult SCN at the mRNA level (Nr3c1) using RT-qPCR and at the protein level by immunohistochemistry, and examined the effects of DEX on the SCN clock of mPer2 mice ex vivo at embryonic day E17, postnatal days P1-2, P3, P5, P10, and adulthood. RESULTS: Surprisingly, we found that Nr3c1 expression gradually increases from the fetal stage to postnatal day (P)28. In the adult SCN, GR immunoreactivity is present in both neurons and glia. The effect of DEX on the SCN clock disappears shortly after birth. Although DEX does not entrain the adult SCN clock, it acutely increases the expression of Gilz and Sgk1, indicating that GRs in the adult SCN can activate downstream signaling pathways. Inhibition of glial metabolism by fluorocitrate had no effect on resistance to DEX, but treatment with tetrodotoxin sensitized the clock to DEX and induced phase shifts similar to those observed at the fetal stage. CONCLUSION: These results indicate that the adult SCN possesses GRs capable of activating GC-signaling pathways, but the clock is resistant to GC in part due to coupling between individual cellular oscillators.
Lee MD, Clark RA, Buckley C
… +4 more, Zhang X, Uhlen P, Wilson C, McCarron JG
Acta Physiol (Oxf)
· 2025 Dec · PMID 41243947
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AIM: The endothelium regulates cardiovascular function by detecting and interpreting multiple extracellular signals from blood and surrounding tissues, even when these inputs are complex and conflicting. The major challe...AIM: The endothelium regulates cardiovascular function by detecting and interpreting multiple extracellular signals from blood and surrounding tissues, even when these inputs are complex and conflicting. The major challenge faced by the endothelium is decoding this dynamic chemical environment to produce coordinated endothelial cellular responses. In addition to the problems of detection, extracellular signals must be processed correctly intracellularly to generate a functional outcome. METHODS: Ca imaging, network analysis and spectral graph theory across ~1000 endothelial cells in intact arteries and veins. RESULTS: The venous endothelial cell population forms distinct, non-overlapping communities, each tuned to specific agonists. Within these communities, responsive cells act as bridges, linking members through the most direct communication route. Activation of one cell increases the likelihood of activation occurring in its neighbors, creating localized zones of high responsiveness. Only a small (5%) subset of cells responds to multiple activators. These multifunctional cells form unique connections that integrate and distribute signals between the agonist-specific sensing communities. We also show that different agonists elicit unique signaling patterns determined by the stimulus, not by intrinsic cellular properties. Finally, signal decoding strategies differ across vascular beds: venous endothelial cells rely on Ca signal frequency, while arterial cells use signal amplitude. CONCLUSION: The endothelium comprises functionally specialized populations. A small subset of pharmacologically distinct cells plays a key role in signal integration. These hubs are especially vulnerable to disconnection and dysfunction in disease, highlighting them as potential therapeutic targets. The findings presented reveal specialized encoding strategies that distinguish the arterio-venous axis.