American Journal Of Physiology. Cell Physiology[JOURNAL]
Sun
200 papers
Exercise beneficially reshapes fasted rat skeletal muscle involving the combined action of β-hydroxybutyrate and palmitoleic acid.
Lara Castillo NA, Khan H, Zotti T … +12 more , Pinto G, Giacco A, Cerulo L, Cuomo A, Cardinale G, Amoresano A, Camerini S, Vito P, Lombardi A, Lanni A, Moreno M, de Lange P
Am J Physiol Cell Physiol · 2026 Apr · PMID 41740633 · Publisher ↗
We previously observed that mild exercise causes structural and functional modifications in fasted skeletal muscle, both in rodents and humans. Wistar rats, housed at thermoneutrality, were submitted to mild exercise dur...
We previously observed that mild exercise causes structural and functional modifications in fasted skeletal muscle, both in rodents and humans. Wistar rats, housed at thermoneutrality, were submitted to mild exercise during a 66 h-period of fasting by five 30-min-treadmill runs at 15 m/min without inclination. To gain deeper insight into the underlying mechanisms/factors, we studied alterations in the proteome, lipidome, and cellular signaling/metabolic pathways, comparing the combined intervention to each separate intervention. Untargeted proteome analysis of gastrocnemius muscle revealed that exercise with fasting inversely modulated proteome networks involved in the proteasome, cellular respiration, and muscle development with respect to fasting alone. Targeted lipidomic analysis revealed palmitoleic acid (P) to be increased by exercise in fasted muscle, an observation that adds to the previously observed increase in muscle β-hydroxybutyrate (BHB). In muscle L6 myoblasts, cultured under conditions that mimicked fasting, we studied P versus BHB-induced alterations in Akt, AMPK, and mTOR signaling, crucial for glucose metabolism and myogenesis. We observed that P counteracted the repressing effect of BHB in L6 muscle cells on Akt Ser 473 phosphorylation and did not induce AMPK Thr172 phosphorylation, as opposed to BHB. These observations reflect the response to exercise we previously observed in fasting muscle. Both compounds increased sarcolemmal GLUT4 levels. BHB normalized P-induced inhibition of mTOR signaling. Finally, the myogenic factors Myogenin and MyoD expression were inversely regulated by BHB and P. In conclusion, we identify P and BHB as important players in the response to exercise during fasting regarding glucose sensitivity and muscle maintenance. We have previously shown that exercise during fasting spares muscle tissue accompanied by increased muscle β-hydroxybutyrate levels and AMPK, Akt, and mTOR signaling. Untargeted proteomic and targeted lipidomic analysis revealed that exercise reversed the fasting-induced muscle protein profile and increased the level of palmitoleic acid. In muscle cells, the combination of β-hydroxybutyrate and palmitoleic acid mimicked the signaling events previously observed in vivo, rendering both factors key triggers in the beneficial effect of exercise during fasting.
Subunit-specific roles of LRRC8 proteins in determining glutamate permeability of astrocytic volume-regulated anion channels.
Chandler ML, Sprague AD, Nalwalk JW … +1 more , Mongin AA
Am J Physiol Cell Physiol · 2026 Apr · PMID 41740631 · Full text
Volume-regulated anion channels (VRACs) are ubiquitous chloride channels that play important roles in cell volume regulation and numerous other physiological processes. VRACs are heteromeric complexes composed of leucine...
Volume-regulated anion channels (VRACs) are ubiquitous chloride channels that play important roles in cell volume regulation and numerous other physiological processes. VRACs are heteromeric complexes composed of leucine-rich repeat-containing proteins LRRC8A-E. LRRC8 subunit composition determines biophysical properties of VRACs, including permeability to small signaling molecules. Here, we used primary astrocyte cultures from wild-type and genetically modified C57BL/6 mice to investigate ) subunit composition of native VRACs in the brain and ) subunit determinants of VRAC permeability to the excitatory neurotransmitter glutamate. Quantitative real-time PCR (qRT-PCR) and RNA-seq analyses revealed high expression of in mouse forebrain and astrocytes. Genetic deletion of the essential LRRC8A protein abolished swelling-activated glutamate release, measured as efflux of the nonmetabolizable d-[H]aspartate, confirming the crucial role of VRACs in this process. RNAi-mediated knockdown of individual subunits identified LRRC8A and LRRC8C as key components of glutamate-permeable astrocytic VRACs. qRT-PCR and Western blot analyses further showed that knockdown of LRRC8A or LRRC8C reciprocally altered the protein stability of the partner subunit without affecting their mRNA levels. A similar pattern of mutual regulation was observed between LRRC8A and LRRC8D. In contrast to LRRC8C, downregulation of LRRC8D had a more limited impact on glutamate release. Additional double-knockdown experiments demonstrated that LRRC8C- and LRRC8D-containing channels form distinct VRAC populations. This model was further supported by Western blot results showing no reciprocal regulation of LRRC8C and LRRC8D stability. Together, these findings refine our understanding of how the subunit organization of native brain VRACs governs gliotransmitter release, with implications for normal brain function and neurological disease. Volume-regulated anion channels (VRACs) are ubiquitously expressed chloride channels composed of LRRC8A-E proteins. In human disorders, gain or loss of VRAC function leads to severe neurological phenotypes, potentially due to altered release of amino acid neurotransmitters. Here, we show that glutamate-permeable VRACs in brain astrocytes are primarily composed of LRRC8A and LRRC8C proteins. These findings provide insight into subunit organization of native VRACs in the CNS, with implications for normal brain function and neurological disease.
Neuroimmune interactions in cardiovascular homeostasis and disease.
Toumpourleka M, Stavrakis S
Am J Physiol Cell Physiol · 2026 Apr · PMID 41740625 · Full text
Cardiovascular homeostasis is an adaptive process shaped by the interplay between the nervous system and the heart. Emerging evidence demonstrates that immune cells integrate within and across these signaling pathways to...
Cardiovascular homeostasis is an adaptive process shaped by the interplay between the nervous system and the heart. Emerging evidence demonstrates that immune cells integrate within and across these signaling pathways to modulate inflammatory responses to injury. This neuroimmune interface has a fundamental role in cardiovascular homeostasis and, when dysregulated, may contribute to the pathogenesis of several cardiovascular diseases. Despite its importance, research on the neuroimmune mechanisms in cardiovascular disease is scarce, possibly because it stands upon an intersection of two traditionally separate fields: immunology and neuroscience. This review provides a comprehensive overview of the role of autonomic nervous system within the brain-heart axis, with a focus on signaling pathways that regulate immune function. We detail the bidirectional afferent and efferent connections among central autonomic centers, cardiovascular, and immune tissues in maintaining homeostasis. Finally, we discuss how these neuroimmune circuits are altered in three major cardiovascular diseases, representative of both low-degree chronic inflammation and autonomic dysfunction: heart failure with preserved ejection fraction, hypertension, and atrial fibrillation. Our synthesis of current literature highlights the necessity for a deeper understanding of neuroimmune interactions. Advancing this knowledge may be crucial for developing targeted therapies that improve patient outcomes.
Characterization of cardiac disease-associated mutations in RyR2 Ca- and caffeine-binding sites.
Chirasani VR, Patwardhan A, Yamaguchi N
Am J Physiol Cell Physiol · 2026 Apr · PMID 41740622 · Full text
Cardiac Ca release channels, type-2 ryanodine receptors (RyR2s), play a pivotal role in cardiac muscle contraction by releasing Ca from the sarcoplasmic reticulum. Over 200 missense mutations in humans have been reported...
Cardiac Ca release channels, type-2 ryanodine receptors (RyR2s), play a pivotal role in cardiac muscle contraction by releasing Ca from the sarcoplasmic reticulum. Over 200 missense mutations in humans have been reported to be associated with cardiac diseases. Here, we characterize three RyR2 variants, Q3925E, W4646R, and Q4937K. Q3925E and W4646R mutations are in the Ca- and caffeine-binding sites, respectively. Our molecular dynamics simulations predicted that the Q4937 residue in the carboxyl terminal domain forms a hydrogen bond with the central domain where the Ca-binding site is located. Three mutant RyR2s were expressed in heterologous cells, and activities of the recombinant mutant RyR2 channels were determined by [H]ryanodine binding methods. As expected, Q3925E greatly reduced Ca-dependent activation and W4646R abolished caffeine activation. Our novel finding is that Q3925E increased inhibitory effects by divalent cations, Ca and Mg, resulting in a strong loss-of-function phenotype. Both W4646R and Q4937K increased affinities for Ca activation, and reduced or unchanged Ca inhibitions, exhibiting typical gain-of-function phenotypes. Caffeine failed to activate the Q3925E mutant at resting Ca but restored its activation at ∼20 µM Ca, where the Q3925E mutant is in the subactivated state. Computational analysis of the mutated structures suggested that the Q3925E mutation does not reduce Ca binding to its site but rearranges domain interface between the central domain involving Ca-binding site and carboxyl terminal domain, which directly interacts with the channel pore. Thus, it is possible that the Q3925E-RyR2 mutation alters signal transmission between activating Ca binding and pore opening. Q3925E in RyR2 is a part of Ca-binding site and is known to associate with cardiac sudden death. Our functional and structural modeling data suggested that the Q3925E mutation does not reduce Ca binding but alter a domain interaction, causing an impaired Ca activation of RyR2. We also found that the Q3925E mutation increases channel inhibition by Mg and Ca, resulting in a strong loss-of-function phenotype.
Monkeypox virus: the complexities of a resurgent threat.
Full F, Port JR, Bojkova D
Am J Physiol Cell Physiol · 2026 Apr · PMID 41730293 · Publisher ↗
Mpox disease has emerged from obscurity into the global spotlight, as the monkeypox virus (MPXV) has sparked multiple independent outbreaks with sustained human-to-human transmission-proving it can spread, adapt, and pe...
Mpox disease has emerged from obscurity into the global spotlight, as the monkeypox virus (MPXV) has sparked multiple independent outbreaks with sustained human-to-human transmission-proving it can spread, adapt, and persist. Furthermore, these events have exposed critical gaps in our understanding of MPXV's molecular virology and its interactions with the host immune system. A wide host range, adaptable genomic architecture, immune evasion, and waning immunity due to the discontinuation of smallpox vaccination are possible factors contributing to increased spill-overs and increasing epidemic potential. This review consolidates current insights into the MPXV lifecycle, outlining the viral molecular machinery and strategies used to hijack host cellular pathways for replication and spread. We further dissect the dynamic interplay between MPXV and host immunity, from interferon resistance to natural killer cell evasion and the tug-of-war with cellular and humoral responses. Finally, we evaluate the current landscape of therapeutic interventions and available vaccination strategies aimed at curbing transmission and reducing disease burden. Throughout, we emphasize the most pressing knowledge gaps that must be addressed to strengthen outbreak resilience and guide effective long-term response strategies.
GFP reporter system reveals cell-to-cell variability in aquaporin-2 expression.
Chen L, Murillo-de-Ozores AR, Park E … +2 more , Ou SM, Knepper MA
Am J Physiol Cell Physiol · 2026 Apr · PMID 41730290 · Publisher ↗
Vasopressin regulates transcription of the aquaporin-2 gene () in collecting duct principal cells. To investigate regulatory mechanisms in gene transcription, we engineered an reporter cell line using CRISPR/Cas9 to in...
Vasopressin regulates transcription of the aquaporin-2 gene () in collecting duct principal cells. To investigate regulatory mechanisms in gene transcription, we engineered an reporter cell line using CRISPR/Cas9 to insert a green fluorescent protein (GFP) cassette at the endogenous gene locus in mpkCCD cells. In the absence of dDAVP (1-desamino-8-D-arginine-vasopressin), a vasopressin analog, these cells exhibited low or undetectable GFP and Aqp2 expression in all cells. dDAVP stimulation (1 nM dDAVP for 48 h) markedly increased both GFP and Aqp2 expression together with reversal upon dDAVP removal. These observations demonstrate that GFP faithfully tracks Aqp2 expression. Interestingly, fewer than 50% of cells express GFP and Aqp2 after dDAVP or forskolin, indicating significant variability even though they were clonally derived. We flow-sorted the GFP cells (Aqp2) and GFP cells (Aqp2), regrew them, and restimulated them separately with dDAVP. Cells originating from GFP cells gave rise to both GFP cells and GFP cells, and GFP cells similarly regenerated both GFP and GFP populations in the same proportion. Flow cytometry analysis of the DNA content showed variability in cell cycle phases, with most GFP cells in G0/G1, and most GFP cells in G2/S. RNA-seq analysis of the GFP and GFP cells revealed increased abundance of cell cycle-related transcripts in the GFP cells. We conclude that: ) heterogeneity in Aqp2 expression is related to cell cycle state and ) the newly generated reporter cell line will likely serve as a useful tool to study transcriptional regulation. To investigate regulatory mechanisms in gene transcription, we engineered an reporter cell line using CRISPR/Cas9 to insert a green fluorescent protein (GFP) cassette at the endogenous gene locus in mpkCCD cells. We demonstrate that the GFP reporter accurately and dynamically tracks the expression and regulation of endogenous Aqp2. We reveal that Aqp2 heterogeneity in mpkCCD cells is at least partly driven by differences in cell cycle phase.
Partial reduction of sympathetic noradrenaline synthesis enhanced insulin secretion and cell-cycle-associated activity of pancreatic β cells in mice.
Ogawa R, Suzuki M, Hara S … +3 more , Sakano D, Kume S, Ichinose H
Am J Physiol Cell Physiol · 2026 Apr · PMID 41730287 · Publisher ↗
Type 2 diabetes is caused by dysfunction of pancreatic β cells. Sympathetic neurons innervate pancreatic β cells and noradrenaline inhibits insulin secretion and proliferation of pancreatic β cells in vitro. Previously,...
Type 2 diabetes is caused by dysfunction of pancreatic β cells. Sympathetic neurons innervate pancreatic β cells and noradrenaline inhibits insulin secretion and proliferation of pancreatic β cells in vitro. Previously, we have generated a genetically engineered mice exhibiting inducible and sympathetic neuron-selective loss of the tyrosine hydroxylase gene (-cKO mice), resulting in approximately 70% decline of pancreatic noradrenaline levels. In this study, we investigated the effects of sustained and downregulated sympathetic noradrenergic signaling on the pancreatic β cells using -cKO mice. Intraperitoneal glucose tolerance test revealed higher glucose tolerance in -cKO mice than the control mice without any difference in insulin tolerance test. -cKO mice also exhibited higher circulating insulin levels under glucose challenge. We also found that proliferative activity of pancreatic β cells increased in -cKO mice. These results indicate that partial and sustained suppression of sympathetic noradrenaline signaling could enhance insulin secretion and proliferative activity of pancreatic β cells. In addition, we found that -cKO mice showed partial alleviation of streptozotocin-induced hyperglycemia accompanied by increased β-cell proliferative response. Our data suggest that sympathetic noradrenaline synthesis can be a potential therapeutic target for diabetes. In this paper, we found that inducible and partial reduction of noradrenaline synthesis in the sympathetic neurons increased circulating insulin levels under glucose challenges and upregulated proliferative activity of pancreatic β cells in mice. Moreover, inducible downregulation of sympathetic noradrenaline signaling also partially attenuated streptozotocin-induced hyperglycemia. These results suggest that sympathetic noradrenaline signaling should control insulin secretion and proliferative activity of β cells and that sympathetic noradrenaline synthesis can be a therapeutic target for diabetes.
High-fat diet and obesity each increase tumor cell proliferation and muscle wasting in experimental cancer cachexia.
Counts BR, Bonetto A, Chan HL … +7 more , Au ED, Jiang Y, Couch ME, Guttridge DC, Ostrowski MC, Koniaris LG, Zimmers TA
Am J Physiol Cell Physiol · 2026 Apr · PMID 41722042 · Full text
High-fat diet (HFD) and associated obesity are suggested to predispose to cancer development, complicate cancer treatment, and accelerate mortality. Paradoxically, obese patients with lung cancer are reported to live lon...
High-fat diet (HFD) and associated obesity are suggested to predispose to cancer development, complicate cancer treatment, and accelerate mortality. Paradoxically, obese patients with lung cancer are reported to live longer, suggesting that high body mass is protective. Given that cachexia-tumor-induced weight loss with adipose and muscle wasting-is prevalent in lung cancer, we speculated that patients with obesity might survive longer due to the protective effect of larger tissue reservoirs, slowing time to fatal wasting. Thus, we modeled this condition using lean and high-fat diet (HFD)-induced obese mice with Lewis lung carcinoma (LLC) tumors versus nontumor-bearing controls. We also assessed the effects of feeding HFD to lean mice with and without LLC tumors. HFD and obese-HFD mice without tumors gained weight over the study, with obese-HFD mice exhibiting low muscle mass with obesity at endpoint. Low-fat diet (LFD)-fed lean mice with LLC tumors (LFD-LLC) showed no change in total body weight, but exhibited reduced skeletal muscle, heart, and fat pad mass along with hepatosplenomegaly at endpoint. HFD and pre-existing obesity both modified the response to Lewis lung carcinoma (LLC) tumors. HFD did not affect tumor-induced weight loss, fat loss, or tumor burden, but worsened loss of gastrocnemius, tibialis anterior, and heart muscle, prevented hepatosplenomegaly, and enhanced tumor cell proliferation and expression of the cachexia-inducing cytokine, interleukin-6 (IL-6). Obese-HFD mice showed greater tumor burden versus LFD and the worst cachexia phenotypes, including greater weight loss and muscle loss than HFD or LFD. This worsened cachexia was associated with increased blood-borne inflammatory cytokines, increased phosphorylated STAT3 in muscle, and increased IL-6 expression in muscle, spleen, and tumor. Obese-HFD was associated with the highest rate of tumor cell proliferation in vivo, and serum from obese HFD mice increased LLC cell proliferation in vitro. Thus, HFD and pre-existing obesity each separately enhance inflammation, cachexia, and tumor growth. These distinct contributions of HFD and chronic adiposity are potential therapeutic targets to slow cachexia and tumor growth in cancer. High-fat diet and obesity are linked to increased cancer risk, but the impact on cachexia development remains unclear. Using mouse models, this study demonstrates high-fat diet and obesity each exacerbate muscle wasting, tumor growth, and tumor and muscle IL-6 expression. Our study reveals distinct, overlapping effects with implications for cancer and cachexia interception.
Placental small extracellular vesicles as modulators of bisphenol A-induced oxidative stress and mitochondrial activation in human astrocytoma cells (U-373 MG).
Nencini S, Pifferi A, Passaponti S … +7 more , Severi FM, Bocchi C, Canaletti S, Romagnoli R, Cresti L, Ermini L, Ietta F
Am J Physiol Cell Physiol · 2026 Apr · PMID 41721783 · Publisher ↗
Astrocytes play a crucial role in maintaining central nervous system homeostasis, supporting neuronal function and regulating oxidative stress. The placenta, through the secretion of small extracellular vesicles (sEVs),...
Astrocytes play a crucial role in maintaining central nervous system homeostasis, supporting neuronal function and regulating oxidative stress. The placenta, through the secretion of small extracellular vesicles (sEVs), facilitates communication between the maternal and fetal environments, potentially mitigating external stressors. Bisphenol A (BPA), an endocrine disruptor, has been implicated in oxidative stress and mitochondrial dysfunction, particularly in the developing brain. However, the mechanisms by which placental sEVs influence astrocyte responses to BPA remain unclear. This study investigates the effects of BPA on astrocyte oxidative stress and mitochondrial activity and explores how placental sEVs modulate these responses. Human glioblastoma astrocytoma (U-373 MG) cells were exposed to environmentally relevant concentrations of BPA (10 nM), with or without placental sEVs isolated from human term placental explants. Reactive oxygen species (ROS) levels, mitochondrial activation, and antioxidant enzyme expression (SOD1, GCLC, and GSTA) were assessed. Direct BPA exposure increased astrocyte ROS levels and mitochondrial activation, indicative of oxidative stress. Placental sEVs were rapidly internalized by astrocytes and counteracted BPA-induced ROS accumulation, restoring mitochondrial homeostasis. Notably, sEVs from BPA-exposed placental explants were more efficiently incorporated into astrocytes, suggesting an adaptive response. sEVs treatment also upregulated antioxidant enzyme expression and reduced inflammatory cytokine markers (CCL2 and IL-1β), indicating a potential protective mechanism. These findings suggest that placental sEVs play a critical role in modulating astrocyte responses to oxidative stress and mitochondrial dysfunction. The ability of sEVs to restore redox homeostasis highlights their potential physiological function in fetal neuroprotection against environmental stressors. The study demonstrates that BPA induces oxidative stress and mitochondrial dysfunction in human astrocytes. It introduces a novel role of sEVs in counteracting these effects by reducing ROS, restoring mitochondrial activity, and upregulating antioxidant enzymes. Notably, sEVs from BPA-exposed placental explants were more efficiently incorporated into astrocytes, suggesting an adaptive protective mechanism. These findings highlight a potential fetal neuroprotective role of placental sEVs against environmental stressors.
Activation of TMEM175 lysosomal ion channels by CysLT1 receptor antagonists.
Li K, Satpute Janve V, Le SD … +5 more , Days EL, Bauer JA, Lazarenko RM, Gulsevin A, Denton JS
Am J Physiol Cell Physiol · 2026 Apr · PMID 41670588 · Publisher ↗
TMEM175 is an AKT-activated lysosomal potassium- and proton-permeable channel that functions to dissipate voltage and pH gradients generated by the V-type H-ATPase. Loss-of-function variants in TMEM175 have been identifi...
TMEM175 is an AKT-activated lysosomal potassium- and proton-permeable channel that functions to dissipate voltage and pH gradients generated by the V-type H-ATPase. Loss-of-function variants in TMEM175 have been identified as genetic risk factors for Parkinson's disease, highlighting the potential of small-molecule activators as a novel therapeutic strategy for this disease. We developed a high-throughput screening (HTS) assay using HEK-293 cells stably overexpressing TMEM175 at the cell surface and screened 960 Food and Drug Administration (FDA)-approved drugs for TMEM175 potentiators. The screen identified 71 activators, including the cysteinyl leukotriene 1 receptor (CysLT1R) antagonists, pranlukast and montelukast. Because HEK-293 cells lack CysLT1R expression, we suspected these drugs may be direct channel activators. Fluorescence and automated patch-clamp assays were used to evaluate the dose dependency of pranlukast, montelukast, zafirlukast, and the known TMEM175 activator, (2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB). These experiments revealed rank-order potencies and efficacies of DCPIB ∼ zafirlukast > montelukast ≫ pranlukast. DCPIB, zafirlukast, and pranlukast activated TMEM175 independently of AKT activation, whereas the AKT inhibitor MK2206 partially inhibited montelukast-dependent TMEM175 activation. Computer modeling revealed a conformation-dependent solvent-accessible cavity near T119 and H449 that could participate in drug-induced activation, prompting us to examine these sites with mutagenesis. Not only did T119A and H449A mutations decrease apparent potencies of DCPIB, zafirlukast, and montelukast, but the T119A mutation produced a constitutively open channel phenotype. This study adds zafirlukast to the short list of moderately potent TMEM175 activators and identifies a region of the channel that contributes to activation gating. TMEM175 regulates lysosomal voltage and pH and is genetically linked to Parkinson's disease. Our study identifies zafirlukast and related drugs as activators, defines their AKT dependency, and maps structural determinants of gating. These results open new avenues for targeting TMEM175 in neurodegenerative diseases.
Comparison of receptor expression and cholecystokinin signaling between left and right nodose ganglia.
Ritchey CR, McCune KX, Peters JH
Am J Physiol Cell Physiol · 2026 Apr · PMID 41661036 · Full text
The bilateral vagus nerves play a critical role in autonomic control and feeding behavior. The left and right vagi innervate different portions of the gastrointestinal tract with recent reports suggesting functional diff...
The bilateral vagus nerves play a critical role in autonomic control and feeding behavior. The left and right vagi innervate different portions of the gastrointestinal tract with recent reports suggesting functional differences between left and right vagal afferents. Vagal afferents originating in the nodose ganglia (NG) detect mechanical and chemical cues, including gut peptides such as cholecystokinin (CCK), which promotes satiation via the CCK1 receptor (CCK1R). Recent work demonstrates that CCK1R-expressing afferents are more abundant and responsive in right NG, but the cellular mechanisms underlying this asymmetry remain unclear. Most CCK1R-containing vagal afferent neurons co-express the cation channel transient receptor potential vanilloid subtype 1 (TRPV1), which contributes to CCK-induced activation of vagal afferent neurons and may explain differences in signaling between the left and right vagal populations. Moreover, the lateralized expression and function of other receptors important to feeding remains to be investigated. Here, we assessed receptor and ion channel expression in left and right NG using NanoString mRNA profiling and examined functional responses to CCK and TRPV1 agonist capsaicin with fluorescent calcium imaging. We found that the left NG showed greater gene expression for TRP channels, including TRPV1, and contained a greater number of TRPV1+ afferents. Meanwhile, right NG had greater expression of the hormone receptor CCK1R and exhibited enhanced calcium responses to CCK. Together, these results identify key differences in receptor/ion channel expression and function between left and right vagal afferents, advancing our understanding of the cellular mechanisms behind lateralized vagal signaling. The left and right vagus nerves control feeding but innervate different parts of the gastrointestinal tract, suggesting differences between left and right vagal afferents and their signaling. We assessed gene expression and functional responses from left and right vagus nerves. We found the left vagus had greater expression of TRP channels, whereas the right vagus had more hormone receptors and exhibited enhanced responses to CCK. These differences advance our understanding of lateralized vagal signaling.
Microglia alter autonomic nucleus neuronal activation after peripheral cytokine challenge.
Castellanos EA, Schwerdtfeger LA, Smith BN … +1 more , Tobet SA
Am J Physiol Cell Physiol · 2026 Mar · PMID 41660994 · Full text
The autonomic nervous system (ANS) coordinates the body's response to stress. Proinflammatory cytokines [e.g., tumor necrosis factor-alpha (TNFα)], released in response to different stressors, may influence underlying pa...
The autonomic nervous system (ANS) coordinates the body's response to stress. Proinflammatory cytokines [e.g., tumor necrosis factor-alpha (TNFα)], released in response to different stressors, may influence underlying pathophysiology involving autonomic dysfunction. The present study evaluated the impact of peripheral TNFα on cellular activation in brain stem nuclei associated with autonomic function, including the dorsal vagal complex (DVC) and the ventral lateral medulla (VLM). Mice received a single intraperitoneal injection of TNFα and were processed 2 h later to identify immunoreactive c-Fos in brain stem nuclei as a measure of cellular activity. The number of c-Fos-immunoreactive cells increased after TNFα challenge within the DVC and VLM. Cells immunoreactive for c-Fos were concentrated lateral to the area postrema (AP), a circumventricular organ medial to the subdivision of the caudal portion of the nucleus of the solitary tract (cNTS) within the DVC. To examine the role of microglia in mediating cellular responses to peripheral TNFα, minocycline was administered into the fourth ventricle to decrease microglial function. Minocycline treatment reduced ionized calcium binding adapter molecule 1 (IBA-1) immunoreactivity in the AP and cNTS. When animals were challenged with TNFα after receiving minocycline, fewer c-Fos-positive cells were induced in the DVC and selectively in the rostral VLM. These findings highlight the spatial selectivity of cells in the brain stem to increased peripheral proinflammatory signaling, as well as the impact of resident microglia on autonomic circuitry responses. This study investigates how peripheral tumor necrosis factor-alpha (TNFα) affects neuronal activity in autonomic nuclei of the brain stem and how microglia contribute to this response. Peripheral TNFα increased neuronal activation (c-Fos expression) in the dorsal vagal complex (DVC) and ventrolateral medulla (VLM), particularly near the area postrema. Inhibiting microglia with intracerebroventricular minocycline reduced both microglial markers and TNFα-induced neuronal activity, suggesting that microglia play a key role in modulating cytokine-driven autonomic signaling in the brain stem.
The angiotensin II receptor antagonist telmisartan promotes renal recovery after ischemia-reperfusion injury by reprogramming fatty acid metabolism.
Chu C, Delić D, Zhang Z … +8 more , Zeng S, Gaballa MMS, Klein T, Elitok S, Hocher CF, Krämer BK, Chen X, Hocher B
Am J Physiol Cell Physiol · 2026 Mar · PMID 41643201 · Publisher ↗
Current clinical guidelines recommend withholding renin-angiotensin-aldosterone system (RAAS) inhibitors during acute kidney injury (AKI) due to concerns over impaired glomerular perfusion. However, their potential to mi...
Current clinical guidelines recommend withholding renin-angiotensin-aldosterone system (RAAS) inhibitors during acute kidney injury (AKI) due to concerns over impaired glomerular perfusion. However, their potential to mitigate post-AKI inflammation and fibrosis remains unexplored. We hypothesized that telmisartan, an angiotensin II receptor blocker (ARB) with reported peroxisome proliferator-activated receptor gamma (PPAR-γ) activity, would enhance recovery from ischemic AKI. Male Wistar rats were subjected to unilateral nephrectomy and 45-min ischemia in the contralateral kidney, or sham surgery. Animals were randomized to receive telmisartan (3 mg/kg/day) or placebo for 10 days, starting 1 wk before injury. Telmisartan treatment significantly accelerated the recovery of renal function and attenuated tubular necrosis, inflammation, and the expression of injury biomarkers. At the whole kidney tissue level at 72 h postischemia-reperfusion injury (IRI), bulk RNA-sequencing compared with healthy control mice without IRI revealed apparent broad metabolic dysfunction, with suppression of fatty acid oxidation and mitochondrial pathways, which may reflect both injury-driven changes in cellular composition and transcriptional regulation within surviving cells. These transcriptomic findings 72 h after IRI were significantly blunted or even abolished by telmisartan. These treatment effects did not show evidence of direct PPAR-γ pathway activation. This study suggests that the metabolic modulatory effects of certain angiotensin II receptor blockers may provide therapeutic benefit during the recovery phase of AKI, independent of direct PPAR-γ signaling. RAAS inhibitors are routinely withheld during acute kidney injury (AKI) because of concerns about impaired renal perfusion. Contrary to this dogma, we show that telmisartan enhances renal recovery following ischemia-reperfusion injury. Transcriptomic analyses reveal that telmisartan restores fatty acid oxidation and mitochondrial-peroxisomal lipid metabolism, key pathways suppressed in AKI. These findings suggest that selected RAAS inhibitors may actively promote post-AKI metabolic recovery rather than merely pose hemodynamic risk.
Publisher's note for Schierwagen et al., volume 325, 2023, p. C129-C140.
Am J Physiol Cell Physiol · 2026 Feb · PMID 41637718 · Publisher ↗
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Publisher's note for Alcober-Boquet et al., volume 326, 2024, p. C880-C892.
Am J Physiol Cell Physiol · 2026 Feb · PMID 41637717 · Publisher ↗
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Tumor-associated macrophages: orchestrators of the tumor microenvironment.
Echols JB, Meehan AW, Marotto KA … +2 more , Ordonez V, Hildreth BE
Am J Physiol Cell Physiol · 2026 Apr · PMID 41631922 · Publisher ↗
Macrophages are critical cellular mediators within the innate immune system and are the central effectors of chronic inflammation at the cellular level. Here, macrophages regulate the ongoing, simultaneous processes of t...
Macrophages are critical cellular mediators within the innate immune system and are the central effectors of chronic inflammation at the cellular level. Here, macrophages regulate the ongoing, simultaneous processes of tissue inflammation, destruction, and repair. They also play an integral role in recruiting key cell types within the inflammatory and wound healing response. Cancer is a chronic inflammatory state and is largely considered a wound that does not heal. As in wound healing, where macrophages engulf and/or destroy foreign insults, macrophages have the potential to also eliminate tumor cells. However, it is now well known that these early proinflammatory, antitumor responses by macrophages are nullified as macrophages repolarize into protumor, anti-inflammatory tumor-associated macrophages (TAMs) in response to tumor cell and microenvironmental-derived factors. After this point, TAMs drive neoplastic progression in multiple distinct ways. This indirect control of tumor progression, where TAMs share great functional overlap with the direct control elicited by neoplastic cells, supports TAMs being central orchestrators and later conductors of the tumor microenvironment (TME)-the focus of our review.
The cardiac neurovascular unit: sympathetic control of the capillary network in aging and transplantation.
Poli L, Olianti C, Pignataro MG … +5 more , Di Bona A, Sacconi L, d'Amati G, Mongillo M, Zaglia T
Am J Physiol Cell Physiol · 2026 Mar · PMID 41609600 · Publisher ↗
Sympathetic nerves are key regulators of cardiac performance, yet their micro-anatomical relationship with the coronary microcirculation remains incompletely defined. Here, we identify a previously underappreciated cardi...
Sympathetic nerves are key regulators of cardiac performance, yet their micro-anatomical relationship with the coronary microcirculation remains incompletely defined. Here, we identify a previously underappreciated cardiac NeuroVascular Unit (NVU), in which sympathetic fibers frequently lie in close anatomical apposition to capillary endothelial cells. Using confocal and ultrastructural imaging in mouse and human hearts, we demonstrate that a substantial fraction of tyrosine hydroxylase-positive processes aligns with the capillary network, suggesting a structural framework for local neurovascular communication. Cardiac aging was associated with fragmentation and rarefaction of sympathetic fibers, accompanied by cardiomyocyte atrophy and capillary remodeling characterized by increased vessel density and reduced caliber. Pharmacological sympathectomy in young mice reproduced these changes, establishing a causal link between sympathetic integrity, cardiomyocyte trophism, and microvascular organization. Control experiments excluded direct vascular toxicity of 6-hydroxydopamine, and combined adrenalectomy-sympathectomy confirmed that these effects were independent of circulating catecholamines. Analysis of transplanted human hearts, an established clinical model of abrupt cardiac denervation, revealed an early-established and persistent reduction in capillary diameter compared with controls, mirroring the phenotype observed in mice. Together, these findings define the cardiac NVU as a structural neurovascular interface integrating sympathetic, endothelial, and myocyte compartments, with potential functional implications. Recognition of this neurovascular architecture revises current paradigms of cardiac autonomic regulation and suggests new avenues for targeting microvascular-neuronal apposition in cardiac aging and transplantation. This study identifies a previously unrecognized cardiac neurovascular unit in which sympathetic fibers lie in close anatomical apposition to capillary endothelial cells. Disruption of this cell-to-cell interface, during aging, pharmacological sympathectomy, or following heart transplantation, is associated with capillary remodeling and cardiomyocyte atrophy. These findings broaden current concepts of cardiac autonomic regulation and highlight the coronary microcirculation as a structural component shaped by sympathetic integrity.
Acute ketone monoester ingestion increases monocyte lysine β-hydroxybutyrylation and plasma β-hydroxybutyrate amino acid conjugates in humans.
Marcotte-Chénard A, Sandilands RE, Teixeira AA … +6 more , McCarthy SF, Moya-Garzon MD, Goldberg E, Long JZ, Islam H, Little JP
Am J Physiol Cell Physiol · 2026 Mar · PMID 41604251 · Publisher ↗
Endogenous ketosis during fasting can induce β-hydroxybutyrylation of lysine residues on proteins (known as Kbhb) in human immune cells and increase circulating β-hydroxybutyrate (BHB) amino acid conjugates, both of whic...
Endogenous ketosis during fasting can induce β-hydroxybutyrylation of lysine residues on proteins (known as Kbhb) in human immune cells and increase circulating β-hydroxybutyrate (BHB) amino acid conjugates, both of which are hypothesized to have functional physiological consequences. It remains unknown if similar modifications occur with acute consumption of an exogenous ketone monoester (KME) supplement [()-3-hydroxybutyl ()-3-hydroxybutyrate], which robustly increases circulating BHB. Thirteen healthy adults (7 females; 6 males, age: 28 ± 7 yr) consumed 0.750 g/kg body mass KME with blood samples collected before and after 2 h, coinciding with peak plasma BHB concentration. Monocytes (CD14) were isolated by negative immunomagnetic selection for Kbhb assessment by immunoblotting. Plasma BHB-amino acid conjugates were quantified by mass spectrometry. Blood BHB concentration significantly increased after KME consumption ( < 0.0001), peaking at 2 h (5.0 ± 0.8 mmol/L). Compared with baseline, monocyte Kbhb was significantly increased after 2 h (∼70% increase; = 0.004). Plasma BHB-amino acid conjugates, including BHB-phenylalanine, -leucine, -valine, and -methionine were also increased at 2 h ( < 0.0001). Changes in capillary blood BHB and BHB-amino acid concentrations were positively correlated ( ≥ 0.58; ≤ 0.046), suggesting a dose-dependent increase. Acute high-dose KME ingestion increases monocyte lysine Kbhb and plasma BHB amino acid conjugates in healthy humans, highlighting the possible immunomodulatory and systemic signaling effects of raising BHB through exogenous ketone supplementation. This study provides the first in vivo evidence that exogenous ketone supplementation elevates lysine Kbhb in monocytes of healthy humans. Exogenous ketone supplementation also increased recently discovered BHB-amino acid conjugates, including BHB-phenylalanine, -leucine, -valine, and -methionine. These results highlight the potential immunomodulatory and systemic signaling effects of exogenous ketones.
Adamts5 deletion exacerbates inflammation and fibrosis resulting in compromised skeletal muscle regeneration.
Dulos J, Sun R, Jovanovska V … +2 more , Kolb F, Stupka N
Am J Physiol Cell Physiol · 2026 Mar · PMID 41604241 · Publisher ↗
The extracellular matrix (ECM) protease Adamts5 and its ECM substrates are critical regulators of inflammation and fibrosis, whether Adamts5 also regulates muscle regeneration is not known. Right tibialis anterior (TA) m...
The extracellular matrix (ECM) protease Adamts5 and its ECM substrates are critical regulators of inflammation and fibrosis, whether Adamts5 also regulates muscle regeneration is not known. Right tibialis anterior (TA) muscles from adult or wild-type mice were injected with glycerol to induce injury. In uninjured muscles and at 7 and 14 days after injury, TA contractile function was determined in situ, followed by an assessment of pathology using histology and immunohistochemistry. Immunoblotting was performed for the versikine fragment, which is generated when Adamts5 cleaves its substrate versican. Versikine protein, which correlates with Adamts5 proteolytic activity, was lower in uninjured and injured TA muscles from versus wild-type mice. In uninjured TA muscles, Adamts5 deletion of the catalytic and ancillary domains decreased the absolute (P) and normalized to muscle size (sP) force output, with no significant effect on muscle mass and myofiber size. Adamts5 deletion compromised regeneration with greater impairment evident at the later timepoint. Force output (P and sP) was lower in mice at 7 and 14 days after injury. TA mass and myofiber size were only decreased at 14 days after injury, whereas embryonic myosin heavy chain expression did not significantly differ between genotypes. Degeneration, mononuclear infiltrates, and ECM deposition including fibronectin protein were greater in injured TA muscles from mice. Resolution of inflammation was also delayed in mice, with more infiltrating macrophages observed at 14 days after injury. In conclusion, Adamts5 regulates the balance between muscle regeneration, fibrosis, and inflammation following glycerol injury. Glycerol injury to mouse hindlimb muscles results in inefficient regeneration and fibrosis. Adamts5 is a secreted protease, which degrades extracellular matrix (ECM) proteins and has an emerging role in inflammation, fibrosis, and muscle development. In Adamts5-deficient mice, muscle degeneration, inflammation, and fibrosis were increased, and contractile function was impaired for up to 14 days after glycerol injury when compared with wild-type mice. These findings demonstrate the significant role of Adamts5 in muscle regeneration.
Have we been overlooking K channels in the era of CFTR modulators?
Becq F
Am J Physiol Cell Physiol · 2026 Mar · PMID 41569642 · Publisher ↗
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