Colardo M, Martella N, Varone M
… +5 more, Pensabene D, Caretti G, Bianchini G, Aramini A, Segatto M
Acta Physiol (Oxf)
· 2025 Jul · PMID 40448398
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AIM: Cancer cachexia is a severe metabolic disorder leading to skeletal muscle atrophy. Muscle wasting is a major clinical problem in cachectic patients, as it limits the efficacy of chemotherapeutic treatments and worse...AIM: Cancer cachexia is a severe metabolic disorder leading to skeletal muscle atrophy. Muscle wasting is a major clinical problem in cachectic patients, as it limits the efficacy of chemotherapeutic treatments and worsens quality of life. Nutritional support based on branched-chain amino acids (BCAA) has been shown to be a promising approach to counteract cachexia-induced muscle atrophy, but its efficacy is still debated. Furthermore, the putative role of di-alanine (Di-Ala) supplementation has yet to be evaluated. The present study therefore sought to assess whether BCAA supplementation, alone or in combination with a Di-Ala peptide, could attenuate muscle wasting in a preclinical model of cancer cachexia. METHODS: To this end, C26 tumor-bearing mice were administered BCAA supplementation, with or without Di-Ala. Body and muscle weights, as well as molecular, biochemical, and morphological analysis, were carried out to characterize prospective changes of markers involved in cachexia and muscle atrophy. RESULTS: The main findings revealed that BCAA supplementation effectively prevented body weight loss and muscle atrophy. Of note, Di-Ala significantly amplified the effects of BCAA. These phenomena were found to be mediated by the suppression of pathways involved in protein catabolism. CONCLUSIONS: Collectively, these results highlight that innovative formulations containing Di-Ala, capable of increasing BCAA bioavailability, may be efficacious in counteracting muscle atrophy, especially during mild-to-moderate cancer cachexia.
De Bartolo A, Romeo N, Angelone T
… +1 more, Rocca C
Acta Physiol (Oxf)
· 2025 Jul · PMID 40433738
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AIM: Timely myocardial reperfusion is essential for restoring blood flow to post-ischemic tissue, thereby reducing cardiac injury and limiting infarct size. However, this process can paradoxically result in additional, i...AIM: Timely myocardial reperfusion is essential for restoring blood flow to post-ischemic tissue, thereby reducing cardiac injury and limiting infarct size. However, this process can paradoxically result in additional, irreversible myocardial damage, known as myocardial ischemia-reperfusion injury (MIRI). The goal of this review is to explore the role of specialized pro-resolving mediators (SPMs) in atherosclerosis and MIRI, and to assess the therapeutic potential of targeting inflammation resolution in these cardiovascular conditions. METHODS: This review summarizes current preclinical and clinical evidence on the involvement of SPMs in the pathogenesis of atherosclerosis and MIRI, acknowledging that several cellular and molecular aspects of their mechanisms of action remain to be fully elucidated. RESULTS: MIRI is a complex phenomenon in which inflammation, initially triggered during ischemia and further amplified upon reperfusion, plays a central role in its pathogenesis. Various cellular and molecular players mediate the initial pro-inflammatory response and the subsequent anti-inflammatory reparative phase following acute myocardial infarction (AMI), contributing both to ischemia- and reperfusion-induced damage as well as to the healing process. SPMs have emerged as key endogenous immunoresolvents with potent anti-inflammatory, antioxidant, and pro-resolving properties that contribute to limit excessive acute inflammation and promote tissue repair. While dysregulated SPM-related signaling has been linked to various cardiovascular diseases (CVD), their precise role in AMI and MIRI remains incompletely understood. CONCLUSION: Targeting inflammation resolution may represent a promising therapeutic strategy for mitigating atheroprogression and addressing a complex condition such as MIRI.
Lauxen JS, Vondenhoff S, Junho CVC
… +9 more, Martin P, Fleig S, Schütt K, Schulze-Späte U, Soehnlein O, Prates-Roma L, Döring Y, Baaten CCFMJ, Noels H
Acta Physiol (Oxf)
· 2025 Jun · PMID 40411205
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BACKGROUND: Patients with chronic kidney disease (CKD) are at increased cardiovascular risk. Since neutrophils play a central role in atherosclerosis and cardiovascular disease, this study analyzed neutrophil function in...BACKGROUND: Patients with chronic kidney disease (CKD) are at increased cardiovascular risk. Since neutrophils play a central role in atherosclerosis and cardiovascular disease, this study analyzed neutrophil function in CKD patients. METHODS: A systematic review of neutrophil function in CKD patients compared to controls was performed according to PRISMA guidelines by searching PubMed and the Web of Science. A meta-analysis summarized the production of reactive oxygen species (ROS) in CKD patients on dialysis in Forest plots. Influencer outlier analyses evaluated risk of bias. RESULTS: Overall, 92 studies were included, of which 18 in the meta-analysis. Although study heterogeneity was high, the systematic review identified primarily reduced phagocytosis capacity but increased neutrophil degranulation and basal ROS production in neutrophils from CKD patients on hemodialysis compared to controls. Phagocytosis and basal ROS production were mainly unaltered in non-dialysis dependent CKD patients and CKD patients on peritoneal dialysis. The meta-analysis confirmed increased ROS generation in basal conditions predominantly in CKD patients on hemodialysis (Hedges g = 1.20, 95% CI: [0.32; 2.09]), with an insufficient study number for a clear comparison to CKD patients on peritoneal dialysis. However, upon neutrophil stimulation with sterile inflammatory triggers, ROS production was also increased in neutrophils from patients on peritoneal dialysis (Hedges g = 0.89, 95% CI: [0.34; 1.43]). CONCLUSION: Increased degranulation and basal ROS formation were observed in neutrophils of CKD patients on hemodialysis, which could contribute to their increased cardiovascular risk. Future studies should compare neutrophil activity in patients of different CKD stages and comorbidities also in relation to cardiovascular outcomes.
Nisr RB, Atrih A, Lara EJG
… +6 more, Lamont D, Luda KM, McCrimmon RJ, Sakamoto K, Rena G, McNeilly AD
Acta Physiol (Oxf)
· 2025 Jun · PMID 40400417
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AIMS: The benefit of salicylate in the treatment of diabetes has been recognized for over a century; however, challenging side effects have prevented widespread use. A better understanding of the relevant enzyme targets...AIMS: The benefit of salicylate in the treatment of diabetes has been recognized for over a century; however, challenging side effects have prevented widespread use. A better understanding of the relevant enzyme targets mediating its anti-hyperglycaemic effect may lead to the development of novel therapies for diabetes. Here, we investigated the contribution of 5'-adenosine monophosphate (AMP)-dependent inhibition of fructose-1,6-bisphosphatase 1 (FBP1) to the anti-hyperglycaemic action of salicylate. METHODS: We studied AMP-insensitive FBP1 G27P knockin (KI) mice through a variety of cellular approaches, including proteomics, Seahorse metabolic analysis, glucose production, and other assays, in addition to a detailed assessment of metabolic responses in vivo. RESULTS: Compared with wild-type littermates, AMP-insensitive FBP1 KI mice were resistant to the effects of the drug on body weight, glucose tolerance, pyruvate disposal, liver lipid content and hepatic glucose production. Compared with wild-type, KI hepatocytes exhibited baseline differences in glycolytic, TCA cycle and fatty acid oxidation enzyme levels, potentially linking gluconeogenic dysregulation and its reversal to non-carbohydrate fuel management. CONCLUSION: Collectively, our data highlight a novel mechanism of action for the effects of salicylate on glycaemia and weight gain, which depends on AMP-mediated allosteric inhibition of FBP1.
Lilliu E, Choi R, Hilber K
… +2 more, Launikonis B, Koenig X
Acta Physiol (Oxf)
· 2025 Jun · PMID 40387448
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AIM: This study investigates the activation and regulation of phasic store-operated calcium entry (pSOCE) in fast- and slow-twitch skeletal muscle fibers. Specifically, we aimed to enhance the sensitivity of pSOCE detect...AIM: This study investigates the activation and regulation of phasic store-operated calcium entry (pSOCE) in fast- and slow-twitch skeletal muscle fibers. Specifically, we aimed to enhance the sensitivity of pSOCE detection in slow-twitch fibers by optimizing ionic conditions and to compare the physiological relevance of pSOCE between fiber types. METHODS: We employed mechanically skinned fast-twitch extensor digitorum longus (EDL) muscle fibers loaded with spectrally distinct Ca-sensitive dyes to simultaneously measure action potential-induced sarcoplasmic reticulum Ca release and t-tubular system Ca dynamics with millisecond resolution. Experimental conditions were optimized by reducing cytosolic Mg and EGTA buffering to enhance Ca release in slow-twitch soleus fibers. Confocal microscopy was used to track t-tubular system Ca depletion and reuptake during electric field stimulation. RESULTS: Skinned soleus fibers exhibited ~8-fold lower Ca release per action potential compared to EDL fibers, yet pSOCE amplitudes were comparable. Reducing Mg and EGTA levels increased Ca release and left pSOCE kinetics in EDL fibers unaltered, but enabled pSOCE measurements in soleus fibers. While pSOCE in EDL fibers followed a linear dependence on the ambient Ca concentration in the t-tubular system, such a relationship was violated in soleus fibers. CONCLUSION: These findings reveal a novel, fiber-type-specific difference in pSOCE regulation. When compared to EDL fibers, soleus fibers exhibited a higher sensitivity to SOCE activation despite releasing less Ca from the sarcoplasmic reticulum upon an action potential. These differences may allow soleus fibers to sustain Ca homeostasis more effectively, be more resilient against disruptions in Ca handling, and entail protection against disease states.
AIM: Microglia exhibit innate immune memory, altering their responses to subsequent challenges. Consumption of high-fat diet (HFD) triggers innate immune responses, but the characteristics of HFD-induced microglial primi...AIM: Microglia exhibit innate immune memory, altering their responses to subsequent challenges. Consumption of high-fat diet (HFD) triggers innate immune responses, but the characteristics of HFD-induced microglial priming remain unclear. We aim to investigate how HFD-induced microglial priming, followed by a lipopolysaccharide (LPS) challenge, affects brain functions. METHODS: Male Wistar rats were divided into control, unprimed, and primed groups. The primed groups received either a single LPS injection (0.5 mg/kg, intraperitoneally) or HFD consumption for 4-8 weeks. Following the priming phase, all rats (except controls) were subjected to an LPS challenge with a 4- or 8-week interval. After 24 h of LPS challenge, cognition, anxiety-, and depressive-like behaviors were assessed. The brain and hippocampus were collected for further analysis. RESULTS: Both LPS- and 4-week HFD-primed groups, followed by LPS challenge, exhibited increased peripheral and brain oxidative stress, impaired neurogenesis, disrupted neurotransmitter balance, and altered glycolysis and Krebs cycle substrates. These changes also caused microglial morphological alterations, elevated C1q levels, and synaptic loss, which were associated with anxiety- and depressive-like behaviors, indicating that 4-week HFD consumption has a similar immune priming ability to a single dose of LPS injection. Extending HFD priming to 8 weeks exacerbated microglial and brain inflammation, synaptic loss, and behavioral deficits. Furthermore, prolonging the interval between priming and LPS challenge worsened inflammation and cognitive decline, suggesting the persistent effects of microglial priming. CONCLUSIONS: HFD consumption persistently and time-dependently primes microglia similar to a single LPS injection, influencing immune responses and contributing to behavioral abnormalities.
Staehr C, Login H, Melnikova EV
… +12 more, Bakun M, Ziemlinska E, Kisiswa L, Ardestani SB, Nolte SS, Beck HC, Hansen LMB, Postnov D, Verkhratsky A, Malik AR, Nykjaer A, Matchkov VV
Acta Physiol (Oxf)
· 2025 Jun · PMID 40342271
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INTRODUCTION: The receptor SorCS2 is involved in the trafficking of membrane receptors and transporters. It has been implicated in brain disorders and has previously been reported to be indispensable for ionotropic gluta...INTRODUCTION: The receptor SorCS2 is involved in the trafficking of membrane receptors and transporters. It has been implicated in brain disorders and has previously been reported to be indispensable for ionotropic glutamatergic neurotransmission in the hippocampus. AIM: We aimed to study the role of SorCS2 in the control of astrocyte-neuron communication, critical for neurovascular coupling. METHODS: Brain slices from P8 and 2-month-old wild-type and SorCS2 knockout (Sorcs2) mice were immunostained for SorCS2, GFAP, AQP4, IB4, and CD31. Neurovascular coupling was assessed in vivo using laser speckle contrast imaging and ex vivo in live brain slices loaded with calcium-sensitive dye. Bulk and cell surface fraction proteomics was analyzed on freshly isolated and cultured astrocytes, respectively, and validated with Western blot and qPCR. RESULTS: SorCS2 was strongly expressed in astrocytes, primarily in their endfeet, of P8 mice; however, it was sparsely represented in 2-month-old mice. Sorcs2 mice demonstrated reduced neurovascular coupling associated with a reduced astrocytic calcium response to neuronal excitation. No differences in vascularization or endothelium-dependent relaxation ex vivo between the 2-month-old groups were observed. Proteomics suggested changes in glutamatergic signaling and suppressed calcium signaling in Sorcs2 brains from both P8 and 2-month-old mice. The increased abundance of glutamate metabotropic receptor 3 in Sorcs2 astrocytes was validated by PCR and Western blot. In cultured Sorcs2 astrocytes, AQP4 abundance was increased in the bulk lysate but reduced in the cell surface fraction, suggesting impaired trafficking. CONCLUSION: The results suggest that SorCS2 expression is important for the development of neurovascular coupling, at least in part by modulating glutamatergic and calcium signaling in astrocytes.
AIM: Amino acids, sugars, short-chain fatty acids (SCFA), vitamins, and other small molecules compose the extracellular metabolome on the airway lumen surface, but how the airway epithelium deals with these molecules has...AIM: Amino acids, sugars, short-chain fatty acids (SCFA), vitamins, and other small molecules compose the extracellular metabolome on the airway lumen surface, but how the airway epithelium deals with these molecules has not been deeply studied. Due to the broad spectrum of metabolites transported by SLC5A8 and SLC5A12, we aim to determine if they are functionally expressed and participate in the absorption of Na, short-chain fatty acids, and monocarboxylates in mouse and human airway epithelium. METHODS: Tracheas isolated from male or female mice and human bronchial epithelial cells (HBECs) were used for electrophysiological studies in the Ussing chamber and to detect members of the SLC16 family by RT-PCR and bulk RNAseq. Additionally, cell lines expressing the human and murine SLC5A8 transporter were employed for uptake studies using a fluorescent lactate probe. RESULTS: We showed for the first time that human and murine airway epithelium express a functional SLC5A8 transporter, facilitating the absorption of glucose metabolites and SCFAs. The Na-coupled monocarboxylate transport was not additive with ENaC-mediated Na absorption in mouse trachea. We observed that valproate acts as an inhibitor of the murine but not of the human SLC5A8 transporter. CONCLUSIONS: Our results demonstrate that several metabolites derived from bacterial and cellular metabolism can be transported from the airway lumen into the epithelial cells, participating in a homeostatic relation of the tissue with its environment.
Aalkjær C, Damkjær M, Baandrup UT
… +15 more, Bertelsen MF, Brøgger T, Brøndum E, Danielsen CC, Funder JA, Grøndahl C, Hasenkam JM, Henriksen PG, Secher NH, Skovgaard N, Smerup MH, Telinius N, Østergaard KH, Bie P, Wang T
Acta Physiol (Oxf)
· 2025 May · PMID 40260757
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BACKGROUND: The circulation of 4-6 m tall giraffes is markedly affected by gravity. To ensure cerebral perfusion, upright giraffes generate a blood pressure in excess of 200 mmHg. Before drinking, the head is lowered by...BACKGROUND: The circulation of 4-6 m tall giraffes is markedly affected by gravity. To ensure cerebral perfusion, upright giraffes generate a blood pressure in excess of 200 mmHg. Before drinking, the head is lowered by 3-5 m, providing exceptional hemodynamic challenges. Here, we provide quantitative hemodynamic measures during head movement and drinking. METHODS: We measured carotid pressure, jugular pressure, heart rate, and blood flow in awake giraffes, along with circulating blood volume and cerebrospinal fluid pressure in anesthetized giraffes. We also analyzed the contractility and innervation of isolated cerebral and extracranial arteries, and the mechanical properties of jugular veins. RESULTS: When heads were lowered for drinking (i) blood pressure at heart level decreased but increased again during drinking, (ii) jugular pressure increased and oscillated during drinking, (iii) heart rate fell, (iv) carotid blood flow was unchanged, while cephalic hemodynamic resistance increased, and (vi) cranial cerebrospinal fluid pressure increased. Small cerebral arteries exhibited strong myogenic responses, particularly at around 100 mmHg, while extracranial arteries responded at higher pressures (200-250 mmHg). The giraffe's blood volume was small and blood pressure sensitive to minor reductions in blood volume. CONCLUSIONS: Central blood pressure decreased when the head was lowered, but drinking per se caused a surprising rise in blood pressure to pre-drinking levels. This rise in blood pressure is likely due to the transfer of esophageal water boli acting on the jugular veins. The cephalic capillaries are protected by a strong myogenic response and sympathetic innervation.