Javier Lucas-Romero, Ivan Rivera-Arconada, Jose Antonio Lopez-Garcia
{"title":"Noise or signal? Spontaneous activity of dorsal horn neurons: patterns and function in health and disease.","authors":"Javier Lucas-Romero, Ivan Rivera-Arconada, Jose Antonio Lopez-Garcia","doi":"10.1007/s00424-024-02971-8","DOIUrl":"10.1007/s00424-024-02971-8","url":null,"abstract":"<p><p>Spontaneous activity refers to the firing of action potentials by neurons in the absence of external stimulation. Initially considered an artifact or \"noise\" in the nervous system, it is now recognized as a potential feature of neural function. Spontaneous activity has been observed in various brain areas, in experimental preparations from different animal species, and in live animals and humans using non-invasive imaging techniques. In this review, we specifically focus on the spontaneous activity of dorsal horn neurons of the spinal cord. We use a historical perspective to set the basis for a novel classification of the different patterns of spontaneous activity exhibited by dorsal horn neurons. Then we examine the origins of this activity and propose a model circuit to explain how the activity is generated and transmitted to the dorsal horn. Finally, we discuss possible roles of this activity during development and during signal processing under physiological conditions and pain states. By analyzing recent studies on the spontaneous activity of dorsal horn neurons, we aim to shed light on its significance in sensory processing. Understanding the different patterns of activity, the origins of this activity, and the potential roles it may play, will contribute to our knowledge of sensory mechanisms, including pain, to facilitate the modeling of spinal circuits and hopefully to explore novel strategies for pain treatment.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Penny L Ljungholm, Anna Ermund, Molly M Söderlund Garsveden, Victor L Pettersson, Jenny K Gustafsson
{"title":"The anion exchanger slc26a3 regulates colonic mucus expansion during steady state and in response to prostaglandin E<sub>2</sub>, while Cftr regulates de novo mucus release in response to carbamylcholine.","authors":"Penny L Ljungholm, Anna Ermund, Molly M Söderlund Garsveden, Victor L Pettersson, Jenny K Gustafsson","doi":"10.1007/s00424-024-02975-4","DOIUrl":"10.1007/s00424-024-02975-4","url":null,"abstract":"<p><p>The intestinal epithelium is covered by mucus that protects the tissue from the luminal content. Studies have shown that anion secretion via the cystic fibrosis conductance regulator (Cftr) regulates mucus formation in the small intestine. However, mechanisms regulating mucus formation in the colon are less understood. The aim of this study was to explore the role of anion transport in the regulation of mucus formation during steady state and in response to carbamylcholine (CCh) and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>). The broad-spectrum anion transport inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS), CftrdF508 (CF) mice, and the slc26a3 inhibitor SLC26A3-IN-2 were used to inhibit anion transport. In the distal colon, steady-state mucus expansion was reduced by SLC26A3-IN-2 and normal in CF mice. PGE<sub>2</sub> stimulated mucus expansion without de novo mucus release in wild type (WT) and CF colon via slc26a3 sensitive mechanisms, while CCh induced de novo mucus secretion in WT but not in CF colon. However, when added simultaneously, CCh and PGE<sub>2</sub> stimulated de novo mucus secretion in the CF colon via DIDS-sensitive pathways. A similar response was observed in CF ileum that responded to CCh and PGE<sub>2</sub> with DIDS-sensitive de novo mucus secretion. In conclusion, this study suggests that slc26a3 regulates colonic mucus expansion, while Cftr regulates CCh-induced de novo mucus secretion from ileal and distal colon crypts. Furthermore, these findings demonstrate that in the absence of a functional Cftr channel, parallel stimulation with CCh and PGE<sub>2</sub> activates additional anion transport processes that help release mucus from intestinal goblet cells.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The ethics of artificial intelligence systems in healthcare and medicine: from a local to a global perspective, and back.","authors":"Tijs Vandemeulebroucke","doi":"10.1007/s00424-024-02984-3","DOIUrl":"https://doi.org/10.1007/s00424-024-02984-3","url":null,"abstract":"<p><p>Artificial intelligence systems (ai-systems) (e.g. machine learning, generative artificial intelligence), in healthcare and medicine, have been received with hopes of better care quality, more efficiency, lower care costs, etc. Simultaneously, these systems have been met with reservations regarding their impacts on stakeholders' privacy, on changing power dynamics, on systemic biases, etc. Fortunately, healthcare and medicine have been guided by a multitude of ethical principles, frameworks, or approaches, which also guide the use of ai-systems in healthcare and medicine, in one form or another. Nevertheless, in this article, I argue that most of these approaches are inspired by a local isolationist view on ai-systems, here exemplified by the principlist approach. Despite positive contributions to laying out the ethical landscape of ai-systems in healthcare and medicine, such ethics approaches are too focused on a specific local healthcare and medical setting, be it a particular care relationship, a particular care organisation, or a particular society or region. By doing so, they lose sight of the global impacts ai-systems have, especially environmental impacts and related social impacts, such as increased health risks. To meet this gap, this article presents a global approach to the ethics of ai-systems in healthcare and medicine which consists of five levels of ethical impacts and analysis: individual-relational, organisational, societal, global, and historical. As such, this global approach incorporates the local isolationist view by integrating it in a wider landscape of ethical consideration so to ensure ai-systems meet the needs of everyone everywhere.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mira Hanna, Sabreen Sayed Elnassag, Dina Hisham Mohamed, Marawan Abd Elbaset, Olfat Shaker, Effat A Khowailed, Sarah Ali Abdelhameed Gouda
{"title":"Melatonin and mesenchymal stem cells co-administration alleviates chronic obstructive pulmonary disease via modulation of angiogenesis at the vascular-alveolar unit.","authors":"Mira Hanna, Sabreen Sayed Elnassag, Dina Hisham Mohamed, Marawan Abd Elbaset, Olfat Shaker, Effat A Khowailed, Sarah Ali Abdelhameed Gouda","doi":"10.1007/s00424-024-02968-3","DOIUrl":"10.1007/s00424-024-02968-3","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is considered a severe disease mitigating lung physiological functions with high mortality outcomes, insufficient therapy, and pathophysiology pathways which is still not fully understood. Mesenchymal stem cells (MSCs) derived from bone marrow play an important role in improving the function of organs suffering inflammation, oxidative stress, and immune reaction. It might also play a role in regenerative medicine, but that is still questionable. Additionally, Melatonin with its known antioxidative and anti-inflammatory impact is attracting attention nowadays as a useful treatment. We hypothesized that Melatonin may augment the effect of MSCs at the level of angiogenesis in COPD. In our study, the COPD model was established using cigarette smoking and lipopolysaccharide. The COPD rats were divided into four groups: COPD group, Melatonin-treated group, MSC-treated group, and combined treated group (Melatonin-MSCs). We found that COPD was accompanied by deterioration of pulmonary function tests in response to expiratory parameter affection more than inspiratory ones. This was associated with increased Hypoxia inducible factor-1α expression and vascular endothelial growth factor level. Consequently, there was increased CD31 expression indicating increased angiogenesis with massive enlargement of airspaces and thinning of alveolar septa with decreased mean radial alveolar count, in addition to, inflammatory cell infiltration and disruption of the bronchiolar epithelial wall with loss of cilia and blood vessel wall thickening. These findings were improved significantly when Melatonin and bone marrow-derived MSCs were used as a combined treatment proving the hypothesized target that Melatonin might augment MSCs aiming at vascular changes.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11166745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elisa Bovo, Jaroslava Seflova, Seth L Robia, Aleksey V Zima
{"title":"Protein carbonylation causes sarcoplasmic reticulum Ca<sup>2+</sup> overload by increasing intracellular Na<sup>+</sup> level in ventricular myocytes.","authors":"Elisa Bovo, Jaroslava Seflova, Seth L Robia, Aleksey V Zima","doi":"10.1007/s00424-024-02972-7","DOIUrl":"10.1007/s00424-024-02972-7","url":null,"abstract":"<p><p>Diabetes is commonly associated with an elevated level of reactive carbonyl species due to alteration of glucose and fatty acid metabolism. These metabolic changes cause an abnormality in cardiac Ca<sup>2+</sup> regulation that can lead to cardiomyopathies. In this study, we explored how the reactive α-dicarbonyl methylglyoxal (MGO) affects Ca<sup>2+</sup> regulation in mouse ventricular myocytes. Analysis of intracellular Ca<sup>2+</sup> dynamics revealed that MGO (200 μM) increases action potential (AP)-induced Ca<sup>2+</sup> transients and sarcoplasmic reticulum (SR) Ca<sup>2+</sup> load, with a limited effect on L-type Ca<sup>2+</sup> channel-mediated Ca<sup>2+</sup> transients and SERCA-mediated Ca<sup>2+</sup> uptake. At the same time, MGO significantly slowed down cytosolic Ca<sup>2+</sup> extrusion by Na<sup>+</sup>/Ca<sup>2+</sup> exchanger (NCX). MGO also increased the frequency of Ca<sup>2+</sup> waves during rest and these Ca<sup>2+</sup> release events were abolished by an external solution with zero [Na<sup>+</sup>] and [Ca<sup>2+</sup>]. Adrenergic receptor activation with isoproterenol (10 nM) increased Ca<sup>2+</sup> transients and SR Ca<sup>2+</sup> load, but it also triggered spontaneous Ca<sup>2+</sup> waves in 27% of studied cells. Pretreatment of myocytes with MGO increased the fraction of cells with Ca<sup>2+</sup> waves during adrenergic receptor stimulation by 163%. Measurements of intracellular [Na<sup>+</sup>] revealed that MGO increases cytosolic [Na<sup>+</sup>] by 57% from the maximal effect produced by the Na<sup>+</sup>-K<sup>+</sup> ATPase inhibitor ouabain (20 μM). This increase in cytosolic [Na<sup>+</sup>] was a result of activation of a tetrodotoxin-sensitive Na<sup>+</sup> influx, but not an inhibition of Na<sup>+</sup>-K<sup>+</sup> ATPase. An increase in cytosolic [Na<sup>+</sup>] after treating cells with ouabain produced similar effects on Ca<sup>2+</sup> regulation as MGO. These results suggest that protein carbonylation can affect cardiac Ca<sup>2+</sup> regulation by increasing cytosolic [Na<sup>+</sup>] via a tetrodotoxin-sensitive pathway. This, in turn, reduces Ca<sup>2+</sup> extrusion by NCX, causing SR Ca<sup>2+</sup> overload and spontaneous Ca<sup>2+</sup> waves.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonna Airaksinen, Satu Siimes, Juha Hartikainen, Seppo Ylä-Herttuala
{"title":"Long-term continuous monitoring of arrhythmias in pigs with insertable cardiac monitors.","authors":"Jonna Airaksinen, Satu Siimes, Juha Hartikainen, Seppo Ylä-Herttuala","doi":"10.1007/s00424-024-02962-9","DOIUrl":"10.1007/s00424-024-02962-9","url":null,"abstract":"<p><p>Arrhythmia detection is essential when assessing the safety of novel drugs and therapies in preclinical studies. Many short-term arrhythmia monitoring methods exist, including non-invasive ECG and Holter. However, there are no reliable, long-term, non-invasive, or minimally invasive methods for cardiac arrhythmia follow-up in large animals that allows free movement with littermates. A long follow-up time is needed when estimating the impact of long-lasting drugs or therapies, such as gene therapy. We evaluated the feasibility and performance of insertable cardiac monitors (ICMs) in pigs for minimally invasive, long-term monitoring of cardiac arrhythmias that allows free movement and species-specific behavior. Multiple implantation sites were tested to assess signal quality. ICMs recognized reliably many different arrhythmias but failed to detect single extrasystoles. They also over-diagnosed T-waves, resulting in oversensing. Muscle activity and natural startles of the animals caused noise, leading to a heterogeneous signal requiring post-recording evaluation. In spite of these shortcomings, the ICMs showed to be very useful for minimally invasive long-term monitoring of cardiac rhythm in pigs.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11166848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140863642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Do mechanosensitive Piezo channels set in motion cell volume regulation?","authors":"Alexander A Mongin","doi":"10.1007/s00424-024-02973-6","DOIUrl":"10.1007/s00424-024-02973-6","url":null,"abstract":"","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nermeen Bastawy, Aliaa E M K El-Mosallamy, Samira H Aljuaydi, Huda O AbuBakr, Rabab Ahmed Rasheed, A S Sadek, R T Khattab, Wael Botros Abualyamin, Shereen E Abdelaal, Amy F Boushra
{"title":"SGLT2 inhibitor as a potential therapeutic approach in hyperthyroidism-induced cardiopulmonary injury in rats.","authors":"Nermeen Bastawy, Aliaa E M K El-Mosallamy, Samira H Aljuaydi, Huda O AbuBakr, Rabab Ahmed Rasheed, A S Sadek, R T Khattab, Wael Botros Abualyamin, Shereen E Abdelaal, Amy F Boushra","doi":"10.1007/s00424-024-02967-4","DOIUrl":"10.1007/s00424-024-02967-4","url":null,"abstract":"<p><p>Hyperthyroidism-induced cardiac disease is an evolving health, economic, and social problem affecting well-being. Sodium-glucose cotransporter protein 2 inhibitors (SGLT2-I) have been proven to be cardio-protective when administered in cases of heart failure. This study intended to investigate the potential therapeutic effect of SGLT2-I on hyperthyroidism-related cardiopulmonary injury, targeting the possible underlying mechanisms. The impact of the SGLT2-I, dapagliflozin (DAPA), (1 mg/kg/day, p.o) on LT4 (0.3 mg/kg/day, i.p)-induced cardiopulmonary injury was investigated in rats. The body weight, ECG, and serum hormones were evaluated. Also, redox balance, DNA fragmentation, inflammatory cytokines, and PCR quantification in heart and lung tissues were employed to investigate the effect of DAPA in experimentally induced hyperthyroid rats along with histological and immunohistochemical examination. Coadministration of DAPA with LT4 effectively restored all serum biomarkers to nearly average levels, improved ECG findings, and reinstated the redox balance. Also, DAPA could improve DNA fragmentation, elevate mtTFA, and lessen TNF-α and IGF-1 gene expression in both organs of treated animals. Furthermore, DAPA markedly improved the necro-inflammatory and fibrotic cardiopulmonary histological alterations and reduced the tissue immunohistochemical expression of TNF-α and caspase-3. Although further clinical and deep molecular studies are required before transposing to humans, our study emphasized DAPA's potential to relieve hyperthyroidism-induced cardiopulmonary injury in rats through its antioxidant, anti-inflammatory, and anti-apoptotic effects, as well as via antagonizing the sympathetic over activity.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11166784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140874770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Allein Plain, Laura Knödl, Ines Tegtmeier, Sascha Bandulik, Richard Warth
{"title":"The ex vivo perfused mouse adrenal gland-a new model to study aldosterone secretion.","authors":"Allein Plain, Laura Knödl, Ines Tegtmeier, Sascha Bandulik, Richard Warth","doi":"10.1007/s00424-024-02950-z","DOIUrl":"10.1007/s00424-024-02950-z","url":null,"abstract":"<p><p>Aldosterone is a steroid hormone that is important for maintaining the volume and ionic composition of extracellular fluids and is produced in the zona glomerulosa of the adrenal cortex. The basic mechanisms controlling aldosterone secretion are known. However, more detailed studies on the regulation of aldosterone secretion often fail due to the lack of suitable models: although secretion can be studied in cultured adrenocortical cells under defined conditions, the differentiation status of the cells is difficult to control and the complex anatomy of the adrenal cortex is lost. In living animals, the physiological context is intact, but the influences are manifold and the examination conditions cannot be sufficiently controlled. One method that closes the gap between cell models and studies in living animals is the isolated perfused adrenal gland. In the past, this method has provided important data on the pathophysiology of adrenal glands from larger animals, but the technique was not used in mice. Here, we developed a method for isolation and perfusion of the mouse adrenal gland to study aldosterone secretion. This technique preserves the complex anatomical and functional context of the mouse adrenal cortex, to ensure defined experimental conditions and to minimize extra-adrenal influences. Initial series of experiments with the ex vivo perfused mouse adrenal gland show that this model offers the possibility for unique insights into pathophysiological regulatory principles and is suitable for the use of genetically modified mouse models.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mei Li, Ahmed A Hasan, Chang Chu, Johann-Georg Hocher, Yvonne Liu, Xiaoli Zhang, Xin Chen, Benito Yard, Bernhard K Krämer, Berthold Hocher
{"title":"Only bioactive forms of PTH (n-oxPTH and Met18(ox)-PTH) inhibit synthesis of sclerostin - evidence from in vitro and human studies.","authors":"Mei Li, Ahmed A Hasan, Chang Chu, Johann-Georg Hocher, Yvonne Liu, Xiaoli Zhang, Xin Chen, Benito Yard, Bernhard K Krämer, Berthold Hocher","doi":"10.1007/s00424-024-02928-x","DOIUrl":"10.1007/s00424-024-02928-x","url":null,"abstract":"<p><p>Sclerostin (SOST) is produced by osteocytes and is known as a negative regulator of bone homeostasis. Parathyroid hormone (PTH) regulates calcium, phosphate as well as vitamin D metabolism, and is a strong inhibitor of SOST synthesis in vitro and in vivo. PTH has two methionine amino acids (positions 8 and 18) which can be oxidized. PTH oxidized at Met18 (Met18(ox)-PTH) continues to be bioactive, whereas PTH oxidized at Met8 (Met8(ox)-PTH) or PTH oxidized at Met8 and Met18 (Met8, Met18(di-ox)-PTH) has minor bioactivity. How non-oxidized PTH (n-oxPTH) and oxidized forms of PTH act on sclerostin synthesis is unknown. The effects of n-oxPTH and oxidized forms of PTH on SOST gene expression were evaluated in UMR106 osteoblast-like cells. Moreover, we analyzed the relationship of SOST with n-oxPTH and all forms of oxPTH in 516 stable kidney transplant recipients using an assay system that can distinguish in clinical samples between n-oxPTH and the sum of all oxidized PTH forms (Met8(ox)-PTH, Met18(ox)-PTH, and Met8, Met18(di-ox)-PTH). We found that both n-oxPTH and Met18(ox)-PTH at doses of 1, 3, 20, and 30 nmol/L significantly inhibit SOST gene expression in vitro, whereas Met8(ox)-PTH and Met8, Met18(di-ox)-PTH only have a weak inhibitory effect on SOST gene expression. In the clinical cohort, multivariate linear regression showed that only n-oxPTH, but not intact PTH (iPTH) nor oxPTH, is independently associated with circulating SOST after adjusting for known confounding factors. In conclusion, only bioactive PTH forms such as n-oxPTH and Met18(ox)-PTH, inhibit SOST synthesis.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}