Kidney International, volume 105, issue 3, pages 562-581

Single-cell RNA sequencing reveals transdifferentiation of parathyroid chief cells into oxyphil cells in patients with uremic secondary hyperthyroidism.

Jianping Mao 1, 2
, 
Huaizhou You 1, 2
, 
Mengjing Wang 1
, 
Mengjing Wang 1, 2
, 
Yong Ba 3
, 
Yongbing Ba 4
, 
Jing Qian 1
, 
Jing Qian 1
, 
P Cheng 1
, 
Chuhan Lu 1
, 
Jing Chen 1
, 
Jing Chen 1, 2
Show full list: 12 authors
1
 
2
 
3
 
OE Biotech Co., Ltd., Shanghai, China | 
4
 
OE Biotech Co, Ltd, Shanghai, China | 
Publication type: Journal Article
Publication date: 2024-03-01
scimago Q1
SJR: 3.886
CiteScore: 23.3
Impact factor: 14.8
ISSN: 00852538, 15231755
Nephrology
Abstract
The parathyroid gland is one of the main organs that regulate calcium and phosphorus metabolism. It is mainly composed of chief cells and oxyphil cells. Oxyphil cell counts are low in the parathyroid glands of healthy adults but are dramatically increased in patients with uremia and secondary hyperparathyroidism (SHPT). Increased oxyphil cell counts are related to drug treatment resistance, but the origin of oxyphil cells and the mechanism of proliferation remain unknown. Herein, three types of parathyroid nodules (chief cell nodules, oxyphil cell nodules and mixed nodules, respectively) excised from parathyroid glands of uremic SHPT patients were used for single-cell RNA sequencing (scRNA-seq), other molecular biology studies, and transplantation into nude mice. Through scRNA-seq of parathyroid mixed nodules from three patients with uremic SHPT, we established the first transcriptomic map of the human parathyroid and found a chief-to-oxyphil cell transdifferentiation characterized by gradual mitochondrial enrichment associated with the uremic milieu. Notably, the mitochondrial enrichment and cellular proliferation of chief cell and oxyphil cell nodules decreased significantly after leaving the uremic milieu via transplantation into nude mice. Remarkably, the phenotype of oxyphil cell nodules improved significantly in the nude mice as characterized by decreased mitochondrial content and the proportion of oxyphil cells to chief cells. Thus, our study provides a comprehensive single-cell transcriptome atlas of the human parathyroid and elucidates the origin of parathyroid oxyphil cells and their underlying transdifferentiating mechanism. These findings enhance our understanding of parathyroid disease and may open new treatment perspectives for patients with chronic kidney disease. The parathyroid gland is one of the main organs that regulate calcium and phosphorus metabolism. It is mainly composed of chief cells and oxyphil cells. Oxyphil cell counts are low in the parathyroid glands of healthy adults but are dramatically increased in patients with uremia and secondary hyperparathyroidism (SHPT). Increased oxyphil cell counts are related to drug treatment resistance, but the origin of oxyphil cells and the mechanism of proliferation remain unknown. Herein, three types of parathyroid nodules (chief cell nodules, oxyphil cell nodules and mixed nodules, respectively) excised from parathyroid glands of uremic SHPT patients were used for single-cell RNA sequencing (scRNA-seq), other molecular biology studies, and transplantation into nude mice. Through scRNA-seq of parathyroid mixed nodules from three patients with uremic SHPT, we established the first transcriptomic map of the human parathyroid and found a chief-to-oxyphil cell transdifferentiation characterized by gradual mitochondrial enrichment associated with the uremic milieu. Notably, the mitochondrial enrichment and cellular proliferation of chief cell and oxyphil cell nodules decreased significantly after leaving the uremic milieu via transplantation into nude mice. Remarkably, the phenotype of oxyphil cell nodules improved significantly in the nude mice as characterized by decreased mitochondrial content and the proportion of oxyphil cells to chief cells. Thus, our study provides a comprehensive single-cell transcriptome atlas of the human parathyroid and elucidates the origin of parathyroid oxyphil cells and their underlying transdifferentiating mechanism. These findings enhance our understanding of parathyroid disease and may open new treatment perspectives for patients with chronic kidney disease. Advancing parathyroid anatomy understanding through single-cell RNA sequencing in uremic secondary hyperparathyroidismKidney InternationalVol. 105Issue 3PreviewThis commentary explores the recent application of single-cell RNA sequencing in the study of uremic secondary hyperparathyroidism, shedding light on the cellular dynamics within parathyroid glands. The use of single-cell RNA sequencing reveals new insights into the differentiation processes of chief and oxyphil cells, challenging traditional views and highlighting the potential of this technology in advancing our understanding of parathyroid anatomy. Full-Text PDF
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Springer Nature
Integrated transcriptomic and proteomic analyses for the characterization of parathyroid oxyphil cells in uremic patients
Mao J., You H., Wang M., Ni L., Zhang Q., Zhang M., Chen J.
Amino Acids scimago Q2 wos Q3 Open Access , 
2022-03-29,  citations by CoLab: 4 ,  Abstract  
Chief cells are the predominant cells in parathyroid glands of healthy adults; however, parathyroid oxyphil cells, whose function is unknown, increase dramatically in patients with secondary hyperparathyroidism (SHPT). Calcitriol and calcimimetics are the most powerful treatments for SHPT, while the mechanisms leading to calcitriol or calcimimetic resistance in oxyphil cell–predominant SHPT are unknown. Here we used transcriptomic and proteomic techniques to characterize oxyphil cells by comparing the differences between chief and oxyphil cell nodules of parathyroid glands in uremic patients. Compared to chief cell nodules, the most marked expression increases in oxyphil cell nodules were for mitochondrion-associated proteins. The mitochondria number and mitochondrial DNA content were also significantly increased in oxyphil cell nodules. Moreover, oxyphil cell nodules expressed parathyroid-specific factors, and exhibited lower levels of proliferation-related proteins but higher synthesis and secretion level of parathyroid hormone (PTH). The protein expression of SHPT-regulating factors, including vitamin-D receptor, calcium-sensing receptor and Klotho, were significantly downregulated in oxyphil cell nodules. Therefore, oxyphil cells characterized by enrich mitochondria in uremic patients showed higher synthesis and secretion of PTH but lower expression of SHPT regulators than chief cells, which may contribute to the pathophysiology of SHPT and the treatment resistance to calcitriol and calcimimetics.
Springer Nature
Advanced oxidation protein products downregulate CYP1A2 and CYP3A4 expression and activity via the NF-κB-mediated signaling pathway in vitro and in vivo
Xun T., Lin Z., Wang X., Zhan X., Feng H., Gan D., Yang X.
Laboratory Investigation scimago Q1 wos Q1 , 
2021-09-01,  citations by CoLab: 8 ,  Abstract  
Uremic toxin accumulation is one possible reason for alterations in hepatic drug metabolism in patients with chronic kidney disease (CKD). However, the types of uremic toxins and underlying mechanisms are poorly understood. In this study, we report the role of advanced oxidation protein products (AOPPs), a modified protein uremic toxin, in the downregulation of cytochromes P450 1A2 (CYP1A2) and P450 3A4 (CYP3A4) expression levels and activities. We found that AOPP accumulation in plasma in a rat CKD model was associated with decreased protein levels of CYP1A2 and CYP3A4. CYP1A2 and CYP3A4 metabolites (acetaminophen and 6β-hydroxytestosterone, respectively,) in liver microsomes were also significantly decreased. In human hepatocytes, AOPPs significantly decreased CYP1A2 and CYP3A4 protein levels in a dose- and time-dependent manner and downregulated their activities; however, bovine serum albumin (BSA), a synthetic precursor of AOPPs, had no effect on these parameters. The effect of AOPPs was associated with upregulation of p-IKKα/β, p-IκBα, p-NF-κB, and inflammatory cytokines protein levels and increases in p-IKKα/β/IKKα, p-IκBα/IκBα, and p-NF-κB/NF-κB phosphorylation ratios. Further, NF-kB pathway inhibitors BAY-117082 and PDTC abolished the downregulatory effects of AOPPs. These findings suggest that AOPPs downregulate CYP1A2 and CYP3A4 expression and activities by increasing inflammatory cytokine production and stimulating NF-κB-mediated signaling. Protein uremic toxins, such as AOPPs, may modify the nonrenal clearance of drugs in patients with CKD by influencing metabolic enzymes. Uremic toxin accumulation can alter hepatic drug metabolism. Advanced oxidation protein products significantly decrease the expression and activity of CYP1A2 and CYP3A4 via direct activation of the NF-κB pathway. Induction of nuclear translocation of NF-κB inhibits the transcription and translation of CYP1A2 and CYP3A4. The inflammatory cytokines IL-6 and/or TNF-α may mediate this process.
The Endocrine Society
Local NF-κB Activation Promotes Parathyroid Hormone Synthesis and Secretion in Uremic Patients
Mao J., Wang M., Ni L., Gong W., Jiang X., Zhang Q., Zhang M., Wen D., Chen J.
Endocrinology scimago Q4 wos Q2 , 
2021-04-28,  citations by CoLab: 8 ,  Abstract  
Abstract Secondary hyperparathyroidism (SHPT) in uremic patients is characterized by parathyroid gland (PTG) hyperplasia and parathyroid hormone (PTH) elevation. Previously, we demonstrated that NF-κB activation contributed to parathyroid cell proliferation in rats with chronic kidney disease. Although vitamin D inhibits inflammation and ameliorates SHPT, the contribution of vitamin D deficiency to SHPT via local NF-κB activation remains to be clarified. PTGs collected from 10 uremic patients with advanced SHPT were used to test the expressions of vitamin D receptor (VDR), NF-κB, and proliferating cell nuclear antigen (PCNA). Freshly excised PTG tissues were incubated for 24 hours in vitro with VDR activator (VDRA) calcitriol or NF-κB inhibitor pyrrolidine thiocarbamate (PDTC). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to investigate the regulation of PTH transcription by NF-κB. We found higher levels of activated NF-κB and lower expression of VDR in nodular hyperplastic PTGs than in diffuse hyperplasia. In cultured PTG tissues, treatment with VDRA or PDTC inhibited NF-κB activation and PCNA expression, and downregulated preproPTH mRNA and intact PTH levels. ChIP assays demonstrated the presence of NF-κB binding sites in PTH promoter. Furthermore, in luciferase reporter assays, addition of exogenous p65 significantly increased PTH luciferase activity by 2.4-fold (P < 0.01), while mutation of NF-κB binding site at position −908 of the PTH promoter suppressed p65-induced PTH reporter activity (P < 0.01). In summary, local NF-κB activation contributes to SHPT and mediates the transcriptional activation of PTH directly in uremic patients. Vitamin D deficiency may be involved in SHPT via the activation of NF-κB pathway.
Elsevier
CREB/ATF3 signaling mediates indoxyl sulfate-induced vascular smooth muscle cell proliferation and neointimal formation in uremia
Chen W., Lai Y., Lee J., Wu S., Hsu Y.
Atherosclerosis scimago Q1 wos Q1 , 
2020-12-01,  citations by CoLab: 18 ,  Abstract  
AbstractBackground and aims Uremic patients are characterized by an increased risk of atherosclerotic cardiovascular diseases. Vascular smooth muscle cell (VSMC) proliferation contributes to neointimal formation, a main pathological feature in atherosclerosis. Activation of CREB/ATF3 signaling is pivotal in VSMC proliferation, yet its role in uremic atherosclerosis is unknown. This study aimed to explore whether CREB/ATF3 signaling is involved in the molecular mechanism underlying neointimal formation in uremia. Methods and results Treatment of VSMCs with uremic toxin (indoxyl sulfate [IS]) activated cAMP/CREB/ATF3/cyclin D signaling, which was reflected by increased VSMC proliferation. Blocking cAMP/PKA/CREB/ATF3 signaling attenuated the promoting effect of IS on cyclin D1 expression and VSMC proliferation. Loss-of-function and time-dependent experiments showed that ATF3 lies downstream of the CREB signaling. Mutational analysis of cyclin D1 promoter along with chromatin immunoprecipitation assays showed that CREB/ATF3 signaling participated in IS-induced cyclin D transcription. In vivo, phosphorylated CREB (an active form of CREB) and ATF3 were prominently upregulated in the neointima of experimental uremic rats, the atherosclerotic plaques of uremic ApoE−/− mice, and the iliac arteries of uremic patients. Notably, the use of lentivirus to knock down ATF3 in the neointima of balloon-injured arteries could suppress the effect of uremia in vivo, including neointimal formation and cyclin D expression. Conclusions In this study, we demonstrated that CREB/ATF3-related signaling may be involved in IS-induced VSMC proliferation and the pathogenesis of neointimal formation during uremia.
American Association for the Advancement of Science (AAAS)
Lineage tracing on transcriptional landscapes links state to fate during differentiation
Weinreb C., Rodriguez-Fraticelli A., Camargo F.D., Klein A.M.
Science scimago Q1 wos Q1 Open Access , 
2020-02-14,  citations by CoLab: 520 ,  PDF,  Abstract  
Mapping cell fate during hematopoiesis Biologists have long attempted to understand how stem and progenitor cells in regenerating and embryonic tissues differentiate into mature cell types. Through the use of recent technical advances to sequence the genes expressed in thousands of individual cells, differentiation mechanisms are being revealed. Weinreb et al. extended these methods to track clones of cells (cell families) across time. Their approach reveals differences in cellular gene expression as cells progress through hematopoiesis, which is the process of blood production. Using machine learning, they tested how well gene expression measurements account for the choices that cells make. This work reveals that a considerable gap still exists in understanding differentiation mechanisms, and future methods are needed to fully understand—and ultimately control—cell differentiation. Science , this issue p. eaaw3381
Springer Nature
25-vitamin D reduces inflammation in uremic environment
Brito R.B., Rebello J.F., Grabulosa C.C., Pinto W., Morales A., Elias R.M., Moyses R.M., Dalboni M.A.
Scientific Reports scimago Q1 wos Q1 Open Access , 
2020-01-10,  citations by CoLab: 18 ,  PDF,  Abstract  
Chronic kidney disease (CKD) is characterized by loss of renal function and a consequent increase of serum uremic toxins, which contribute to inflammation status. Deficiency of 25-vitamin D, often found in patients with CKD, has been included as an inflammatory factor since it might modulate the immune system. The aim of this study was to investigate the role of 25-vitamin D on inflammatory pathways in healthy and uremic environment. Toll-like receptor 4 (TLR4), oxidative stress (ROS), vitamin D receptor (VDR), 1-α hydroxylase (CYP27), 24 hydroxylase, cathelicidin, and MCP-1 were evaluated in monocytes exposed to a uremic serum pool compared with healthy pool. The human monocytes lineage (U937) was incubated with or without 25-vitamin D (50 ng/ml for 24 hours). TRL4, VDR, CYP27, CYP24, and ROS were evaluated by flow cytometry. We used ELISA to measure IL-6, TNF-α, IL-10, cathelicidin, and MCP-1 in the cell culture supernatant. We observed a higher expression of TRL-4, IL-6, TNF-α, IL-10, cathelicidin and MCP-1 in monocytes incubated with uremic serum when compared with serum from healthy individuals. Supplementation of 25-vitamin D was able to reduce the expression of TRL4, cathelicidin, and MCP-1 in the uremic environment. There was no difference in the expression of VDR, CYP27 and CYP24 intracellular enzymes. This in vitro study showed that the uremic pool activates inflammatory response in monocytes, which was reversed by 25-vitamin D supplementation; this finding suggests that 25-vitamin D has an anti-inflammatory role in the uremic environment.
Elsevier
1,25(OH)2 D3 attenuates indoxyl sulfate–induced epithelial-to-mesenchymal cell transition via inactivation of PI3K/Akt/β-catenin signaling in renal tubular epithelial cells
Chang L., Sun H., Tsai C., Kuo C., Liu K., Lii C., Huang C., Li C.
Nutrition scimago Q2 wos Q2 , 
2020-01-01,  citations by CoLab: 10 ,  Abstract  
Objectives Indoxyl sulfate (IS), a uremic toxin, has been shown to promote the epithelial-to-mesenchymal transition (EMT) of human proximal tubular cells and to accelerate the progression of chronic kidney disease (CKD). Despite the well-known protective role of 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3] in EMT, the effect of 1,25(OH)2 D3 on IS-induced EMT in human proximal tubular epithelial cells and the underlying mechanism remain unclear. The aim of this study was to determine whether IS (0-1 mM) dose-dependently inhibited the protein expression of E-cadherin and increased the protein expression of alpha-smooth muscle actin, N-cadherin, and fibronectin. Methods This study investigated the molecular mechanism by which 1,25(OH)2 D3 attenuates IS-induced EMT. HK-2 human renal tubular epithelial cells was used as the study model, and the MTT assay, Western Blotting, siRNA knockdown technique were used to explore the effects of 1,25(OH)2 D3 on EMT in the presence of IS. Results Pretreatment with 1,25(OH)2 D3 inhibited the IS-induced EMT-associated protein expression in HK-2 cells. IS induced the phosphorylation of Akt (S473) and β-catenin (S552) and subsequently increased the nuclear accumulation of β-catenin. Pretreatment with 1,25(OH)2 D3 and LY294002 (phosphoinositide 3-kinase [PIK3] inhibitor) significantly inhibited the IS-induced phosphorylation of Akt and β-catenin, nuclear β-catenin accumulation, and EMT-associated protein expression. Conclusions Results from the present study revealed that the anti-EMT effect of 1,25(OH)2 D3 is likely through inhibition of the PI3K/Akt/β-catenin pathway, which leads to down-regulation of IS-driven EMT-associated protein expression in HK-2 human renal tubular epithelial cells.
MDPI
Inflammation and Oxidative Stress in Chronic Kidney Disease—Potential Therapeutic Role of Minerals, Vitamins and Plant-Derived Metabolites
Rapa S.F., Di Iorio B.R., Campiglia P., Heidland A., Marzocco S.
International Journal of Molecular Sciences scimago Q1 wos Q2 Open Access , 
2019-12-30,  citations by CoLab: 298 ,  PDF,  Abstract  
Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary.
Elsevier
The uremic toxin p-cresol promotes the invasion and migration on carcinoma cells via Ras and mTOR signaling
Hsu Y., Huang H., Chang H.
Toxicology in Vitro scimago Q2 wos Q3 , 
2019-08-01,  citations by CoLab: 15 ,  Abstract  
P-cresol (PC) shows toxic effects on a variety of cells such as renal proximal tubular cells, glomerular mesangial cells, vascular smooth muscle cells, vascular endothelial cells, cardiomyocytes, cardiac fibroblasts, monocytes, osteoblasts and osteoclasts. The molecular mechanism and role of PC in the progression of urothelial carcinoma have not been documented. To understand the impact of PC on bladder cancer progression, human bladder cancer TSGH8301 cells were treated PC with various concentration (25-100 μM). MTT assay revealed the toxicity of PC on TSGH8301 cells dose-dependently. MMP-2 and MMP-9 expressions of the PC-treated cells were enhanced by using gelatin zymography. The wound healing assay and transwell migration analysis were performed to assay the migratory and invasive effects of PC on TSGH8301 cell and the migrated cell numbers were markedly increased by PC treatment. Moreover, we further detected the expression of Ras, PI3K and Akt proteins that involved in the invasion/migration of the cancer. Inhibiting the Ras and mTOR signaling pathways by Y27632 or/and everolimus improved cancer cell progression induced by PC. This study may clarify the impact of PC on migration and invasion of carcinoma cells.
Elsevier
Mitochondrial adventures at the organelle society
Diogo C.V., Yambire K.F., Fernández Mosquera L., Branco F. T., Raimundo N.
Biochemical and Biophysical Research Communications scimago Q1 wos Q3 , 
2018-05-01,  citations by CoLab: 46 , 
Elsevier
Comparative proteomic analysis of chief and oxyphil cell nodules in refractory uremic hyperparathyroidism by iTRAQ coupled LC-MS/MS
Li S., Mao J., Wang M., Zhang M., Ni L., Tao Y., Huang B., Chen J.
Journal of Proteomics scimago Q2 wos Q2 , 
2018-05-01,  citations by CoLab: 7 ,  Abstract  
SHPT is one of the most common complications of CKD-MBD. Recent studies indicate that oxyphil cell proliferation is related to SHPT progression, while not inhibited by current treatments. The aim of this study was to analyze the correlation between oxyphil cell and clinical indicators in SHPT, further explore the protein expression differences of oxyphil cell. Among 33 MHD patients, 84.8% patients have one or more oxyphil dominant glands and the overall oxyphil cells proportion was 39.5 ± 16.3%. Univariate correlation and multivariable linear regression model showed that oral calcitriol dosage and treatment duration were independently correlated to oxyphil cell ratio. Proteomic study showed that mitochondrial protein, protein synthesis, and cell cycle regulation were significantly altered in oxyphil cell nodules. DBP was downregulated in oxyphil nodules on protein level, which may contribute to calcitriol resistance by reducing vitamin D transport. Through KEGG and PPI network analysis, Wnt signaling, TGF-β, ubiquitin mediated proteolysis and cell cycle pathways were significantly enriched in oxyphil cell nodules. Among which, MIF-CUL1 axis was significantly increased. These results suggest that the limitations of vitamin D in SHPT treatment is closely related to oxyphil cell and may be attributed to the dysregulation of vitamin D transport and ubiquitin regulation of oxyphil cell.Secondary hyperparathyroidism in end stage renal patients is one of the major challenges nephrology field faces. Emerging data indicate that oxyphil cell may participate in the pathophysiology of secondary hyperparathyroidism, while both calcimimetics and vitamin D receptor activators treatments are underperformed in controlling oxyphil cell proliferation. In the present study, we validated that the proliferation of oxyphil cells is associated with calcitriol treatment, and discovered that oxyphil cell nodules were significantly different from chief cells nodules in protein expression of mitochondria, protein synthesis and cell cycle regulation. It is noteworthy that DBP was downregulated in oxyphil nodules on protein level and may therefore participate in the resistance of calcitriol therapy by reducing the vitamin D transport capacity. Wnt signaling, TGF-β, ubiquitin mediated proteolysis and cell cycle pathways were significantly enriched in oxyphil cell nodules, among which, MIF-CUL1 axis may play an important role in the regulation of oxyphil proliferation and calcitriol resistance through ubiquitin mediated proteolysis. These results suggest that calcitriol treatment has limitations in oxyphil cell predominant SHPT, which may be attributed to the dysregulation of vitamin D transport and ubiquitin regulation of oxyphil cell, and the influence of microenvironment in uremia status may be the underlying reason.
Wiley
Cycling our way to fit fat
Townsend L.K., Knuth C.M., Wright D.C.
Physiological Reports scimago Q2 wos Q3 Open Access , 
2017-04-13,  citations by CoLab: 27 ,  PDF,  Abstract  
Adipose tissue is increasingly being recognized as a key regulator of whole body carbohydrate and lipid metabolism. In conditions of obesity and insulin resistance mitochondrial content in this tissue is reduced, while treatment with insulin sensitizing drugs such as thiazolidinediones (TZDs) increase mitochondrial content. It has been known for decades that exercise increases mitochondrial content in skeletal muscle and now several laboratories have shown similar effects in adipose tissue. To date the specific mechanisms mediating this effect have not been fully identified. In this review we highlight recent work suggesting that increases in lipolysis and subsequently fatty acid re‐esterification trigger the activation of 59 AMP‐activated protein kinase (AMP) activated protein kinase and ultimately the induction of mitochondrial biogenesis. It is our current view that this pathway could be a unifying mechanism linking numerous systemic factors (catecholamines, interleukin‐6, meteorin‐like) to induction of mitochondrial biogenesis following exercise.
Springer Nature
Upregulation of skeletal muscle PGC-1α through the elevation of cyclic AMP levels by Cyanidin-3-glucoside enhances exercise performance
Matsukawa T., Motojima H., Sato Y., Takahashi S., Villareal M.O., Isoda H.
Scientific Reports scimago Q1 wos Q1 Open Access , 
2017-03-20,  citations by CoLab: 44 ,  PDF,  Abstract  
Regular exercise and physical training enhance physiological capacity and improve metabolic diseases. Skeletal muscles require peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) in the process of their adaptation to exercise owing to PGC-1α’s ability to regulate mitochondrial biogenesis, angiogenesis, and oxidative metabolism. Cyanidin-3-glucoside (Cy3G) is a natural polyphenol and a nutraceutical factor, which has several beneficial effects on human health. Here, the effect of Cy3G on exercise performance and the underlying mechanisms involved were investigated. ICR mice were given Cy3G (1 mg/kg, orally) everyday and made to perform weight-loaded swimming exercise for 15 days. The endurance of mice orally administered with Cy3G was improved, enabling them to swim longer (time) and while the levels of exercise-induced lactate and fatigue markers (urea nitrogen, creatinine and total ketone bodies) were reduced. Additionally, the expression of lactate metabolism-related genes (lactate dehydrogenase B and monocarboxylate transporter 1) in gastrocnemius and biceps femoris muscles was increased in response to Cy3G-induced PGC-1α upregulation. In vitro, using C2C12 myotubes, Cy3G-induced elevation of intracellular cyclic AMP levels increased PGC-1α expression via the Ca2+/calmodulin-dependent protein kinase kinase pathway. This study demonstrates that Cy3G enhances exercise performance by activating lactate metabolism through skeletal muscle PGC-1α upregulation.
The Royal Society
Mitochondrial metabolites: undercover signalling molecules
Frezza C.
Interface Focus scimago Q1 wos Q1 , 
2017-02-17,  citations by CoLab: 104 ,  Abstract  
Mitochondria are one of most characterized metabolic hubs of the cell. Here, crucial biochemical reactions occur and most of the cellular adenosine triphosphate (ATP) is produced. In addition, mitochondria act as signalling platforms and communicate with the rest of the cell by modulating calcium fluxes, by producing free radicals, and by releasing bioactive proteins. It is emerging that mitochondrial metabolites can also act as second messengers and can elicit profound (epi)genetic changes. This review describes the many signalling functions of mitochondrial metabolites under normal and stress conditions, focusing on metabolites of the tricarboxylic acid cycle. We provide a new framework for understanding the role of mitochondrial metabolism in cellular pathophysiology.
Springer Nature
Indoxyl sulfate – the uremic toxin linking hemostatic system disturbances with the prevalence of cardiovascular disease in patients with chronic kidney disease
Kamiński T.W., Pawlak K., Karbowska M., Myśliwiec M., Pawlak D.
BMC Nephrology scimago Q2 wos Q2 Open Access , 
2017-01-25,  citations by CoLab: 84 ,  PDF,  Abstract  
During chronic kidney disease progression, kidney-specific risk factors for cardiovascular disease come into play. The present study investigated the impact of indoxyl sulfate, dietary tryptophan-derived uremic toxin, accumulated in the blood of patients with chronic kidney disease on hemostatic parameters, markers of inflammation, oxidative stress and monocyte to macrophage transition. Fifty-one CKD patients not undergoing hemodialysis were enrolled in the study. Coagulation factors, fibrinolytic parameters, adhesion molecules, endothelial dysfunction markers, oxidative stress as well as inflammation markers were examined using immune-enzymatic method. Indoxyl sulfate levels were assessed using high-performance liquid chromatography. Biochemical parameters were determined by routine laboratory techniques using an automated analyzers. All assessed parameters were compared with controls and subjected to cross-sectional statistical analysis. Elevated concentrations of indoxyl sulfate, the vast majority of parameters affecting hemostasis, and markers of renal insufficiency conditions were observed. Part of hemostatic factors, namely tissue factor, von Willebrand factor, thrombomodulin, soluble urokinase-type plasminogen activator receptor, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion protein were correlated with the fraction of indoxyl sulfate. A significant quantity of assessed parameters showed strong correlations with superoxide-dismutase, renal insufficiency rate, C-reactive protein, and neopterin. Levels of indoxyl sulfate were independently associated with markers of impaired endothelial function (thrombomodulin, adhesion molecules), oxidative stress (superoxide-dismutase) and monocytes activation determinant (neopterin), which indicate unconventional links between these systems and the role of indoxyl sulfate. Furthermore, parameters that correlated with the levels of indoxyl sulfate (von Willebrand factor, soluble urokinase-type plasminogen activator receptor, soluble intercellular adhesion molecule-1) were positively associated with the prevalence of cardiovascular disease in a CKD patients. The study demonstrated that in conditions of chronic exposure to uremic toxins, indoxyl sulfate seems to be one of the “missing links” between impaired renal function and prevalence of cardiovascular events, especially hemostatic disorders. The main functions of the action appear to be altered monocytes activation, intensified inflammatory process, and augmented oxidative stress by this uremic toxin.
Found 3
By date By citations
Oxford University Press
Pathophysiology and therapies of CKD-associated secondary hyperparathyroidism
Mazzaferro S., Tartaglione L., Cohen-Solal M., Hoang Tran M., Pasquali M., Rotondi S., Ureña Torres P.
CKJ: Clinical Kidney Journal scimago Q1 wos Q1 Open Access , 
2025-03-13,  citations by CoLab: 1 ,  PDF,  Abstract  
ABSTRACT Uremic secondary hyperparathyroidism (SHP) refers to the biochemical abnormalities that characterize CKD-MBD. However, historically parathyroid hormone (PTH) is identified as the key culprit hormone and the essential biomarker of secondary hyperparathyroidism. SHP represents the adaptive response to several mineral abnormalities that initiate and maintain increased PTH secretion through classical mineral derangements and more recently elucidated hormonal dysregulations. Among classic factors involved in the pathogenesis of SHP, phosphate, calcium, and calcitriol have a prominent role. The discovery of new pathogenetic factors involved in the development of SHP (and the eventual CKD-MBD) including fibroblast growth factor-23 (FGF23) and klotho provides new hypothesis and perspectives to our understanding of this complex metabolic disturbance. Recently more than serum phosphate a critical role in regulating FGF23 synthesis and the progression of CKD is ascribed to phosphate pool, reflected by production of glycerol-3-phosphate and the formation of excessive CPP-2. Finally, also skeletal resistance to PTH action, due to dysregulation of the Wnt–β-catenin system and intestinal dysbiosis, affecting the PTH actions on bone are causal factor of SHP. Identifying all the actors at play is mandatory to allow the most precise therapeutic prescription in the individual patient. This paper aims to review, in particular, the pathophysiology of SHP, which is essential to envisage the eventual therapeutic options for the associated MBD.
Taylor & Francis
High-salt diets provoke phosphorus absorption from the small intestine in mice
Yang M., You H., Ni L., Mao J., Chen J.
Clinical and Experimental Hypertension scimago Q3 wos Q3 Open Access , 
2025-02-25,  citations by CoLab: 0 ,  PDF, 
Elsevier
Advancing parathyroid anatomy understanding through single-cell RNA sequencing in uremic secondary hyperparathyroidism
Ben-Dov I.Z.
Kidney International scimago Q1 wos Q1 , 
2024-03-01,  citations by CoLab: 0 ,  Abstract  
This commentary explores the recent application of single-cell RNA sequencing in the study of uremic secondary hyperparathyroidism, shedding light on the cellular dynamics within parathyroid glands. The use of single-cell RNA sequencing reveals new insights into the differentiation processes of chief and oxyphil cells, challenging traditional views and highlighting the potential of this technology in advancing our understanding of parathyroid anatomy.

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