bims-supasi 2024-10-27 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2024–10–27
eight papers selected by
Jonathan Wolf Mueller, University of Birmingham

Handgrip Strength and Dehydroepiandrosterone Sulfate in a Frailty Unit: A Retrospective Study.
Resveratrol Mitigates Uremic Toxin-Induced Intestinal Barrier Dysfunction in Chronic Kidney Disease by Promoting Mitophagy and Inhibiting Apoptosis Pathways.
Identification of HSPG2 as a bladder pro-tumor protein through NID1/AKT signaling.
Age-dependent changes in visceral adiposity are associated with decreased plasma levels of DHEA-S in sigma-1 receptor knockout male mice.
Healthy plasma lipidomic signatures depend on sex, age, body mass index, and contraceptives but not perceived stress.
Natural history of valve disease in patients with mucopolysaccharidosis II and the impact of enzyme replacement therapy.
Genetically encoded green fluorescent sensor for probing sulfate transport activity of solute carrier family 26 member a2 (Slc26a2) protein.
Comparative Effects of Acetate- and Citrate-Based Dialysates on Dialysis Dose and Protein-Bound Uremic Toxins in Hemodiafiltration Patients: Exploring the Impact of Calcium and Magnesium Concentrations.

Cureus. 2024 Sep;16(9): e69753

Handgrip Strength and Dehydroepiandrosterone Sulfate in a Frailty Unit: A Retrospective Study.

Daniano Caires, Miguel Homem Costa, João Miguel Freitas, Rafael Ferreira Nascimento, Tiago Teófilo, Luís Ramos Dos Santos, João Gouveia, Carolina Carvalhinha.

   INTRODUCTION: Frailty is characterized by vulnerability and decline in physical, mental, and social activity, significantly contributing to adverse health outcomes. Frailty encompasses nutritional status, muscle strength, inflammation, and hormones. Dehydroepiandrosterone sulfate (DHEAS) is one of the hormones hypothesized to play a role in frailty. Handgrip strength (HGS) correlates with overall muscle strength. The fatigue, resistance, ambulation, illnesses, and loss of weight (FRAIL) scale can be used to readily screen frailty. Identifying markers associated with frailty can facilitate its early diagnosis, risk stratification, and target interventions to prevent or mitigate its negative consequences. This study sought to evaluate the associations between frailty, HGS, and DHEAS in a Portuguese frailty unit (FU).
METHODS: We developed an observational retrospective study in an FU. Patients admitted to the FU underwent a rehabilitation program. We assessed frailty with the FRAIL scale. We assayed DHEAS upon admission to the FU. We measured HGS at admission (i-HGS) and discharge (f-HGS). We also considered HGS variation (∆ HGS) and length of stay.
RESULTS: Out of 119 subjects, 97 fulfilled the eligibility criteria (mean age 78.35 ± 9.58 years; 44.33% men). Overall, 88 (90.72%) patients had a FRAIL scale score of 3 or more. DHEAS values were not significantly different in either the categories of the FRAIL scale or frailty status. DHEAS values were also not significantly correlated with either i-HGS, f-HGS, ∆ HGS, age, or FU length of stay. Frail patients had a significantly lower i-HGS (p = 0.002) and f-HGS (p = 0.001) and a significantly higher length of stay (p = 0.006). Also, the i-HGS and f-HGS significantly decreased with the increase of the FRAIL scale score (p < 0.0001 for both). The cut-off values of the i-HGS and the f-HGS for detecting frail patients in our study were 13.3 kg and 19.1 kg, respectively (p < 0.0001 for both). The i-HGS was significantly and independently associated with the frailty status of frail (p = 0.001), with a 15% probability reduction of a patient being frail for every kilogram increase in the i-HGS.
CONCLUSION: Frail patients assessed with the FRAIL scale had a significantly lower i-HGS and f-HGS and a higher length of stay. In this study, we found frailty and DHEAS to be not associated and DHEAS values to be not correlated with i-HGS or f-HGS. In our opinion, the creation of an FU with an initial FRAIL scale screening and HGS measurement might have a significant impact on identifying frail people and ensuring the implementation of a multimodal multidisciplinary approach.

Keywords:  dehydroepiandrosterone sulfate; frail scale; frailty; frailty unit; handgrip strength

DOI:  https://doi.org/10.7759/cureus.69753
Int J Med Sci. 2024 ;21(13): 2437-2449

Resveratrol Mitigates Uremic Toxin-Induced Intestinal Barrier Dysfunction in Chronic Kidney Disease by Promoting Mitophagy and Inhibiting Apoptosis Pathways.

Cai-Mei Zheng, Yi-Chou Hou, Kuo-Wang Tsai, Wan-Chung Hu, Hsiu-Chien Yang, Min-Tser Liao, Kuo-Cheng Lu.

  Background: Chronic Kidney Disease (CKD) is a systemic progressive disorder related to uremic toxins. Uremic toxins disturb intestinal epithelial destruction and barrier dysfunction leading to gut-renal axis disorders in CKD. We examine the protective role of Resveratrol (RSV) against uremic toxin indoxyl sulphate (IS) related intestinal barrier disturbances among CKD.
METHODS: 5/6 nephrectomized mice and isolated primary mouse intestinal epithelial cells (IEC-6) are used to assess the influence of IS on intestinal epithelial tight junction barriers. Serum biochemistry parameters, hematoxylin & eosin (H&E) and immunohistochemistry staining (IHC), Western blot analysis, q-PCR, and si-RNA targeted against AhR were used in this study.
RESULTS: IS decreases the expression of tight junction proteins (TJPs) ZO-1 and claudins, increases the apoptosis and impairs mitophagy within IECs. Treatment with RSV not only reduces the loss of TJPs but also modulates mitophagy markers LC3 and P62, and concurrently decreases the levels of apoptosis-related proteins. Significantly, RSV ameliorates intestinal barrier dysfunction in CKD by modulating mitophagy via the IRF1-DRP1 axis, restoring autophagy, and inhibiting apoptosis through the activation of the PI3K/Akt-Ho-1 anti-oxidant pathway, and mTOR regulated pathways.
CONCLUSION: This study establishes RSV as a potential therapeutic agent that can ameliorate gut-renal axis disturbances in CKD. These findings provide valuable insights into mechanisms underlying RSV RSV-mediated gut-renal axis, highlighting its effectiveness as a potential treatment option for CKD-associated intestinal barrier dysfunction.

Keywords:  apoptosis; autophagy; indoxyl sulfate; intestinal barrier; mitophagy; resveratrol; tight junction proteins

DOI:  https://doi.org/10.7150/ijms.100963
Cancer Cell Int. 2024 Oct 23. 24(1): 345

Identification of HSPG2 as a bladder pro-tumor protein through NID1/AKT signaling.

Cong Li, Pengwei Luo, Fengzhu Guo, Xu Jia, Min Shen, Ting Zhang, Shusen Wang, Ting Du.

   PURPOSE: Heparan sulfate proteoglycans (HSPGs) are complex molecules found on the cell membrane and within the extracellular matrix, increasingly recognized for their role in tumor progression. This study aimed to investigate the involvement of Heparan sulfate proteoglycan 2 (HSPG2) in the progression of bladder cancer.
METHODS: We identified HSPG2 as a promoter of bladder tumor progression using single-cell RNA sequencing and transcriptome analysis of sequencing data from seven patient samples obtained from the Gene Expression Omnibus (GEO) database (GSE135337). Transcript profiles of 28 normal tissues and 407 bladder tumor tissues were analyzed for HSPG2 expression and survival outcomes using the Sanger tools and cBioPortal databases. HSPG2-overexpressing T24 and Biu-87 cell lines were generated, and cell proliferation and migration were assessed using CCK-8 and Transwell assays. Western blotting and immunostaining were performed to evaluate the activation of Nidogen-1 (NID1)/protein kinase B (AKT) signaling. Mouse models with patient-derived tumor organoids (HSPG2high and HSPG2low) were established to assess anticancer effects.
RESULTS: Our results demonstrated a marked upregulation of HSPG2 in malignant bladder tumors, which correlated significantly with poor patient prognosis. HSPG2 overexpression consistently enhanced bladder tumor cell proliferation and conferred chemotherapy resistance, as shown in both in vitro and in vivo experiments. Mechanistically, HSPG2 upregulated NID1 expression, leading to the activation of the AKT pro-survival signaling pathway and promoting sustained tumor growth in bladder cancer.
CONCLUSION: This study highlights the critical pro-tumor role of HSPG2/NID1/AKT signaling in bladder cancer and suggests its potential as a therapeutic target in clinical treatment.

Keywords:  AKT; Bladder cancer; HSPG2; NID1

DOI:  https://doi.org/10.1186/s12935-024-03527-7
Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Oct 18. pii: S1388-1981(24)00121-5. [Epub ahead of print] 159571

Age-dependent changes in visceral adiposity are associated with decreased plasma levels of DHEA-S in sigma-1 receptor knockout male mice.

Stelfa Gundega, Miteniece Anna, Svalbe Baiba, Vavers Edijs, Makrecka-Kuka Marina, Kupats Einars, Kunrade Liga, Parfejevs Vadims, Riekstina Una, Dambrova Maija, Zvejniece Liga.

  The sigma-1 receptor (S1R) is involved in intracellular lipid synthesis and transport. Recent studies have shown that its genetic inactivation impairs adipogenic differentiation in vitro. This study investigated the role of S1R in adipose tissue physiology and metabolic health using adult and old WT and S1R KO mice. Visceral fat mass was increased in adult, but not old S1R-KO male mice compared to that of WT mice, despite having similar body weights, food intake, and energy expenditure. The average adipocyte size was 64 % larger in adult KO mice than in adult WT mice. Adult S1R-KO mice showed reduced plasma dehydroepiandrosterone sulfate (DHEA-S) and elevated fasting plasma leptin concentrations. Lipidomic analysis revealed alterations in plasma metabolite concentrations, particularly reduced levels of sphingomyelins, ceramides, phosphatidylcholines, lysophosphatidylcholines, and cholesteryl esters in adult mice. Decreased expression of Pparγ, Adipoq, and Atgl was detected in visceral white adipose tissue (vWAT) isolated from adult KO mice. Additionally, Fabp4 and Adipoq expression levels were significantly lower in KO adipose-derived stromal cells than in WT adipose-derived stromal cells. A fivefold increase in the mitochondrial fatty acid oxidation rate and a 43 % increase in electron transfer coupling capacity were detected in adult S1R-KO vWAT. In summary, our investigation revealed an age-dependent association between increased visceral adiposity and decreased plasma levels of DHEA-S in S1R-deficient male mice. These findings underscore the potential role of S1R in regulating metabolic processes in adipose tissue and suggest that DHEA-S is a potential mediator of adiposity changes in the absence of S1R.

Keywords:  Adipose tissue-derived stromal cells; Dehydroepiandrosterone sulfate; Lipid metabolism; Mitochondrial function; Sigma-1 receptor; White adipose tissue

DOI:  https://doi.org/10.1016/j.bbalip.2024.159571
Am J Physiol Cell Physiol. 2024 Oct 22.

Healthy plasma lipidomic signatures depend on sex, age, body mass index, and contraceptives but not perceived stress.

Lisa Hahnefeld, Juliane Hackel, Sandra Trautmann, Carlo Angioni, Yannick Schreiber, Robert Gurke, Dominique Thomas, Sabine Wicker, Gerd Geisslinger, Irmgard Tegeder.

  Perceived stress is thought to contribute to the pathogenesis of metabolic, vascular, mental, and immune diseases, with different susceptibilities in women and men. The present study investigated if and how perceived stress and/or demographic variables including sex, age, body mass index, regular prescription drugs, occasional analgesics, or dietary supplements manifested in plasma lipidomic profiles, obtained by targeted and untargeted mass spectrometry analyses. The study included 217 healthy women and 108 healthy men, aged 18-68 years, who were recruited in a 2:1 female:male ratio to account for women with/without contraceptives. As expected, dehydroepiandrosterone sulfate (DHEAS) and ceramides were higher in men than women, and DHEAS decreased with age, while ceramides increased. Contrary to expectations, neither DHEAS nor ceramides were associated with perceived stress (PSQ30 questionnaire), which was however, associated with BMI in men, but not in women. None of the lipid species or classes showed a similar "age X sex X BMI" interaction, but the endocannabinoid palmitoylethanolamide (PEA) correlated with BMI and hypertension. Independent of perceived stress, lysophosphatidylcholines (LPCs) were lower in women than men, whereas LPC metabolites, lysophosphatidic acids (LPAs), were higher in women. The LPA:LPC ratio was particularly high in women using oral contraceptives suggesting a strong hormone-induced extracellular conversion of LPCs to LPAs, which is catalyzed by the phospholipase D, autotaxin. The results reveal complex sex differences in perceived stress and lipidomic profiles, the latter being exacerbated by contraceptive use, but perceived stress and lipids were not directly correlated.

Keywords:  age; contraceptives; lipidomic; perceived stress; sex

DOI:  https://doi.org/10.1152/ajpcell.00630.2024
J Inherit Metab Dis. 2024 Oct 23.

Natural history of valve disease in patients with mucopolysaccharidosis II and the impact of enzyme replacement therapy.

Christoph Kampmann, Christina Lampe, Christiane M Wiethoff, Laila Arash-Kaps, Eugen Mengel, Joerg Reinke, Michael Beck, Julia B Hennermann, Tariq Abu-Tair.

  Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare, X-linked lysosomal storage disease caused by reduced activity of iduronate-2-sulfatase (I2S), with subsequent cellular accumulation of the glycosaminoglycans (GAGs), heparan sulfate, and dermatan sulfate (DS). DS is a major component of the extracellular matrix of heart valves, which can be affected in MPS II. We investigated the natural history of valve disease in MPS II and the impact of long-term intravenous enzyme replacement therapy (ERT) with recombinant I2S (idursulfase). In total, 604 cardiac examinations were assessed from serial follow-up of 80 male patients (49 neuronopathic). Valve disease was classified according to standard practice from hemodynamic features evident from echocardiography. The natural history group comprised 48 patients (up to 14.8 years of follow-up; median, 2.6 years; 24 patients started ERT during the study); 56 patients were treated (up to 14.2 years of follow-up; median, 6.2 years). Lifetime GAG burden (calculated from urinary GAG measurements) correlated significantly with the degree of valve disease. Onset of moderate-to-severe valve disease was significantly delayed in treated (median age at onset, 29.1 ± 2 [95% CI: 25.2-32.9] years; Kaplan-Meier estimation) versus untreated patients (17.6 ± 1 [95% Cl: 15.8-19.4] years; p < 0.0001). Cox regression modeling found that long-term ERT reduced the probability of developing severe valve disease (χ2, 32.736; significant after 5 years of ERT). Overall, this study found that valve disease severity in MPS II correlates with GAG burden and that progression is delayed by long-term ERT.

Keywords:  Hunter syndrome; glycosaminoglycans; heart valve disease; lysosomal storage disorder

DOI:  https://doi.org/10.1002/jimd.12808
Commun Biol. 2024 Oct 23. 7(1): 1375

Genetically encoded green fluorescent sensor for probing sulfate transport activity of solute carrier family 26 member a2 (Slc26a2) protein.

Cuixin Lai, Lina Yang, Vishaka Pathiranage, Ruizhao Wang, Fedor V Subach, Alice R Walker, Kiryl D Piatkevich.

Genetically encoded fluorescent biosensors became indispensable tools for biological research, enabling real-time observation of physiological processes in live cells. Recent protein engineering efforts have resulted in the generation of a large variety of fluorescent biosensors for a wide range of biologically relevant processes, from small ions to enzymatic activity and signaling pathways. However, biosensors for imaging sulfate ions, the fourth most abundant physiological anion, in mammalian cells are still lacking. Here, we report the development and characterization of a green fluorescent biosensor for sulfate named Thyone. Thyone, derived through structure-guided design from bright green fluorescent protein mNeonGreen, exhibited a large negative fluorescence response upon subsecond association with sulfate anion with an affinity of 11 mM in mammalian cells. By integrating mutagenesis analyses with molecular dynamics simulations, we elucidated the molecular mechanism of sulfate binding and revealed key amino acid residues responsible for sulfate sensitivity. High anion selectivity and sensitivity of Thyone allowed for imaging of sulfate anion transients mediated by sulfate transporter heterologously expressed in cultured mammalian cells. We believe that Thyone will find a broad application for assaying the sulfate transport in mammalian cells via anion transporters and exchangers.

DOI: https://doi.org/10.1038/s42003-024-07020-9
Toxins (Basel). 2024 Oct 01. pii: 426. [Epub ahead of print]16(10):

Comparative Effects of Acetate- and Citrate-Based Dialysates on Dialysis Dose and Protein-Bound Uremic Toxins in Hemodiafiltration Patients: Exploring the Impact of Calcium and Magnesium Concentrations.

Diana Rodríguez-Espinosa, Elena Cuadrado-Payán, Naira Rico, Mercè Torra, Rosa María Fernández, Miquel Gómez, Laura Morantes, Gregori Casals, Maria Rodriguez-Garcia, Francisco Maduell, José Jesús Broseta.

  Modern hemodialysis employs weak acids as buffers to prevent bicarbonate precipitation with calcium or magnesium. Acetate, the most used acid, is linked to chronic inflammation and poor dialysis tolerance. Citrate has emerged as a potential alternative, though its effect on dialysis efficiency is not clear. This study aims to compare the efficacy of acetate- and citrate-based dialysates, focusing on protein-bound uremic toxins and dialysis doses. This single-center prospective crossover study includes prevalent patients participating in a thrice-weekly online hemodiafiltration program. Four dialysates were tested: two acetate-based (1.25 and 1.5 mmol/L calcium) and two citrate-based (1.5 mmol/L calcium with 0.5 and 0.75 mmol/L magnesium). Pre- and post-dialysis blood samples of eighteen patients were analyzed for urea, creatinine, p-cresyl sulfate, indoxyl sulfate, and albumin. Statistical significance was assessed using paired t-tests and repeated measures of ANOVA. There were no significant differences in dialysis dose (Kt), urea, creatinine, or indoxyl sulfate reduction ratios between acetate- and citrate-based dialysates. However, a significant decrease in the reduction ratio of p-cresyl sulfate was observed with the acetate dialysate containing 1.25 mmol/L calcium and the citrate dialysate with 0.5 mmol/L magnesium compared to the acetate dialysate containing 1.5 mmol/L calcium and the citrate dialysate with 0.75 mmol/L magnesium (51.56 ± 4.75 and 53.02 ± 4.52 vs. 65.25 ± 3.38 and 58.66 ± 4.16, p 0.007). No differences in dialysis dose were found between acetate- and citrate-based dialysates. However, citrate dialysates with lower calcium and magnesium concentrations may reduce the albumin displacement of p-cresyl sulfate. Further studies are needed to understand the observed differences and optimize the dialysate composition for the better clearance of protein-bound uremic toxins.

Keywords:  acetate; citrate; dialysis efficiency; hemodialysis; indoxyl sulfate; p-cresyl sulfate; protein-bound toxins; uremic toxins

DOI:  https://doi.org/10.3390/toxins16100426