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Cystatin 6 (CST6) and Legumain (LGMN) are potential mediators in the pathogenesis of preeclampsia
Get PDFPreeclampsia results from placental insufficiency and causes maternal endothelial dysfunction and multi-organ damage. Our in-silico analysis identified Cystatin 6 (CST6), a cysteine protease inhibitor, as located on the placental surface where it might be released into maternal circulation. This study aimed to characterise CST6 and one of its high affinity targets, Legumain (LGMN), in preeclampsia and assess its biomarker potential by measuring levels in maternal circulation. Placental CST6 mRNA expression was significantly increased in 78 pregnancies complicated by early-onset preeclampsia (delivering at < 34 weeks’ gestation) relative to 30 gestation matched controls (P < 0.0001). LGMN mRNA expression was significantly decreased (P = 0.0309). Circulating CST6 was increased in 35 pregnancies complicated by early-onset preeclampsia (< 34 weeks’ gestation) relative to 27 gestation matched controls (P = 0.0261), and LGMN levels remained unchanged. At 36 weeks’ gestation, circulating CST6 was significantly increased (P = 0.001), while LGMN was significantly decreased (P = 0.0135) in 21 pregnancies preceding diagnosis of preeclampsia at term, compared to 184 pregnancies that did not develop preeclampsia. Human trophoblast stem cells (hTSC) were differentiated into syncytiotrophoblast or extravillous trophoblast (EVT) to evaluate CST6 and LGMN expression in these trophoblast lineages. CST6 and LGMN mRNA expression were significantly increased across 96 h after syncytiotrophoblast (P = 0.0066 and P = 0.0010 respectively) and EVT differentiation (P = 0.0618 and P = 0.0016 respectively), with the highest expression in syncytiotrophoblast. Computational analysis of two publicly available single-cell and single-nuclei RNA sequencing datasets correlated with the expression pattern observed in vitro. When syncytiotrophoblast cells were exposed to hypoxia (1% O(2) vs. 8% O(2)), CST6 expression significantly increased (P = 0.0079), whilst LGMN expression was unchanged. The vascular endothelium may serve as an additional source of circulating CST6 and LGMN in preeclampsia. Induction of dysfunction in endothelial cells by TNFα, caused reduced CST6 expression (P = 0.0036), whilst LGMN expression remained unchanged. Administering recombinant CST6 to endothelial cells enhanced markers of endothelial dysfunction and LGMN expression in the presence of TNFα. These findings indicate an inverse relationship between CST6 and LGMN in the placenta and maternal circulation in preeclampsia. We suggest elevated circulating levels of CST6 may be induced by placental hypoxia. This study provides novel insight into the dysregulation of CST6 and LGMN in preeclampsia and introduces their potential roles in human pregnancy and associated pathology
Persistent abdominal pain and diarrhea after appendectomy-Crohn's disease versus intestinal tuberculosis
Get PDFCASE PRESENTATION: In Western Europe, intestinal tuberculosis is a rare differential diagnosis for Crohn's disease. In this report, we present a case of intestinal tuberculosis in a 59-year-old female initially suspected of Crohn's disease with persistent abdominal pain and diarrhea after appendectomy. CONCLUSION:
This case highlights the need for TB culture in patients with positive IGRA and suspected Crohn's disease
Magnetic resonance imaging of renal oxygenation
No full textRenal hypoxia has a key role in the pathophysiology of many kidney diseases. MRI provides surrogate markers of oxygenation, offering a critical opportunity to detect renal hypoxia. However, studies that have assessed the diagnostic performance of oxygenation MRI for kidney disorders have provided inconsistent results because MRI metrics do not fully capture the complexity of renal oxygenation. Most oxygenation MRI studies are descriptive in nature and fail to detail the pathophysiological importance of the imaging findings. These limitations have restricted the clinical application of oxygenation MRI and the full potential of this technology to facilitate early diagnosis, risk prediction and treatment monitoring of kidney disease has not yet been realized. Understanding of the relationship between renal tissue oxygenation and MRI metrics, which is affected by kidney size, tubular volume fraction and renal blood volume fraction, and measurement of these factors using novel MR methods is imperative for correct physiological interpretation of renal MR oximetry findings. Next steps to enable the clinical adoption of MR oximetry should involve multidisciplinary collaboration to address standardization of acquisition and data analysis protocols and establish reference values of MRI metrics
Bradykinin receptors in metabolic disorders: a comprehensive review
Get PDFThe kallikrein–kinin system and its B1 and B2 receptors are key regulators in metabolic disorders such as obesity, diabetes, and insulin resistance. Obesity, a chronic and multifactorial condition often associated with comorbidities like type 2 diabetes and dyslipidemia, remains poorly understood at the metabolic level. The kinin B2 receptor (B2R) is involved in blood pressure regulation and glucose metabolism, promoting glucose uptake in skeletal muscle via bradykinin. Studies in B2R-KO mice demonstrate that the absence of this receptor predisposes animals to glucose intolerance under a high-fat diet and impairs adaptive thermogenesis, indicating a protective role for B2R in metabolic homeostasis and insulin sensitivity. In contrast, the kinin B1 receptor (B1R) is inducible under pathological conditions and is activated by kinin metabolites. Mouse models lacking B1R exhibit improved metabolic profiles, including protection against high-fat diet-induced obesity and insulin resistance, enhanced energy expenditure, and increased leptin sensitivity. B1R inactivation in adipocytes enhances insulin responsiveness and glucose tolerance, supporting its role in the development of insulin resistance. Moreover, B1R deficiency improves energy metabolism and thermogenic responses to adrenergic and cold stimuli, promoting the activation of brown adipose tissue and the browning of white adipose tissue. Collectively, these findings suggest that B1R and B2R represent promising therapeutic targets for the treatment of metabolic disorders
Multicenter longitudinal quality assessment of MS-based proteomics in plasma and serum
No full textAdvancing MS-based proteomics toward clinical applications evolves around developing standardized start-to-finish and fit-for-purpose workflows for clinical specimens. Steps along the method design involve the determination and optimization of several bioanalytical parameters such as selectivity, sensitivity, accuracy, and precision. In a joint effort, eight proteomics laboratories belonging to the MSCoreSys initiative including the CLINSPECT-M, MSTARS, DIASyM, and SMART-CARE consortia performed a longitudinal round-robin study to assess the analysis performance of plasma and serum as clinically relevant samples. A variety of LC-MS/MS setups including mass spectrometer models from ThermoFisher and Bruker as well as LC systems from ThermoFisher, Evosep, and Waters Corporation were used in this study. As key performance indicators, sensitivity, precision, and reproducibility were monitored over time. Protein identifications range between 300 and 400 IDs across different state-of-the-art MS instruments, with timsTOF Pro, Orbitrap Exploris 480, and Q Exactive HF-X being among the top performers. Overall, 71 proteins are reproducibly detectable in all setups in both serum and plasma samples, and 22 of these proteins are FDA-approved biomarkers, which are reproducibly quantified (CV < 20% with label-free quantification). In total, the round-robin study highlights a promising baseline for bringing MS-based measurements of serum and plasma samples closer to clinical utility
ME/CFS and PASC patient-derived immunoglobulin complexes disrupt mitochondrial function and alter inflammatory marker secretion
No full textAutoimmunity is a key clinical feature in both post-infectious Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of COVID (PASC). Passive transfer of immunoglobulins from patients’ sera into mice induces some clinical features of PASC. IgG-induced transfer of disease phenotypes has long been appreciated, yet the exact mechanism of disease development remains largely elusive. Here, we demonstrate that IgG isolated from post-infectious ME/CFS patients selectively induces mitochondrial fragmentation in human endothelial cells, thereby altering mitochondrial energetics. This effect is lost upon cleavage of IgG into its Fab and Fc fragments. The digested Fab fragment from ME/CFS alone was able to alter the mitochondrial energetics, resembling the effect of intact IgG. In contrast, the Fc fragment alone induced a hypometabolic phenotype characterized by a trend towards reduced overall ATP content. IgG from ME/CFS and PASC patients induced distinct but separate cytokine secretion profiles in healthy PBMCs. Proteomics analysis of IgG-bound immune complexes revealed significant changes within the immune complexes of ME/CFS patients, affecting extracellular matrix organization, while the same from PASC patients pointed towards alterations in hemostasis and blood clot regulation. We demonstrate that IgGs from ME/CFS patients carry a chronic protective stress response that promotes mitochondrial adaptation via fragmentation, without altering mitochondrial ATP generation capacity in endothelial cells. Together, these results highlight a potential pathogenic role of IgG in post-infectious ME/CFS and point to novel therapeutic strategies targeting antibody-mediated metabolic dysregulation
Fasting, ketogenic, and anti-inflammatory diets in multiple sclerosis: a randomized controlled trial with 18-month follow-up
Get PDFBACKGROUND: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adulthood leading to disability and early retirement. Ketone-based diets improve the disease course in MS animal models and health outcomes in different pilot studies of neurodegenerative diseases. METHODS: We enrolled 105 individuals with relapsing-remitting MS (RRMS) in an 18-month, randomized, controlled study, and randomized them into (1) standard healthy diet (SD) as recommended by the German Nutrition Society, (2) fasting diet (FD) with 7-day fasts every 6 months with intermittent fasting at 6 of 7 days a week or (3) ketogenic diet (KD) with 20–40 g carbohydrates per day. Primary outcome was the number of new MRI lesions after 18 months in the KD and FD compared to SD and compared to baseline. Secondary outcomes included further MRI outcomes, disease biomarkers as well as metabolic, and clinical MS outcomes. RESULTS: Eighty-one participants completed the study. The primary endpoint number of new T2 lesions after 18 months did not change in any of the groups (SD 0 (0-(-1)), FD 0 (2 − 0), KD 0 (2 − 0)). Secondary endpoints were analyzed exploratorily: Compared to baseline, in the FD group, Neurofilament light chain (NfL) -concentrations were lower at 9 months (-1.94 pg/mL, p = 0.042) and depressive symptoms improved slightly at 18 months (p = 0.079). In the KD group, cognition improved at 18 months (symbol digit modalities test + 3.7, p = 0.020). Cardiometabolic risk markers (body mass index, abdominal fat, blood lipids, adipokines, blood pressure) improved in all three groups at 9 months differently and were partially associated with clinical outcomes in the FD and KD group. CONCLUSION: The results suggest beneficial effects of dietary interventions, underscoring their potential as a complementary strategy in the treatment of RRMS. To further clarify the impact of such interventions on the disease course and patient-centered outcomes — such as cognitive function and depressive symptoms — future studies with larger, more homogeneous study populations are warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03508414. Retrospectively registered on 25 April 2018
Unrecognized myocardial fibrosis detected by contrast-enhanced cardiovascular MRI in patients with ischemic stroke
No full textEmpagliflozin reduces left ventricular mass increase and improves cardiomyocyte hypertrophy after 5/6 nephrectomy
Get PDFLeft ventricular hypertrophy (LVH) is a common cardiac complication in patients with cardiorenal syndrome. Empagliflozin has demonstrated cardio-renal protective effects in clinical studies, potentially linked to reductions in left ventricular mass (LVM). Using a 5/6 nephrectomy rat model to induce cardiorenal syndrome, we administered two doses of Empagliflozin (3 mg/kg/day and 15 mg/kg/day) via gavage for 95 days, with Telmisartan as a positive control. Cardiac structure and function were assessed using echocardiography, histological analysis, and serum biomarkers. Single-nucleus RNA sequencing (snRNA-seq) and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to investigate molecular mechanisms. The 5/6 nephrectomy increased serum creatinine, troponin T, LVM, ejection fraction, and cardiomyocyte diameter. Empagliflozin treatment significantly decreased LVM and cardiomyocyte hypertrophy, comparable to Telmisartan. snRNA-seq revealed no changes in major cardiac cell populations but identified differential expression of cardiomyocyte development genes, including Fhl2, Tbx20, and Angpt1. qRT-PCR data for Fhl2 and Tbx20 aligned with the snRNA-seq data, showing that Empagliflozin increased Fhl2 expression and decreased Tbx20 expression. Immunofluorescence showed increased myocardial infiltration of M2 macrophages, CD4 + T cells, and CD8 + T cells in Empagliflozin-treated rats, but there was no difference between the 5/6 nephrectomized rats and normal rats. In a non-diabetic cardiorenal syndrome model, Empagliflozin effectively attenuated left ventricular hypertrophy and cardiomyocyte enlargement. These effects appear mediated by the regulation of genes involved in cardiomyocyte development and myocardial remodeling (Fhl2 and Tbx20), rather than cardiomyocyte proliferation. These findings highlight Empagliflozin’s cardioprotective potential in cardiorenal syndrome and provide a foundation for further clinical exploration
The B cell dilemma: diversity or fidelity?
Get PDFThe ability of B lymphocytes to diversify immunoglobulin (Ig) genes is central to the generation of high-affinity, class-switched antibodies and the establishment of effective humoral immunity. This diversification is achieved through three DNA remodeling processes that occur at defined stages of B cell development and maturation: V(D) J recombination, somatic hypermutation (SHM), and class switch recombination (CSR). These reactions all rely on the induction of programmed DNA lesions at Ig genes and their productive resolution by ubiquitous DNA repair pathways. However, such physiological sources of genotoxic stress render B cells vulnerable to genome instability, including mutations and chromosomal translocations that drive malignancies. Therefore, B cells have evolved complex regulatory networks that ensure efficient Ig gene diversification while minimizing the risk of unproductive or deleterious repair outcomes. In this review, we integrate foundational studies with recent mechanistic advances to outline how B cells exploit, coordinate, and constrain DNA repair to balance immune receptor diversification with the preservation of genome integrity