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Genome Medicine Jun 2024Chronic kidney disease (CKD) is a progressive disease for which there is no effective cure. We aimed to identify potential drug targets for CKD and kidney function by...
BACKGROUND
Chronic kidney disease (CKD) is a progressive disease for which there is no effective cure. We aimed to identify potential drug targets for CKD and kidney function by integrating plasma proteome and transcriptome.
METHODS
We designed a comprehensive analysis pipeline involving two-sample Mendelian randomization (MR) (for proteins), summary-based MR (SMR) (for mRNA), and colocalization (for coding genes) to identify potential multi-omics biomarkers for CKD and combined the protein-protein interaction, Gene Ontology (GO), and single-cell annotation to explore the potential biological roles. The outcomes included CKD, extensive kidney function phenotypes, and different CKD clinical types (IgA nephropathy, chronic glomerulonephritis, chronic tubulointerstitial nephritis, membranous nephropathy, nephrotic syndrome, and diabetic nephropathy).
RESULTS
Leveraging pQTLs of 3032 proteins from 3 large-scale GWASs and corresponding blood- and tissue-specific eQTLs, we identified 32 proteins associated with CKD, which were validated across diverse CKD datasets, kidney function indicators, and clinical types. Notably, 12 proteins with prior MR support, including fibroblast growth factor 5 (FGF5), isopentenyl-diphosphate delta-isomerase 2 (IDI2), inhibin beta C chain (INHBC), butyrophilin subfamily 3 member A2 (BTN3A2), BTN3A3, uromodulin (UMOD), complement component 4A (C4a), C4b, centrosomal protein of 170 kDa (CEP170), serologically defined colon cancer antigen 8 (SDCCAG8), MHC class I polypeptide-related sequence B (MICB), and liver-expressed antimicrobial peptide 2 (LEAP2), were confirmed. To our knowledge, 20 novel causal proteins have not been previously reported. Five novel proteins, namely, GCKR (OR 1.17, 95% CI 1.10-1.24), IGFBP-5 (OR 0.43, 95% CI 0.29-0.62), sRAGE (OR 1.14, 95% CI 1.07-1.22), GNPTG (OR 0.90, 95% CI 0.86-0.95), and YOD1 (OR 1.39, 95% CI 1.18-1.64,) passed the MR, SMR, and colocalization analysis. The other 15 proteins were also candidate targets (GATM, AIF1L, DQA2, PFKFB2, NFATC1, activin AC, Apo A-IV, MFAP4, DJC10, C2CD2L, TCEA2, HLA-E, PLD3, AIF1, and GMPR1). These proteins interact with each other, and their coding genes were mainly enrichment in immunity-related pathways or presented specificity across tissues, kidney-related tissue cells, and kidney single cells.
CONCLUSIONS
Our integrated analysis of plasma proteome and transcriptome data identifies 32 potential therapeutic targets for CKD, kidney function, and specific CKD clinical types, offering potential targets for the development of novel immunotherapies, combination therapies, or targeted interventions.
Topics: Humans; Renal Insufficiency, Chronic; Proteome; Transcriptome; Biomarkers; Kidney; Proteomics; Quantitative Trait Loci; Genome-Wide Association Study; Molecular Targeted Therapy; Multiomics
PubMed: 38898508
DOI: 10.1186/s13073-024-01356-x -
Scientific Reports Jun 2024This study probes the utility of biomarkers for microsatellite instability (MSI) detection and elucidates the molecular dynamics propelling colorectal cancer (CRC)...
This study probes the utility of biomarkers for microsatellite instability (MSI) detection and elucidates the molecular dynamics propelling colorectal cancer (CRC) progression. We synthesized a primer panel targeting 725 MSI loci, informed by The Cancer Genome Atlas (TCGA) and ancillary databases, to construct an amplicon library for next-generation sequencing (NGS). K-means clustering facilitated the distillation of 8 prime MSI loci, including activin A receptor type 2A (ACVR2A). Subsequently, we explored ACVR2A's influence on CRC advancement through in vivo tumor experiments and hematoxylin-eosin (HE) staining. Transwell assays gauged ACVR2A's role in CRC cell migration and invasion, while colony formation assays appraised cell proliferation. Western blotting illuminated the impact of ACVR2A suppression on CRC's PI3K/AKT/mTOR pathway protein expressions under hypoxia. Additionally, ACVR2A's influence on CRC-induced angiogenesis was quantified via angiogenesis assays. K-means clustering of NGS data pinpointed 32 MSI loci specific to tumor and DNA mismatch repair deficiency (dMMR) tissues. ACVR2A emerged as a pivotal biomarker, discerning MSI-H tissues with 90.97% sensitivity. A curated 8-loci set demonstrated 100% sensitivity and specificity for MSI-H detection in CRC. In vitro analyses corroborated ACVR2A's critical role, revealing its suppression of CRC proliferation, migration, and invasion. Moreover, ACVR2A inhibition under CRC-induced hypoxia markedly escalated MMP3, CyclinA, CyclinD1, and HIF1α protein expressions, alongside angiogenesis, by triggering the PI3K/AKT/mTOR cascade. The 8-loci ensemble stands as the optimal marker for MSI-H identification in CRC. ACVR2A, a central element within this group, deters CRC progression, while its suppression amplifies PI3K/AKT/mTOR signaling and angiogenesis under hypoxic stress.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability; Activin Receptors, Type II; Disease Progression; Animals; Cell Movement; Mice; Cell Line, Tumor; Cell Proliferation; Biomarkers, Tumor; Signal Transduction; Male; High-Throughput Nucleotide Sequencing; Female; Proto-Oncogene Proteins c-akt
PubMed: 38898042
DOI: 10.1038/s41598-024-62753-1 -
BMC Medical Genomics Jun 2024Fibrodysplasia Ossificans Progressiva (FOP; OMIM #135100) is an ultrarare genetic disorder characterised by congenital bilateral hallux valgus (CBHV), intermittent soft...
BACKGROUND
Fibrodysplasia Ossificans Progressiva (FOP; OMIM #135100) is an ultrarare genetic disorder characterised by congenital bilateral hallux valgus (CBHV), intermittent soft tissue swellings and progressive heterotopic ossification. We report a three-month-old girl with great toe abnormalities similar to FOP, in whom comprehensive clinical workup and genetic investigations illustrates an alternative diagnosis.
CASE PRESENTATION
A three-month-old girl presented with CBHV. The antenatal period was unremarkable, she was born by spontaneous vaginal delivery with an uneventful subsequent course, except for maternal concern of her bent toes which received reassurance from several health professionals. Her mother's persisting concerns were explored via the internet and social media leading her to request referral to an expert bone centre for consideration of FOP. On examination, she was thriving, there was no dysmorphism, subcutaneous lumps, skeletal or extra-skeletal deformity except for shortened great toes with lateral deviation of the proximal and distal phalanges. FOP was a feasible diagnosis, for which CBHV is highlighted as an early sign. A cautionary potential diagnosis of FOP was counselled, including advice to defer intramuscular immunisations until genetic results available. Genetic investigation was undertaken through rapid whole genomic sequencing (WGS), with analysis of data from a skeletal dysplasia gene panel, which demonstrated no ACVR1variants. The only finding was a heterozygous variant of unknown significance in BMPR1B (c1460T>A, p.(Val487Asp)), which encodes a bone morphogenic receptor involved in brachydactyly syndromes A1, A2 and D and acromesomelic dysplasia 3 (only the latter being an autosomal recessive condition).
CONCLUSION
This report highlights that CBHV serves as a vital diagnostic indicator of FOP and affected infants should be considered and investigated for FOP, including precautionary management whilst awaiting genetic studies. The second educational aspect is that CBHV may not represent a generalised skeletal disorder, or one much less significant than FOP. Receptor-ligand BMP and Activins mediated interactions are instrumental in the intricate embryology of the great toe. Recognition of non-FOP conditions caused by alterations in different genes are likely to increase with new genomic technology and large gene panels, enhancing understanding of bone signaling pathways.
Topics: Humans; Myositis Ossificans; Female; Hallux Valgus; Infant; Bone Morphogenetic Protein Receptors, Type I
PubMed: 38879467
DOI: 10.1186/s12920-024-01931-6 -
Theriogenology May 2024Since the first mouse induced pluripotent stem cells (iPSCs) was derived, the in vitro culture of domestic iPSCs functionally and molecularly comparable with mouse iPSCs...
Since the first mouse induced pluripotent stem cells (iPSCs) was derived, the in vitro culture of domestic iPSCs functionally and molecularly comparable with mouse iPSCs has been a challenge. Here, we established dairy goat iPSCs (giPSCs) from goat ear fibroblast cells with mouse iPSCs morphology, the expression of pluripotent markers and differentiation ability in vitro delivered by piggyBac transposon with nine Dox-inducible exogenous reprogramming factors. These reprogramming factors were bOMSK (bovine OCT4, CMYC, SOX2, and KLF4), pNhL (porcine NANOG and human LIN28), hRL (human RARG and LRH1), and SV40 Large T. Notably, AF-giPSCs (induced in activin A and bFGF condition) were capable of differentiation in embryoid bodies in vitro and could contribute to interspecies chimerism in mouse E6.5 embryos in vitro, demonstrating that AF-giPSCs have the developmental capability to generate some embryonic cell lineages. Moreover, Wnt/β-catenin signaling has an important role in driving goat induced trophoblast-like stem cells (giTLSCs) from Dox-independent giPSCs. This study will support further establishment of the stable giPSC lines without any integration of exogenous genes.
PubMed: 38878464
DOI: 10.1016/j.theriogenology.2024.05.036 -
Stem Cells and Development Jun 2024Prolonged tissue ischemia and inflammation lead to organ deterioration and are often accompanied by microvasculature rarefaction, fibrosis, and elevated systemic Activin...
Prolonged tissue ischemia and inflammation lead to organ deterioration and are often accompanied by microvasculature rarefaction, fibrosis, and elevated systemic Activin A (ActA), the level of which frequently correlates with disease severity. Mesenchymal stromal cells are prevalent in the perivascular niche and are likely involved in tissue homeostasis and pathology. This study investigated the effects of inflammatory cells on modulation of phenotype of adipose stromal cell (ASC) and the role of ActA in this process. Peripheral blood mononuclear cells were activated with LPS (aPBMC) and presented to ASC. Expression of smooth muscle/myofibroblast markers and ActA, TGFβ1-3 and CTGF was assessed in ASC. Silencing approaches were used to dissect the signaling cascade of aPBMC-induced acquisition of a myofibroblast phenotype by ASC. ASC co-cultured with aPBMC or exposed to the secretome of aPBMC upregulated smooth muscle cell markers αSMA, SM22α, and Calponin I, increased contractility, and initiated expression of ActA. IL-1β was sufficient to replicate this response, whereas blocking IL-1β eliminated aPBMC effects. ASC-derived ActA stimulated CTGF and αSMA expression in ASC; the latter independent of CTGF. Induction of αSMA in ASC by IL-1β or ActA-enriched media relied on extracellular enzymatic activity. ActA upregulated mRNA levels of several extracellular matrix proteins in ASC, albeit to a lesser degree than TGFβ1, and marginally increased cell contractility. In conclusion, the study suggests that aPBMC induce myofibroblast phenotype with weak fibrotic activity in perivascular progenitors, like ASC, through the IL-1β-ActA signaling axis, which also promotes CTGF secretion and these effects require ActA extracellular enzymatic processing.
PubMed: 38877807
DOI: 10.1089/scd.2024.0092 -
PLoS Genetics Jun 2024The Transforming Growth Factor beta (TGF-β) family consists of numerous secreted peptide growth factors that play significant roles in cell function, tissue patterning,...
The Transforming Growth Factor beta (TGF-β) family consists of numerous secreted peptide growth factors that play significant roles in cell function, tissue patterning, and organismal homeostasis, including wound repair and immunity. Typically studied as homodimers, these ligands have the potential to diversify their functions through ligand interactions that may enhance, repress, or generate novel functions. In the nematode Caenorhabditis elegans, there are only five TGF-β ligands, providing an opportunity to dissect ligand interactions in fewer combinations than in vertebrates. As in vertebrates, these ligands can be divided into bone morphogenetic protein (BMP) and TGF-β/Activin subfamilies that predominantly signal through discrete signaling pathways. The BMP subfamily ligand DBL-1 has been well studied for its role in the innate immune response in C. elegans. Here we show that all five TGF-β ligands play a role in survival on bacterial pathogens. We also demonstrate that multiple TGF-β ligand pairs act nonredundantly as part of this response. We show that the two BMP-like ligands-DBL-1 and TIG-2-function independently of each other in the immune response, while TIG-2/BMP and the TGF-β/Activin-like ligand TIG-3 function together. Structural modeling supports the potential for TIG-2 and TIG-3 to form heterodimers. Additionally, we identify TIG-2 and TIG-3 as members of a rare subset of TGF-β ligands lacking the conserved cysteine responsible for disulfide linking mature dimers. Finally, we show that canonical DBL-1/BMP receptor and Smad signal transducers function in the response to bacterial pathogens, while components of the DAF-7 TGF-β/Activin signaling pathway do not play a major role in survival. These results demonstrate a novel potential for BMP and TGF-β/Activin subfamily ligands to interact and may provide a mechanism for distinguishing the developmental and homeostatic functions of these ligands from an acute response such as the innate immune response to bacterial pathogens.
Topics: Animals; Caenorhabditis elegans; Transforming Growth Factor beta; Signal Transduction; Caenorhabditis elegans Proteins; Immunity, Innate; Ligands; Bone Morphogenetic Proteins; Activins; Neuropeptides
PubMed: 38875298
DOI: 10.1371/journal.pgen.1011324 -
AJNR. American Journal of Neuroradiology Jun 2024Four distinct vascular anomalies can be seen to affect the brain on fetal imaging: vein of Galen malformations, non-galenic arteriovenous pial fistulas, dural sinus... (Review)
Review
Four distinct vascular anomalies can be seen to affect the brain on fetal imaging: vein of Galen malformations, non-galenic arteriovenous pial fistulas, dural sinus malformations, and intracranial venous malformations. These congenital disorders affect the arteries and veins of the developing brain and are rarely seen beyond the neonatal stage. The four fetal cerebrovascular anomalies are associated with quite disparate natural histories and prognoses. MRI plays a pivotal role in the evaluation of fetuses with these conditions due to its ability to definitively establish the diagnosis, to detect subtle parenchymal injuries, to delineate the course of abnormal vessels in detail and to some extent the nature of vascular flow, and to identify ischemic, thrombotic, and hemorrhagic complications. Recently, an investigational transurterine embolization procedure targeted at treating fetuses with vein of Galen malformations who are at high risk for neonatal decompensation has emerged as a promising alternative to expectant management and post-natal embolization, with imaging being used to identify suitable patients for the intervention and in pre-procedural planning. This manuscript reviews the essential imaging and clinical features of these four fetal neurovascular anomalies and underscores the practical aspects related to counseling, prognosis, and the multidisciplinary management of these entities.ABBREVIATIONS: ACVRL1= activin A receptor like type 1; b-SSFP=Balanced Steady State Free precession; DSM= Dural Sinus Malformation; Ephrin B4= Ephrin type-B receptor 4; icVM= Intracranial Venous Malformation; ITGB1= Integrin Subunit Beta 1; NOTCH1= Neurogenic locus notch homolog protein 1; PTPN11= Protein Tyrosine Phosphatase Non-Receptor Type 11; RASA1= RAS P21 Protein Activator 1; SSFSE= Single-shot fast spin echo; VOGM=Vein of Galen Malformation.
PubMed: 38866434
DOI: 10.3174/ajnr.A8377 -
Medicine Jun 2024To investigate the expression of Inhibin B between various clinical stages, Chinese medicine dialectic typing, and in nasopharyngeal carcinoma (NPC) tissues and serum,... (Observational Study)
Observational Study
To investigate the expression of Inhibin B between various clinical stages, Chinese medicine dialectic typing, and in nasopharyngeal carcinoma (NPC) tissues and serum, and to evaluate the potential of Inhibin B as a new biomarker for NPC. Paraffin specimens of pathologically confirmed NPC tissues and paracancerous tissues were retrospectively collected, and the expression of Inhibin α (INHA) and Inhibin βB (INHBB) was detected by SP method, and their relationship with clinicopathological indexes was analyzed; in addition, patients with NPC who had received radiotherapy were included as the study subjects, and Epstein-Barr virus DNA (EBV-DNA), INHA, and INHBB in patients were detected by using the fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and chemiluminescent immuno-sandwiching method, respectively. EBV-DNA, EBV-viral capsid antigen-immunoglobulin A (VCA IgA), INHA, and INHBB were detected in the patients, respectively, and their relationships with traditional Chinese medicine (TCM) patterns were also analyzed. The expression of INHA and INHBB in NPC tissues was lower than that in paracancerous tissues, and the expression of INHA in NPC patients was correlated with lymphatic metastasis, clinical staging, and TCM staging; the levels of EBV-DNA and VCA IgA were higher than that of healthy populations in NPC patients and were higher than that of patients with stage III + IV than that of patients with stage I + II, and the levels of INHA and INHBB were lower than those of healthy populations and were lower than those of patients with stage III + IV than that of patients with stage I + II. The levels of INHA and INHBB in nasopharyngeal cancer patients were lower than those in healthy people, and the levels in stage III + IV patients were lower than those in stage I + II patients. The levels of EBV-DNA and VCA IgA in nasopharyngeal cancer patients were correlated with the Chinese medicine patterns, and had different patterns. The expression of Inhibin B may be related to the progression of NPC, and it has certain typing significance for different TCM syndromes of NPC, which is helpful for TCM typing diagnosis.
Topics: Humans; Male; Female; Nasopharyngeal Neoplasms; Nasopharyngeal Carcinoma; Medicine, Chinese Traditional; Middle Aged; Retrospective Studies; Adult; DNA, Viral; Inhibins; Herpesvirus 4, Human; Biomarkers, Tumor; Neoplasm Staging; Inhibin-beta Subunits; Aged; Antigens, Viral; Immunoglobulin A; Capsid Proteins
PubMed: 38847724
DOI: 10.1097/MD.0000000000038416 -
Frontiers in Cardiovascular Medicine 2024Pulmonary hypertension (PH) is a pathological condition that affects approximately 1% of the population. The prognosis for many patients is poor, even after treatment....
INTRODUCTION
Pulmonary hypertension (PH) is a pathological condition that affects approximately 1% of the population. The prognosis for many patients is poor, even after treatment. Our knowledge about the pathophysiological mechanisms that cause or are involved in the progression of PH is incomplete. Additionally, the mechanism of action of many drugs used to treat pulmonary hypertension, including sotatercept, requires elucidation.
METHODS
Using our graph-powered knowledge mining software in combination with a very small patient metabolite data set, we demonstrate how we derive detailed mechanistic hypotheses on the mechanisms of PH pathophysiology and clinical drugs.
RESULTS
In PH patients, the concentration of hypoxanthine, 12(S)-HETE, glutamic acid, and sphingosine 1 phosphate is significantly higher, while the concentration of L-arginine and L-histidine is lower than in healthy controls. Using the graph-based data analysis, gene ontology, and semantic association capabilities of , led us to connect the differentially expressed metabolites with G-protein signaling and SRC. Then, we associated SRC with IL6 signaling. Subsequently, we found associations that connect SRC, and IL6 to activin and BMP signaling. Lastly, we analyzed the mechanisms of action of several existing and novel pharmacological treatments for PH. elucidated the interplay between G-protein, IL6, activin, and BMP signaling. Those pathways regulate hallmark pathophysiological processes of PH, including vasoconstriction, endothelial barrier function, cell proliferation, and apoptosis.
DISCUSSION
The results highlight the importance of SRC, ERK1, AKT, and MLC activity in PH. The molecular pathways affected by existing and novel treatments for PH also converge on these molecules. Importantly, sotatercept affects SRC, ERK1, AKT, and MLC simultaneously. The present study shows the power of mining knowledge graphs using 's diverse set of data analytics functionalities for developing knowledge-driven hypotheses on PH pathophysiological and drug mechanisms and their interactions. We believe that and our presented approach will be valuable for future mechanistic studies of PH, other diseases, and drugs.
PubMed: 38845688
DOI: 10.3389/fcvm.2024.1341145 -
Cell Communication and Signaling : CCS May 2024Optimizing the efficiency of definitive endoderm (DE) differentiation is necessary for the generation of diverse organ-like structures. In this study, we used the small...
Optimizing the efficiency of definitive endoderm (DE) differentiation is necessary for the generation of diverse organ-like structures. In this study, we used the small molecule inhibitor saracatinib (SAR) to enhance DE differentiation of human embryonic stem cells and induced pluripotent stem cells. SAR significantly improved DE differentiation efficiency at low concentrations. The interaction between SAR and Focal Adhesion Kinase (FAK) was explored through RNA-seq and molecular docking simulations, which further supported the inhibition of DE differentiation by p-FAK overexpression in SAR-treated cells. In addition, we found that SAR inhibited the nuclear translocation of Yes-associated protein (YAP), a downstream effector of FAK, which promoted DE differentiation. Moreover, the addition of SAR enabled a significant reduction in activin A (AA) from 50 to 10 ng/mL without compromising DE differentiation efficiency. For induction of the pancreatic lineage, 10 ng/ml AA combined with SAR at the DE differentiation stage yielded a comparative number of PDX1/NKX6.1 pancreatic progenitor cells to those obtained by 50 ng/ml AA treatment. Our study highlights SAR as a potential modulator that facilitates the cost-effective generation of DE cells and provides insight into the orchestration of cell fate determination.
Topics: Humans; Cell Differentiation; Endoderm; Benzodioxoles; Signal Transduction; Quinazolines; Transcription Factors; Induced Pluripotent Stem Cells; Adaptor Proteins, Signal Transducing; YAP-Signaling Proteins; Focal Adhesion Kinase 1; Human Embryonic Stem Cells; Activins; Molecular Docking Simulation
PubMed: 38816763
DOI: 10.1186/s12964-024-01679-7