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Sheng Li Xue Bao : [Acta Physiologica... Jun 2024Hemoglobinopathies are one of the most common single-gene genetic disorders globally, with approximately 1% to 5% of the global population carrying the mutated gene for... (Review)
Review
Hemoglobinopathies are one of the most common single-gene genetic disorders globally, with approximately 1% to 5% of the global population carrying the mutated gene for thalassemia. Thalassemia are classified into transfusion-dependent thalassemia and non-transfusion-dependent thalassemia based on the need for blood transfusion. Traditional treatment modalities include blood transfusion, splenectomy, hydroxyurea therapy, and iron chelation therapy, which are now widely used for clinical treatment and constitute the main methods recommended in the β-thalassemia treatment guidelines. However, there are multiple barriers and limitations to the application of these approaches, and there is an urgent need to explore new therapeutic approaches. With the in-depth study of the pathophysiological process of β-thalassemia, a deeper understanding of the pathogenesis of the disease has been gained. It has been demonstrated that the pathogenesis of thalassemia is closely related to ineffective erythropoiesis (IE), imbalance in the ratio of α/β-globin protein chains and iron overload. New therapeutic approaches are emerging for different pathogenic mechanisms. Among them, new drugs for the treatment of IE mainly include activin receptor II trap ligands, Janus kinase 2 inhibitors, pyruvate kinase activators, and glycine transporter protein 1 inhibitors. Correcting the imbalance in the hemoglobin chain is mainly due to emerging technologies such as bone marrow transplantation and gene editing. Measures in reducing iron overload are associated with inhibiting the activity of transferrin and hepcidin. These new approaches provide new ideas and options for the treatment and management of β-thalassemia.
Topics: beta-Thalassemia; Humans; Genetic Therapy; Blood Transfusion; Janus Kinase 2; Activin Receptors, Type II; Splenectomy; Gene Editing; Iron Chelating Agents; Bone Marrow Transplantation; Iron Overload; Erythropoiesis; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins
PubMed: 38939943
DOI: No ID Found -
Theriogenology Jun 2024Although anti-Müllerian hormone (AMH) is involved in the regulation of granulosa cell function in female animals, its role in tissues other than ovarian follicles...
Although anti-Müllerian hormone (AMH) is involved in the regulation of granulosa cell function in female animals, its role in tissues other than ovarian follicles remains poorly understood. It has also been suggested that cows with high circulating AMH concentrations have increased fertility; however, the mechanism has not been elucidated. This study was conducted to identify the presence of the AMH-signaling system and its target cells in the bovine corpus luteum formed from an ovulated follicle. Immunoblotting revealed that the proteolytically cleaved C-terminal region in AMH (AMH), a biologically active peptide, was present in trace amounts in the early corpus luteum and significantly increased during the mid to regressed stages. AMH and cleaved N-terminal region (AMH) in AMH generate a noncovalent isoform that improves the activity of AMH signaling. An immunohistochemical analysis revealed that AMH, AMH, and type II AMH receptor (AMHR2) were localized to luteal cells during the entire estrous cycle. AMH in the corpus luteum seemed to be newly synthesized since AMH expression was detected. These findings suggest that AMH signaling is involved in the regulation of luteal cell function through an autocrine and post-translational processing mechanism. The level of AMHR2 and mRNA expression of AMHR2 and type I AMH receptors (activin-like kinase 2, 3, and 6) were highest in the mid stage. Thus, AMH signaling in the corpus luteum may also be regulated by changes in the receptor levels. Since the transforming growth factor-beta superfamily, to which AMH belongs, is a multifunctional polypeptide growth factor, further studies are needed to evaluate whether AMH signaling has a role in facilitating or inhibiting luteal cell functions.
PubMed: 38924892
DOI: 10.1016/j.theriogenology.2024.06.017 -
Scientific Reports Jun 2024Visfatin (VIS) is a hormone belonging to the adipokines' group secreted mainly by the adipose tissue. VIS plays a crucial role in the control of energy homeostasis,...
Visfatin (VIS) is a hormone belonging to the adipokines' group secreted mainly by the adipose tissue. VIS plays a crucial role in the control of energy homeostasis, inflammation, cell differentiation, and angiogenesis. VIS expression was confirmed in the hypothalamic-pituitary-gonadal (HPG) axis structures, as well as in the uterus, placenta, and conceptuses. We hypothesised that VIS may affect the abundance of proteins involved in the regulation of key processes occurring in the corpus luteum (CL) during the implantation process in pigs. In the present study, we performed the high-throughput proteomic analysis (liquid chromatography with tandem mass spectrometry, LC-MS/MS) to examine the in vitro influence of VIS (100 ng/mL) on differentially regulated proteins (DRPs) in the porcine luteal cells (LCs) on days 15-16 of pregnancy (implantation period). We have identified 511 DRPs, 276 of them were up-regulated, and 235 down-regulated in the presence of VIS. Revealed DRPs were assigned to 162 gene ontology terms. Western blot analysis of five chosen DRPs, ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1), lanosterol 14-α demethylase (CYP51A1), inhibin subunit beta A (INHBA), notch receptor 3 (NOTCH3), and prostaglandin E synthase 2 (mPGES2) confirmed the veracity and accuracy of LC-MS/MS method. We indicated that VIS modulates the expression of proteins connected with the regulation of lipogenesis and cholesterologenesis, and, in consequence, may be involved in the synthesis of steroid hormones, as well as prostaglandins' metabolism. Moreover, we revealed that VIS affects the abundance of protein associated with ovarian cell proliferation, differentiation, and apoptosis, as well as CL new vessel formation and tissue remodelling. Our results suggest important roles for VIS in the regulation of ovarian functions during the peri-implantation period.
Topics: Animals; Female; Swine; Embryo Implantation; Nicotinamide Phosphoribosyltransferase; Proteome; Luteal Cells; Pregnancy; Proteomics; Tandem Mass Spectrometry; Chromatography, Liquid; Inhibin-beta Subunits
PubMed: 38918475
DOI: 10.1038/s41598-024-65577-1 -
PLoS Biology Jun 2024In the highly regulative embryo of the sea urchin Paracentrotus lividus, establishment of the dorsal-ventral (D/V) axis critically depends on the zygotic expression of...
In the highly regulative embryo of the sea urchin Paracentrotus lividus, establishment of the dorsal-ventral (D/V) axis critically depends on the zygotic expression of the TGF-β nodal in the ventral ectoderm. nodal expression is first induced ubiquitously in the 32-cell embryo and becomes progressively restricted to the presumptive ventral ectoderm by the early blastula stage. This early spatial restriction of nodal expression is independent of Lefty, and instead relies on the activity of Panda, a maternally expressed TGF-β ligand related to Lefty and Inhibins, which is required maternally for D/V axis specification. However, the mechanism by which Panda restricts the early nodal expression has remained enigmatic and it is not known if Panda works like a BMP ligand by opposing Nodal and antagonizing Smad2/3 signaling, or if it works like Lefty by sequestering an essential component of the Nodal signaling pathway. In this study, we report that Panda functions as an antagonist of the TGF-β type II receptor ACVRII (Activin receptor type II), which is the only type II receptor for Nodal signaling in the sea urchin and is also a type II receptor for BMP ligands. Inhibiting translation of acvrII mRNA disrupted D/V patterning across all 3 germ layers and caused acvrII morphants to develop with a typical Nodal loss-of-function phenotype. In contrast, embryos overexpressing acvrII displayed strong ectopic Smad1/5/8 signaling at blastula stages and developed as dorsalized larvae, a phenotype very similar to that caused by over activation of BMP signaling. Remarkably, embryos co-injected with acvrII mRNA and panda mRNA did not show ectopic Smad1/5/8 signaling and developed with a largely normal dorsal-ventral polarity. Furthermore, using an axis induction assay, we found that Panda blocks the ability of ACVRII to orient the D/V axis when overexpressed locally. Using co-immunoprecipitation, we showed that Panda physically interacts with ACVRII, as well as with the Nodal co-receptor Cripto, and with TBR3 (Betaglycan), which is a non-signaling receptor for Inhibins in mammals. At the molecular level, we have traced back the antagonistic activity of Panda to the presence of a single proline residue, conserved with all the Lefty factors, in the ACVRII binding motif of Panda, instead of a serine as in most of TGF-β ligands. Conversion of this proline to a serine converted Panda from an antagonist that opposed Nodal signaling and promoted dorsalization to an agonist that promoted Nodal signaling and triggered ventralization when overexpressed. Finally, using phylogenomics, we analyzed the emergence of the agonist and antagonist form of Panda in the course of evolution. Our data are consistent with the idea that the presence of a serine at that position, like in most TGF-β, was the ancestral condition and that the initial function of Panda was possibly in promoting and not in antagonizing Nodal signaling. These results highlight the existence of key functional and structural elements conserved between Panda and Lefty, allow to draw an intriguing parallel between sea urchin Panda and mammalian Inhibin α and raise the unexpected possibility that the original function of Panda may have been in activation of the Nodal pathway rather than in its inhibition.
PubMed: 38913712
DOI: 10.1371/journal.pbio.3002701 -
PloS One 2024In Drosophila coordinated proliferation of two neural stem cells, neuroblasts (NB) and neuroepithelial (NE) cells, is pivotal for proper larval brain growth that...
Multiple isoforms of the Activin-like receptor baboon differentially regulate proliferation and conversion behaviors of neuroblasts and neuroepithelial cells in the Drosophila larval brain.
In Drosophila coordinated proliferation of two neural stem cells, neuroblasts (NB) and neuroepithelial (NE) cells, is pivotal for proper larval brain growth that ultimately determines the final size and performance of an adult brain. The larval brain growth displays two phases based on behaviors of NB and NEs: the first one in early larval stages, influenced by nutritional status and the second one in the last larval stage, promoted by ecdysone signaling after critical weight checkpoint. Mutations of the baboon (babo) gene that produces three isoforms (BaboA-C), all acting as type-I receptors of Activin-type transforming growth factor β (TGF-β) signaling, cause a small brain phenotype due to severely reduced proliferation of the neural stem cells. In this study we show that loss of babo function severely affects proliferation of NBs and NEs as well as conversion of NEs from both phases. By analyzing babo-null and newly generated isoform-specific mutants by CRISPR mutagenesis as well as isoform-specific RNAi knockdowns in a cell- and stage-specific manner, our data support differential contributions of the isoforms for these cellular events with BaboA playing the major role. Stage-specific expression of EcR-B1 in the brain is also regulated primarily by BaboA along with function of the other isoforms. Blocking EcR function in both neural stem cells results in a small brain phenotype that is more severe than baboA-knockdown alone. In summary, our study proposes that the Babo-mediated signaling promotes proper behaviors of the neural stem cells in both phases and achieves this by acting upstream of EcR-B1 expression in the second phase.
Topics: Animals; Drosophila Proteins; Larva; Protein Isoforms; Neural Stem Cells; Cell Proliferation; Brain; Neuroepithelial Cells; Drosophila melanogaster; Signal Transduction; Activin Receptors
PubMed: 38913612
DOI: 10.1371/journal.pone.0305696 -
Frontiers in Cell and Developmental... 2024Mammalian germ cells are derived from primordial germ cells (PGCs) and ensure species continuity through generations. Unlike irreversible committed mature germ cells,...
Mammalian germ cells are derived from primordial germ cells (PGCs) and ensure species continuity through generations. Unlike irreversible committed mature germ cells, migratory PGCs exhibit a latent pluripotency characterized by the ability to derive embryonic germ cells (EGCs) and form teratoma. Here, we show that inhibition of p38 mitogen-activated protein kinase (MAPK) by chemical compounds in mouse migratory PGCs enables derivation of chemically induced Embryonic Germ-like Cells (cEGLCs) that do not require conventional growth factors like LIF and FGF2/Activin-A, and possess unique naïve pluripotent-like characteristics with epiblast features and chimera formation potential. Furthermore, cEGLCs are regulated by a unique PI3K-Akt signaling pathway, distinct from conventional naïve pluripotent stem cells described previously. Consistent with this notion, we show by performing analysis that inhibition of p38 MAPK in organ culture supports the survival and proliferation of PGCs and also potentially reprograms PGCs to acquire indefinite proliferative capabilities, marking these cells as putative teratoma-producing cells. These findings highlight the utility of our model in mimicking teratoma formation, thereby providing valuable insights into the cellular mechanisms underlying tumorigenesis. Taken together, our research underscores a key role of p38 MAPK in germ cell development, maintaining proper cell fate by preventing unscheduled pluripotency and teratoma formation with a balance between proliferation and differentiation.
PubMed: 38911025
DOI: 10.3389/fcell.2024.1410177 -
American Journal of Obstetrics and... Jun 2024It is estimated that over 2 million cases of fetal death occur worldwide every year, but, despite the high incidence, several basic and clinical characteristics of this...
BACKGROUND
It is estimated that over 2 million cases of fetal death occur worldwide every year, but, despite the high incidence, several basic and clinical characteristics of this disorder are still unclear. Placenta is suggested to play a central role in fetal death. Placenta produces hormones, cytokines and growth factors that modulate functions of the placental-maternal unit. Fetal death has been correlated with impaired secretion of some of these regulatory factors.
OBJECTIVE(S)
The aim of the present study was to evaluate, in placentas collected from fetal death, the gene expression of inflammatory, proliferative and protective factors.
STUDY DESIGN
Cases of fetal death in singleton pregnancy were retrospectively selected, excluding pregnancies complicated by fetal anomalies, gestational diabetes, intrauterine growth restriction and moderate to severe maternal diseases. A group of placentas collected from healthy singleton term pregnancies were used as controls. Groups were compared regarding maternal and gestational age, fetal sex and birth weight. Placental mRNA expression of inflammatory (IL-6), proliferative (Activin A, TGF-β1) and regulatory (VEGF, VEGFR2, ATP-binding cassette (ABC) transporters ABCB1 and ABCG2, sphingosine 1-phosphate (S1P) signaling pathway) markers was conducted using real-time PCR. Statistical analysis and graphical representation of the data were performed using the GraphPad Prism 5 software. For the statistical analysis, Student's t-test was used, and P values < 0.05 were considered significant.
RESULTS
Placental mRNA expression of IL-6 and VEGFR2 resulted significantly higher in the fetal death group compared to controls (P<0.01), while activin A, ABCB1 and ABCG2 expression resulted significantly lower (P<0.01). A significant alteration in the S1P signaling pathway was found in the fetal death group, with an increased expression of the specific receptor isoforms sphingosine 1-phosphate receptor 1, 3 and 4 (S1P, S1P, S1P) and of sphingosine kinase 2 (SK2), one of the enzyme isoforms responsible for S1P synthesis (P<0.01).
CONCLUSION
(s): The present study confirmed a significantly increased expression of placental IL-6 and VEGFR2 mRNA, and for the first time showed an increased expression of S1P receptors and SK2 as well as a decreased expression of activin A and of selected ATP-binding cassette transporters, suggesting that multiple inflammatory and protective factors are deranged in placenta of fetal death.
PubMed: 38908653
DOI: 10.1016/j.ajog.2024.06.011 -
Drugs Jun 2024Sotatercept (sotatercept-csrk; WINREVAIR) is an activin signalling inhibitor that is being developed by Merck and Co., Inc. (Rahway, NJ, USA) for the treatment of... (Review)
Review
Sotatercept (sotatercept-csrk; WINREVAIR) is an activin signalling inhibitor that is being developed by Merck and Co., Inc. (Rahway, NJ, USA) for the treatment of pulmonary arterial hypertension. Sotatercept recently received approval in the USA for the treatment of adults with pulmonary arterial hypertension [World Health Organisation (WHO) Group 1] to increase exercise capacity, improve WHO functional class and reduce the risk of clinical worsening events. This article summarizes the milestones in the development of sotatercept leading to this first approval for pulmonary arterial hypertension.
PubMed: 38904927
DOI: 10.1007/s40265-024-02058-9 -
Current Opinion in Nephrology and... Jun 2024Pulmonary hypertension is a common comorbidity in patients with chronic kidney disease (CKD), but therapeutic options are limited. We discuss the epidemiology of...
PURPOSE OF REVIEW
Pulmonary hypertension is a common comorbidity in patients with chronic kidney disease (CKD), but therapeutic options are limited. We discuss the epidemiology of pulmonary hypertension in patients with CKD and review therapies for pulmonary hypertension with a focus on emerging treatments for pulmonary arterial hypertension (PAH).
RECENT FINDINGS
The definition of pulmonary hypertension has been updated to a lower threshold of mean pulmonary artery pressures of more than 20 mmHg, potentially leading to more patients with CKD to qualify for the diagnosis of pulmonary hypertension. Endothelin receptor antagonists, a class of medications, which demonstrated efficacy in patients with PAH, have been shown to slow progression of CKD, but their efficacy in lowering pulmonary artery pressures and their effects on reducing cardiovascular mortality in this population remains unproven. Sotatercept, a novel activin signaling inhibitor, which was previously studied in dialysis patients has been shown to increase exercise capacity in patients with PAH. These studies may lead to new specific therapies for pulmonary hypertension in patients with CKD.
SUMMARY
Pulmonary hypertension is common in patients with CKD. Although our understanding of factors leading to pulmonary hypertension in this population have evolved, evidence supporting disease-specific therapy in CKD is limited arguing for larger, long-term studies.
PubMed: 38899951
DOI: 10.1097/MNH.0000000000001008 -
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