Search Results (248)

Haploid embryos constitute a valuable model for genetic and epigenetic studies; however, their developmental competence is reduced compared with diploid counterparts. This study evaluated whether supplementation of the culture medium with specific small molecules could improve developmental competence and outgrowth establishment of parthenogenetic haploid embryos. The effects of TGF-β inhibition (A83-01), WNT pathway modulation (CHIR99021 and IWR-1), and activin A (AA) supplementation were assessed from the morula stage onward under serum-free conditions. A83-01 treatment did not improve blastocyst formation or morphology and was associated with reduced total cell numbers relative to IVF controls. CHIR99021 supplementation increased the number of SOX2-positive cells compared with IWR-1 and vehicle-treated embryos, suggesting partial support of pluripotency; however, overall developmental progression remained inferior to diploid controls. In contrast, activin A significantly increased the proportion of haploid morulae developing into blastocysts and improved hatching rates. Nevertheless, AA supplementation did not restore CDX2-positive cell numbers or total cell counts to diploid levels. Furthermore, neither CHIR99021 nor AA affect DNA fragmentation levels, although a tendency toward increased TUNEL-positive cells was observed. Activin A treatment also failed to improve embryonic outgrowth formation. Collectively, these findings demonstrate that although activin A enhances blastocyst yield and hatching in bovine haploid embryos, modulation of TGF-β or WNT signaling alone is insufficient to restore diploid-like proliferative developmental competence. Full article

Background: Sotatercept, a first-in-class activin-signaling inhibitor, demonstrated efficacy in pulmonary arterial hypertension (PAH) in the pivotal PULSAR and STELLAR trials. However, whether these benefits and the drug’s distinct safety profile translate to routine clinical practice in the treatment of idiopathic PAH remains unclear. Methods: We conducted a retrospective study using the TriNetX global health research network. Adult patients with idiopathic PAH treated with standard-of-care (SoC) background therapies were identified. Those receiving add-on sotatercept were matched 1:1 with patients on background therapy alone using propensity score matching. Results: A total of 1378 matched patients (689 per arm) were included. The median follow-up was 13.8 months for the SoC group and 10.3 months for the sotatercept group; therefore, the analysis was limited to up to 12 months. Sotatercept was associated with a 49% reduction in the risk of all-cause mortality (HR = 0.51, p = 0.002). A significant reduction was observed in all-cause hospitalizations for the sotatercept arm (HR = 0.44; 12-month rate 6.3% vs. 11.5%, p = 0.010). Safety analysis revealed 2.5-fold increased odds of epistaxis (OR = 2.68, p < 0.001) and 4-fold increased odds of erythrocytosis (OR = 4.26, p < 0.001) with sotatercept, while thrombocytopenia rates were similar (OR = 0.98, p = 0.946). Sotatercept seems to be associated with a higher risk of hypertension compared to background therapy alone (OR = 1.85, p = 0.155). Conclusions: In this large real-world cohort, the addition of sotatercept to SoC background therapy significantly improved survival in idiopathic PAH. While bleeding events, erythrocytosis and elevated blood pressure seemed to be more frequent with sotatercept, the overall safety profile was acceptable, suggesting that the substantial survival and hospitalization benefits outweigh these risks in routine clinical practice. Full article

Pulmonary hypertension (PH) can be defined as a mean pulmonary artery pressure (mPAP) greater than 20 mm Hg at rest during right heart catheterization (RHC). The reported prevalence of PH throughout the globe has been estimated to impact approximately 1% of the total population, with a majority of those afflicted being women more than men. Numerous etiologies give rise to the pathophysiology of PH, including heart disease (i.e., left-sided heart failure), lung diseases, and other unclear causes related to chronic stages and complications surrounding long-standing pulmonary thromboembolisms, side effects of certain medications, and genetic and environmental factors. Untreated PH can lead to severe morbidities such as cardio-renal syndrome and congestive hepatopathy (cardiac cirrhosis). Management of PH focuses on decreasing pulmonary pressures by using vasodilators such as prostanoids, and phosphodiesterase type 5 (PDE-5) inhibitors, as well as newer treatments such as sotatercept, which inhibits activin signaling, thereby inhibiting excessive cell growth in the pulmonary artery vasculature and down-regulating the pro-proliferative pathways. Full article

Heterotopic ossification (HO), the pathological formation of mature bone in non-skeletal soft tissues (e.g., muscles, tendons), severely impairs patient mobility and quality of life. Despite decades of research, systematic analysis of signaling networks across HO subtypes (acquired traumatic HO, hereditary Fibrodysplasia Ossificans Progressiva (FOP), Progressive Osseous Heteroplasia (POH)) remains insufficient, and clinical therapies suffer from high recurrence and severe side effects. This review synthesizes recent advances in HO pathogenesis: FOP involves gain-of-function activin A receptor type I (ACVR1) mutations (mostly R206H), disrupting bone morphogenetic protein (BMP)/Activin A signaling; POH arises from paternal guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) loss-of-function mutations, derepressing Hedgehog signaling via reduced cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) activity; tHO features trauma-induced inflammation/hypoxia activating BMP/transforming growth factor–beta (TGF-β) pathways. Key signaling crosstalk (e.g., BMP-Yes-associated protein (YAP)-Indian hedgehog (IHH)) is integrated, and novel therapies (ACVR1 inhibitors, Activin A antibodies, retinoic acid receptor gamma (RARγ) agonists, adeno-associated virus (AAV)-mediated ACVR1 silencing) are highlighted, with emphasis on subtype-specific efficacy. A stratified, mechanism-based HO management framework is proposed, aiming to accelerate precision therapy development and advance understanding of aberrant tissue regeneration. Full article

Bidirectional communication between the oocyte and surrounding follicular cells coordinates follicle growth, meiotic maturation, and the acquisition of competence. We aimed to identify genes related to follicular crosstalk and the secretory pathway as candidate mediators of cumulus–oocyte complex (COC) crosstalk in cattle. Expressed sequence tags (ESTs) from bovine COCs were retrieved from databases and screened for genes related to secretion and the secretory pathway using SignalP and SecretomeP, and transmembrane proteins were removed, yielding 13 candidate genes. Candidate expression was examined in two GEO RNA-seq datasets to assess enrichment in oocytes versus cumulus cells. RT–qPCR profiling across tissues and reproductive cell types enabled principal component analysis and correlation/network analysis, visualized as heatmaps and Cytoscape, revealing an INBHA-SERPINE2-SDF2L1 co-expression pattern. INHBA and SERPINE2 protein products are secreted, whereas SDF2L1 protein is a secretory pathway-associated, endoplasmic reticulum-resident chaperone. Promoter sequences of INHBA, SERPINE2, and SDF2L1 were scanned with FIMO using JASPAR motifs, identifying shared SMAD-associated motifs and FSH/cAMP-related motif families. The data support a co-regulation model in which endocrine FSH/cAMP and activin/TGF-β–SMAD inputs converge on a shared transcriptional program consistent with a putative INHBA–SERPINE2–SDF2L1 co-regulated module, linking cumulus extracellular matrix remodeling/protease control with oocyte ER protein folding capacity during COC maturation. Full article

Several reproductive issues in both men and women are caused by changes in the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). For males to sustain spermatogenesis and Leydig cell function, and for females to ensure orderly folliculogenesis, ovulation, and ovarian steroidogenesis, precise coordination of LH and FSH secretion is necessary. Pituitary responsiveness, the frequency or amplitude of gonadotropin-releasing hormone pulses, or the dysregulation of feedback signals mediated by sex steroids and inhibins all disrupt the balance between LH and FSH secretion. Oligozoospermia, luteal-phase abnormalities, anovulation, or complete spermatogenic failure are possible clinical signs of these alterations. In addition to functional neuroendocrine disturbances, emerging genetic and epigenetic evidence, including pathogenic variants in genes such as gonadotropin-releasing hormone receptor, kisspeptin, kisspeptin receptor, luteinizing hormone beta subunit, follicle-stimulating hormone beta subunit, follicle-stimulating hormone receptor, and luteinizing hormone/choriogonadotropin receptor, has highlighted the role of inherited and acquired molecular defects in disrupting gonadotropin regulation. This narrative review synthesizes contemporary mechanistic, clinical, translational, and genetic evidence elucidating how dysregulated secretion of LH and FSH contributes to reproductive dysfunction. The molecular processes that regulate gonadotropin synthesis and release, as well as neuroendocrine regulation, gene-level determinants of hypothalamic–pituitary–gonadal (HPG) axis dysfunction, and the clinical phenotypes that result from their disruption, are all given special attention. We conclude with a discussion of new treatment strategies that target local intragonadal regulators to enhance gametogenic capacity, modulate gonadotropin signaling, or restore physiological gonadotropin-releasing hormone (GnRH) pulsatility, with consideration of how genetic insights may inform personalized therapeutic approaches. Full article

Background/Objectives: Pulmonary arterial hypertension (PAH) is a rare but life-threatening disease that presents particular therapeutic challenges in children. It is characterized by pulmonary vasoconstriction and vascular remodeling, leading to right ventricular strain and eventually right heart failure. Although advances in pharmacotherapy have improved outcomes, treatment options remain limited. This review aims to evaluate the potential role of sotatercept, a novel fusion protein recently approved for adult PAH, and to assess the translatability of adult data to the pediatric population. Methods: A narrative synthesis of preclinical studies and randomized controlled trials was conducted to summarize the current evidence on sotatercept. In addition, pathophysiological, developmental, and therapeutic differences between adult and pediatric PAH were critically examined to assess relevance and applicability to younger patients. Results: Clinical trials in adults (PULSAR, STELLAR, ZENITH, HYPERION) confirm sotatercept’s efficacy on background therapy, with significant reductions in pulmonary vascular resistance, improvements in 6 min walk distance, enhanced right ventricular function, and risk reductions in clinical worsening events. However, extrapolation to pediatric PAH faces challenges including etiological differences (e.g., PAH-CHD predominance, PPHN in infants), age-inappropriate endpoints (e.g., 6MWD infeasible in young children), variable growth-related pharmacokinetics, and compensatory RV physiology delaying overt failure. Safety concerns are manageable in adults but raise pediatric-specific alarms: activin inhibition’s theoretical tumorigenic potential (dual tumor suppressor/promoter role), pubertal/fertility disruption (FSH suppression, gonadal maturation delay), and skeletal growth interference—unproven clinically yet demanding long-term monitoring. The ongoing MOONBEAM trial will provide initial pharmacokinetic/safety data in children. Conclusions: Sotatercept represents a promising, first-in-class therapeutic option for PAH with the potential to transform disease management. Nevertheless, dedicated pediatric studies are crucial to confirm safety, efficacy, and appropriate dosing and to define its role in the long-term treatment of children with PAH. Full article

Reproductive efficiency substantially determines livestock productivity, and suboptimal fertility continues to limit productivity across species. Inhibin immunization represents a novel strategy to enhance fertility by neutralizing inhibin’s negative feedback on follicle-stimulating hormone (FSH) secretion. This comprehensive review synthesizes evidence from ruminants (cattle, sheep, goats, camels, and buffalo) and non-ruminants (pigs, donkeys, rabbits, and avian species), evaluating inhibin immunization mechanisms and reproductive outcomes. Immunoneutralization of inhibin consistently elevates FSH, activin A, and estradiol, thereby promoting ovarian follicular recruitment and spermatogenesis. In females, this approach has been widely reported to increase ovulatory activity and improve embryo production and quality. In males, immunization enhances testicular function and semen quality while mitigating seasonal infertility. However, species-specific variations in response and dose-dependent luteal suppression (particularly in pigs) necessitate optimized protocols. While inhibin immunization shows consistent benefits when integrated with multiple ovulation and embryo transfer (MOET) and in vitro fertilization (IVF), standardized protocols and long-term fertility data remain insufficient for commercial implementation. This review identifies critical evidence gaps and safety considerations essential for clinical translation. Full article

Pulmonary arterial hypertension (PAH) is characterized by dysfunction and remodeling of the pulmonary artery endothelium and smooth muscle. In heritable PAH, heterozygous loss-of-function mutations in the type II Bone Morphogenetic Protein (BMP) receptor gene (BMPR2) are the most common genetic cause. However, the mechanisms by which reduced BMPR2 levels alter endothelial signaling to drive PAH pathogenesis remain incompletely understood. To determine how BMPR2 levels govern signaling output and endothelial functional responses, we modulated BMPR2 expression in human pulmonary artery endothelial cells (PAECs) and assessed ligand-dependent SMAD1/5/8 signaling, proliferation, and caspase-3/7 activity. We found that BMP9 and BMP10 robustly activated SMAD1/5/8 signaling and promoted proliferation in PAECs, whereas the other ligands in this panel did not elicit a comparable signaling or proliferative response under these assay conditions. A moderate (~50%) reduction in BMPR2 protein levels (an in vitro approximation of haploinsufficiency) attenuated BMP9/10-induced SMAD1/5/8 activation, abolished proliferative responses, and was associated with a modest increase in caspase-3/7 activity, consistent with caspase pathway activation and early stress/injury signaling. Under BMPR2-limiting conditions, BMP9/10 responses became sensitive to Activin type II receptor blockade by bimagrumab, consistent with a context-dependent contribution of Activin type II receptors. Conversely, BMPR2 overexpression enhanced BMP9/10-dependent SMAD signaling and proliferation. Together, these findings support a receptor–dosage model where physiological BMPR2 expression is required to sustain homeostatic BMP9/10 signaling in pulmonary artery endothelium. This framework provides a basis for interpreting context-dependent pathway effects in PAH. Full article

Cited2 is a transcriptional regulator essential for embryonic development and cellular homeostasis. Studies in vertebrate models highlight its critical roles in heart, placental, neural tube, and hematopoietic development. In humans, CITED2 variants are associated with congenital heart disease. Functionally, Cited2 interacts with the transcriptional co-regulators p300/CBP and modulates the activity of multiple transcription factors. In embryonic stem cells (ESC), Cited2 supports pluripotency, self-renewal, and differentiation potential. Here, we performed comparative transcriptomic analysis after acute Cited2 depletion in mouse ESC to define its role in maintaining self-renewal, lineage competence, and cell survival. Loss of Cited2 rapidly destabilized the pluripotency network and induced aberrant activation of developmental gene programs. Nodal/Activin pathway targets, including key regulators of mesoderm, cardiac, and neural development, were markedly downregulated, consistent with Cited2-null embryonic phenotypes. Cited2 depletion also altered the expression of genes involved in DNA damage response, immune signaling, and apoptosis, correlating with the increased γH2AX accumulation and decreased cell viability at least in part involving p53. Comparison with p300-, CBP-, and Cited2-depletion datasets revealed only partial overlap between affected gene sets. These results position Cited2 as a core regulator preserving ESC identity, genomic stability, and proper lineage engagement during early differentiation. Full article

Skeletal muscle is increasingly recognized as a dynamic endocrine and paracrine organ that communicates with distal tissues through a diverse secretome of peptides, proteins, metabolites, and extracellular vesicles (EVs), collectively referred to as myokines and exerkines. Beyond cataloging individual factors, emerging evidence suggests that muscle-derived signals can convey information through an integrated, context-dependent “endocrine code”—a pattern defined by secretion kinetics, co-released signal combinations, delivery modalities, and target-tissue receptor landscapes. This review synthesizes current evidence on (i) conceptual and experimental criteria for defining bona fide myokines, (ii) mechanisms governing myokine expression, processing, and release across exercise modes and physiological states, and (iii) major muscle–organ axes that connect physical activity to systemic metabolic homeostasis, immune remodeling, tissue regeneration, and neurocognitive adaptation. We further discuss non-protein mediators such as lactate, succinate, and β-aminoisobutyric acid, and highlight EVs as a multiplexed delivery modality whose interpretation requires stringent isolation, contamination controls, and functional validation. Finally, we evaluate translational opportunities—including biomarker panels, therapeutic targeting of the myostatin/activin, fibroblast growth factor 21 (FGF21), and growth differentiation factor 15 (GDF15) pathways, and precision exercise prescriptions informed by multi-omics and artificial intelligence—while emphasizing analytical standardization, causal validation, and transparent reporting as prerequisites for clinical impact. Full article

Red light suppresses melatonin and helps in improving reproductive efficiency in donkeys during the non-breeding season (November–February). In this study, the effects of red, blue, and white LED light were assessed. For this purpose, 40 adult Dezhou donkeys were divided into 4 groups, each receiving equal treatment for 40 days. All groups received 8 h of natural light. Additionally, the red group received 6 h of 50 lux of red LED light (468 nm) directed at a single eye. The blue group received 6 h of 50 lux of blue LED light (468 nm). The white group received 6 h of 50 lux of white LED light (468 nm), and the control group received only 8 h of natural sunlight. Blood samples were collected on the 21st, 28th, 34th, and 40th day of the experiment to analyze plasma hormone concentrations of progesterone (P4), Inhibin B (INH-B), Testosterone (T), Activin-A, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), Antimullerian Hormone (AMH), and Melatonin. In conclusion, red LED light directed at one eye showed the most promising results, elevating plasma hormone concentrations of testosterone (T), Activin A, LH, FSH, AMH, and melatonin. Full article

Objective: This study evaluated the effects of a 12-week High-Intensity Functional Training (HIFT) program combined with thylakoid supplementation on plasma adipo-myokine levels (Decorin, Myostatin, Follistatin, Activin A, and TGF-β1) in men with obesity. Secondary outcomes included anthropometric indices, lipid profiles, and insulin resistance markers. Methods: Sixty men with obesity (age: 27.6 ± 8.4 years; BMI: 32.6 ± 2.6 kg/m²) were randomly assigned to four groups (n = 15 per group): Placebo (PG), Supplement (SG), HIFT + placebo (TPG), and HIFT + supplement (TSG). To ensure robustness against the 27% attrition rate, statistical analyses included both per-protocol and intention-to-treat (ITT) models. HIFT was performed for 3 sessions/week (Borg scale: 15–17). Results: Following Bonferroni correction for multiple endpoints, repeated-measures ANOVA showed significant Time × Group interactions for most adipo-myokines and metabolic markers. Both training groups (TPG and TSG) demonstrated improvements in body composition and insulin sensitivity compared to PG (p < 0.05). While no significant differences were observed between TPG and TSG for systemic metabolic markers, preliminary data suggested that thylakoid supplementation might provide modest complementary modulations in specific myokines (e.g., decorin and follistatin). However, these observed trends did not reach clinical superiority over exercise alone in the broader metabolic profile. Conclusions: Twelve weeks of HIFT is an effective primary driver for modulating the adipo-myokine network in obese men. Although thylakoid supplementation showed potential for selective complementary effects on certain myokines, these findings are exploratory given the small sample size. The clinical significance and long-term complementary value of thylakoid-exercise interactions require further validation in larger, more diverse cohorts. Full article

Sarcopenia, defined as the progressive decline of muscle mass, strength, and function, severely compromises autonomy and quality of life in older adults. This systematic review evaluated synergistic effects of protein supplementation combined with resistance exercise on biochemical and functional biomarkers of sarcopenia. The search for scientific evidence was conducted in PubMed, Scopus, ScienceDirect, and Cochrane databases (2019–2025), applying explicit inclusion and exclusion criteria, like only randomized controlled trials in humans, published in English, Spanish, or French, were included to ensure high-quality evidence. After selection, the risk of bias of the articles was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. Seven randomized controlled trials, with a total of 260 participants, met the eligibility criteria. Interventions combining resistance exercise three times per week at 60–80% of one-repetition maximum with daily protein supplementation of at least 15 g, mainly from dairy sources, showed synergistic effects. Improvements were observed in inflammatory and anabolic biomarkers, with reductions in myostatin, activin, and IL-6, and increases in IGF-1, follistatin, and IL-10. Functional outcomes included gains in muscle strength, fat-free mass, and muscle fiber cross-sectional area. Despite heterogeneity in duration and sample size, findings support this combined approach as a promising and clinically applicable strategy to prevent and treat sarcopenia. No external funding was received, and the review is registered in PROSPERO (CRD42025640989). Full article

Background/Objectives: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) represents one of the major contributors to morbidity and mortality in Rheumatoid arthritis (RA), yet its underlying molecular mechanisms remain incompletely defined. Activin A, a member of the transforming growth factor-β (TGF-β) superfamily, has emerged as a key regulator of inflammation, fibroblast activation, and tissue remodeling. However, its role in RA patients with interstitial lung disease (ILD) has not been fully elucidated. We aimed to investigate circulating levels of Activin A, Follistatin-Like Protein-1 (FSTL1), and Follistatin-Like Protein-3 (FSTL3) in patients with RA, RA-ILD, idiopathic pulmonary fibrosis (IPF), and healthy controls and explore their associations with disease activity and pulmonary function parameters. Methods: This cross-sectional study included 90 participants: healthy controls (n = 20), RA (n = 25), RA-ILD (n = 21), and IPF (n = 24). Serum biomarkers were quantified using validated enzyme-linked immunosorbent assays (ELISAs). Clinical characteristics, inflammatory markers, disease activity indices, and pulmonary function tests were recorded. Group comparisons and correlation analyses were performed using appropriate parametric and non-parametric statistical methods. Results: Circulating Activin A levels were progressively increased from controls to RA, RA-ILD, and IPF, with significantly higher concentrations in all disease groups relative to controls. FSTL1 levels were significantly reduced in RA-ILD patients compared with RA and controls, while FSTL3 levels were markedly elevated in IPF. Activin A did not correlate with disease activity indices or pulmonary function parameters, whereas FSTL1 correlated positively with diffusing capacity of the lungs for carbon monoxide and disease duration, and FSTL3 showed an inverse association with lactate dehydrogenase. Conclusions: Activin A may be associated with the fibroinflammatory burden in both RA-ILD and IPF. The observation of altered circulating levels of Follistatin-like proteins—key regulatory molecules with multifaceted biological functions—suggests that the underlying pathogenesis is complex and governed by tightly regulated, interconnected signaling pathways. Full article